Sample records for renin-angiotensin system suppression

  1. Sodium butyrate suppresses angiotensin II-induced hypertension by inhibition of renal (pro)renin receptor and intrarenal renin-angiotensin system.

    PubMed

    Wang, Lei; Zhu, Qing; Lu, Aihua; Liu, Xiaofen; Zhang, Linlin; Xu, Chuanming; Liu, Xiyang; Li, Haobo; Yang, Tianxin

    2017-09-01

    Butyrate, a short-chain fatty acid, is the end product of the fermentation of complex carbohydrates by the gut microbiota. Recently, sodium butyrate (NaBu) has been found to play a protective role in a number of chronic diseases. However, it is still unclear whether NaBu has a therapeutic potential in hypertension. The present study was aimed to investigate the role of NaBu in angiotensin II (Ang II)-induced hypertension and to further explore the underlying mechanism. Ang II was infused into uninephrectomized Sprague-Dawley rats with or without intramedullary infusion of NaBu for 14 days. Mean arterial blood pressure was recorded by the telemetry system. Renal tissues, serum samples, and 24-h urine samples were collected to examine renal injury and the regulation of the (pro)renin receptor (PRR) and renin. Intramedullary infusion of NaBu in Sprague-Dawley rats lowered the Ang II-induced mean arterial pressure from 129 ± 6 mmHg to 108 ± 4 mmHg (P < 0.01). This corresponded with an improvement in Ang II-induced renal injury, including urinary albumin, glomerulosclerosis, and renal fibrosis, as well as the expression of inflammatory mediators tumor necrosis factor α, interleukin 6. The renal expression of PRR, angiotensinogen, angiotensin I-converting enzyme and the urinary excretion of soluble PRR, renin, and angiotensinogen were all increased by Ang II infusion but decreased by NaBu treatment. In cultured innermedullary collecting duct cells, NaBu treatment attenuated Ang II-induced expression of PRR and renin. These results demonstrate that NaBu exerts an antihypertensive action, likely by suppressing the PRR-mediated intrarenal renin-angiotensin system.

  2. Classical Renin-Angiotensin System in Kidney Physiology

    PubMed Central

    Sparks, Matthew A.; Crowley, Steven D.; Gurley, Susan B.; Mirotsou, Maria; Coffman, Thomas M.

    2014-01-01

    The renin-angiotensin system has powerful effects in control of the blood pressure and sodium homeostasis. These actions are coordinated through integrated actions in the kidney, cardio-vascular system and the central nervous system. Along with its impact on blood pressure, the renin-angiotensin system also influences a range of processes from inflammation and immune responses to longevity. Here, we review the actions of the “classical” renin-angiotensin system, whereby the substrate protein angiotensinogen is processed in a two-step reaction by renin and angiotensin converting enzyme, resulting in the sequential generation of angiotensin I and angiotensin II, the major biologically active renin-angiotensin system peptide, which exerts its actions via type 1 and type 2 angiotensin receptors. In recent years, several new enzymes, peptides, and receptors related to the renin-angiotensin system have been identified, manifesting a complexity that was previously unappreciated. While the functions of these alternative pathways will be reviewed elsewhere in this journal, our focus here is on the physiological role of components of the “classical” renin-angiotensin system, with an emphasis on new developments and modern concepts. PMID:24944035

  3. Reproduction and the renin-angiotensin system

    NASA Technical Reports Server (NTRS)

    Ganong, W. F.

    1995-01-01

    A unique aspect of the circulating renin-angiotensin system and the many independent tissue renin-angiotensin systems is their interactions at multiple levels with reproduction. These interactions, which have received relatively little attention, include effects of estrogens and possibly androgens on hepatic and renal angiotensinogen mRNA; effects of androgens on the Ren-2 gene and salivary renin in mice; the prorenin surge that occurs with but outlasts the LH surge during the menstrual cycle; the inhibitory effects of estrogens on thirst and water intake; the tissue renin-angiotensin systems in the brain, the anterior pituitary, and the ovaries and testes, that is, in all the components of the hypothalamo-pituitary-gonadal axis; the presence of some components of the renin-angiotensin system in the uterus and the fetoplacental unit; and the possible relation of renin and angiotensin to ovulation and fetal well-being. These interactions are described and their significance considered in this short review.

  4. Dietary Sodium Suppresses Digestive Efficiency via the Renin-Angiotensin System.

    PubMed

    Weidemann, Benjamin J; Voong, Susan; Morales-Santiago, Fabiola I; Kahn, Michael Z; Ni, Jonathan; Littlejohn, Nicole K; Claflin, Kristin E; Burnett, Colin M L; Pearson, Nicole A; Lutter, Michael L; Grobe, Justin L

    2015-06-11

    Dietary fats and sodium are both palatable and are hypothesized to synergistically contribute to ingestive behavior and thereby obesity. Contrary to this hypothesis, C57BL/6J mice fed a 45% high fat diet exhibited weight gain that was inhibited by increased dietary sodium content. This suppressive effect of dietary sodium upon weight gain was mediated specifically through a reduction in digestive efficiency, with no effects on food intake behavior, physical activity, or resting metabolism. Replacement of circulating angiotensin II levels reversed the effects of high dietary sodium to suppress digestive efficiency. While the AT1 receptor antagonist losartan had no effect in mice fed low sodium, the AT2 receptor antagonist PD-123,319 suppressed digestive efficiency. Correspondingly, genetic deletion of the AT2 receptor in FVB/NCrl mice resulted in suppressed digestive efficiency even on a standard chow diet. Together these data underscore the importance of digestive efficiency in the pathogenesis of obesity, and implicate dietary sodium, the renin-angiotensin system, and the AT2 receptor in the control of digestive efficiency regardless of mouse strain or macronutrient composition of the diet. These findings highlight the need for greater understanding of nutrient absorption control physiology, and prompt more uniform assessment of digestive efficiency in animal studies of energy balance.

  5. Local renin-angiotensin system contributes to hyperthyroidism-induced cardiac hypertrophy.

    PubMed

    Kobori, H; Ichihara, A; Miyashita, Y; Hayashi, M; Saruta, T

    1999-01-01

    We have reported previously that thyroid hormone activates the circulating and tissue renin-angiotensin systems without involving the sympathetic nervous system, which contributes to cardiac hypertrophy in hyperthyroidism. This study examined whether the circulating or tissue renin-angiotensin system plays the principal role in hyperthyroidism-induced cardiac hypertrophy. The circulating renin-angiotensin system in Sprague-Dawley rats was fixed by chronic angiotensin II infusion (40 ng/min, 28 days) via mini-osmotic pumps. Daily i.p. injection of thyroxine (0.1 mg/kg per day, 28 days) was used to mimic hyperthyroidism. Serum free tri-iodothyronine, plasma renin activity, plasma angiotensin II, cardiac renin and cardiac angiotensin II were measured with RIAs. The cardiac expression of renin mRNA was evaluated by semiquantitative reverse transcriptase-polymerase chain reaction. Plasma renin activity and plasma angiotensin II were kept constant in the angiotensin II and angiotensin II+thyroxine groups (0.12+/-0.03 and 0.15+/-0.03 microgram/h per liter, 126+/-5 and 130+/-5 ng/l respectively) (means+/-s.e.m.). Despite stabilization of the circulating renin-angiotensin system, thyroid hormone induced cardiac hypertrophy (5.0+/-0.5 vs 3.5+/-0.1 mg/g) in conjunction with the increases in cardiac expression of renin mRNA, cardiac renin and cardiac angiotensin II (74+/-2 vs 48+/-2%, 6.5+/-0.8 vs 3.8+/-0.4 ng/h per g, 231+/-30 vs 149+/-2 pg/g respectively). These results indicate that the local renin-angiotensin system plays the primary role in the development of hyperthyroidism-induced cardiac hypertrophy.

  6. Association studies suggest a key role for endothelin-1 in the pathogenesis of preeclampsia and the accompanying renin-angiotensin-aldosterone system suppression.

    PubMed

    Verdonk, Koen; Saleh, Langeza; Lankhorst, Stephanie; Smilde, J E Ilse; van Ingen, Manon M; Garrelds, Ingrid M; Friesema, Edith C H; Russcher, Henk; van den Meiracker, Anton H; Visser, Willy; Danser, A H Jan

    2015-06-01

    Women with preeclampsia display low renin-angiotensin-aldosterone system activity and a high antiangiogenic state, the latter characterized by high levels of soluble Fms-like tyrosine kinase (sFlt)-1 and reduced placental growth factor levels. To investigate whether renin-angiotensin-aldosterone system suppression in preeclampsia is because of this disturbed angiogenic balance, we measured mean arterial pressure, creatinine, endothelin-1 (ET-1), and renin-angiotensin-aldosterone system components in pregnant women with a high (≥85; n=38) or low (<85; n=65) soluble Fms-like tyrosine kinase-1/placental growth factor ratio. Plasma ET-1 levels were increased in women with a high ratio, whereas their plasma renin activity and plasma concentrations of renin, angiotensinogen, and aldosterone were decreased. Plasma renin activity-aldosterone relationships were identical in both the groups. Multiple regression analysis revealed that plasma renin concentration correlated independently with mean arterial pressure and plasma ET-1. Plasma ET-1 correlated positively with soluble Fms-like tyrosine kinase-1 and negatively with plasma renin concentration, and urinary protein correlated with plasma ET-1 and mean arterial pressure. Despite the lower plasma levels of renin and angiotensinogen in the high-ratio group, their urinary levels of these components were elevated. Correction for albumin revealed that this was because of increased glomerular filtration. Subcutaneous arteries obtained from patients with preeclampsia displayed an enhanced, AT2 receptor-mediated response to angiotensin II. In conclusion, a high antiangiogenic state associates with ET-1 activation, which together with the increased mean arterial pressure may underlie the parallel reductions in renin and aldosterone in preeclampsia. Because ET-1 also was a major determinant of urinary protein, our data reveal a key role for ET-1 in the pathogenesis of preeclampsia. Finally, the enhanced angiotensin responsiveness

  7. Resveratrol promotes regression of renal carcinoma cells via a renin-angiotensin system suppression-dependent mechanism.

    PubMed

    Li, Jianchang; Qiu, Mingning; Chen, Lieqian; Liu, Lei; Tan, Guobin; Liu, Jianjun

    2017-02-01

    The aim of the present study was to investigate the effect of resveratrol on renal carcinoma cells and explore possible renin-angiotensin system-associated mechanisms. Subsequent to resveratrol treatment, the cell viability, apoptosis rate, cytotoxicity levels, caspase 3/7 activity and the levels of angiotensin II (AngII), AngII type 1 receptor (AT1R), vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) were evaluated in renal carcinoma cells. The effects of AngII, AT1R, VEGF and COX-2 on resveratrol-induced cell growth inhibition and apoptosis were also examined. The results indicated that resveratrol treatment may suppress growth, induce apoptosis, and decrease AngII, AT1R, VEGF and COX-2 levels in renal carcinoma ACHN and A498 cells. In addition, resveratrol-induced cell growth suppression and apoptosis were reversed when co-culturing with AT1R or VEGF. Thus, resveratrol may suppress renal carcinoma cell proliferation and induce apoptosis via an AT1R/VEGF pathway.

  8. The Renal Renin-Angiotensin System

    ERIC Educational Resources Information Center

    Harrison-Bernard, Lisa M.

    2009-01-01

    The renin-angiotensin system (RAS) is a critical regulator of sodium balance, extracellular fluid volume, vascular resistance, and, ultimately, arterial blood pressure. In the kidney, angiotensin II exerts its effects to conserve salt and water through a combination of the hemodynamic control of renal blood flow and glomerular filtration rate and…

  9. Nervous kidney. Interaction between renal sympathetic nerves and the renin-angiotensin system in the control of renal function.

    PubMed

    DiBona, G F

    2000-12-01

    Increases in renal sympathetic nerve activity regulate the functions of the nephron, the vasculature, and the renin-containing juxtaglomerular granular cells. Because increased activity of the renin-angiotensin system can also influence nephron and vascular function, it is important to understand the interactions between the renal sympathetic nerves and the renin-angiotensin system in the control of renal function. These interactions can be intrarenal, for example, the direct (by specific innervation) and indirect (by angiotensin II) contributions of increased renal sympathetic nerve activity to the regulation of renal function. The effects of increased renal sympathetic nerve activity on renal function are attenuated when the activity of the renin-angiotensin system is suppressed or antagonized with ACE inhibitors or angiotensin II-type AT(1)-receptor antagonists. The effects of intrarenal administration of angiotensin II are attenuated after renal denervation. These interactions can also be extrarenal, for example, in the central nervous system, wherein renal sympathetic nerve activity and its arterial baroreflex control are modulated by changes in activity of the renin-angiotensin system. In addition to the circumventricular organs, whose permeable blood-brain barrier permits interactions with circulating angiotensin II, there are interactions at sites behind the blood-brain barrier that depend on the influence of local angiotensin II. The responses to central administration of angiotensin II-type AT(1)-receptor antagonists into the ventricular system or microinjected into the rostral ventrolateral medulla are modulated by changes in activity of the renin-angiotensin system produced by physiological changes in dietary sodium intake. Similar modulation is observed in pathophysiological models wherein activity of both the renin-angiotensin and sympathetic nervous systems is increased (eg, congestive heart failure). Thus, both renal and extrarenal sites of

  10. Peripheral and central interactions between the renin-angiotensin system and the renal sympathetic nerves in control of renal function.

    PubMed

    DiBona, G F

    2001-06-01

    Increases in renal sympathetic nerve activity (RSNA) regulate the functions of the nephron, the vasculature, and the renin-containing juxtaglomerular granular cells. As increased activity of the renin-angiotensin system can also influence nephron and vascular function, it is important to understand the interactions between RSNA and the renin-angiotensin system in the control of renal function. These interactions can be intrarenal, that is, the direct (via specific innervation) and indirect (via angiotensin II) contributions of increased RSNA to the regulation of renal function. The effects of increased RSNA on renal function are attenuated when the activity of the renin-angiotensin system is suppressed or antagonized with angiotensin-converting enzyme inhibitors or angiotensin II-type AT1 receptor antagonists. The effects of intrarenal administration of angiotensin II are attenuated following renal denervation. These interactions can also be extrarenal, that is, in the central nervous system, wherein RSNA and its arterial baroreflex control are modulated by changes in activity of the renin-angiotensin system. In addition to the circumventricular organs, the permeable blood-brain barrier of which permits interactions with circulating angiotensin II, there are interactions at sites behind the blood-brain barrier that depend on the influence of local angiotensin II. The responses to central administration of angiotensin II type AT1 receptor antagonists, into the ventricular system or microinjected into the rostral ventrolateral medulla, are modulated by changes in activity of the renin-angiotensin system produced by physiological changes in dietary sodium intake. Similar modulation is observed in pathophysiological models wherein activity of both the renin-angiotensin and sympathetic nervous systems is increased (e.g., congestive heart failure). Thus, both renal and extrarenal sites of interaction between the renin-angiotensin system and RSNA are involved in

  11. Anthology of the renin-angiotensin system: a one hundred reference approach to angiotensin II antagonists.

    PubMed

    Ménard, J

    1993-04-01

    To provide a historical overview of the renin-angiotensin system as a guide to the introduction of a new therapeutic pathway, non-peptide inhibition of a angiotensin II. One hundred references were selected as a personal preference, for their originality or for their potential impact on medicine. This review raises the following questions for future research. (1) Will the long-term cardiovascular effects of angiotensin converting enzyme (ACE) inhibition, angiotensin II antagonism and renin inhibition be similar or not, and dependent or independent of blood pressure levels? (2) What are the local-regional interactions between vasoconstrictor and vasodilator systems, and does the renin-angiotensin system synchronize these regional hemodynamic regulatory mechanisms? (3) If hypertension is the result of an interaction between genetic and environmental factors, do proteins secreted through constitutive pathways contribute to the genetic abnormality (prorenin, angiotensinogen, ACE) while regulated secretion (renin) and other regulatory mechanisms (angiotensin II receptors) provide biological support for the environmental effects?

  12. The importance of the renin-angiotensin system in normal cardiovascular homeostasis

    NASA Technical Reports Server (NTRS)

    Haber, E.

    1975-01-01

    Studies were carried out on adult mongrel dogs (20 to 30 kilograms) to investigate the importance of the renin-angiotensin system. Results indicate that the renin-angiotensin system plays a major role in the maintenance of circulatory homeostasis when extracellular fluid volume is depleted. It was also found that angiotensin II concentration, in addition to renal perfusion pressure, is a factor in the regulation of renin release.

  13. Renin-Angiotensin System in Diabetes.

    PubMed

    Rein, Johannes; Bader, Michael

    2017-11-17

    The renin-angiotensin system (RAS) has two different axes, the classical one with the effector peptide angiotensin II and the new one with the effector peptide angiotensin (1-7). Both peptides have been shown to be involved in the pathogenesis of diabetes mellitus and its consequences, nephropathy, retinopathy and cardiomyopathy in animal models and patients. In diabetes, angiotensin II acts mostly deleterious and angiotensin (1-7) protective. In this review we summarize the knowledge about the role of the different RAS axes in diabetes mellitus and the use of drugs interfering with the RAS in the therapy of the disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  14. Cholecalciferol administration blunts the systemic renin-angiotensin system in essential hypertensives with hypovitaminosis D.

    PubMed

    Carrara, Davide; Bernini, Matteo; Bacca, Alessandra; Rugani, Ilaria; Duranti, Emiliano; Virdis, Agostino; Ghiadoni, Lorenzo; Taddei, Stefano; Bernini, Giampaolo

    2014-03-01

    Vitamin D plasma levels are negatively associated with blood pressure and cardiovascular mortality, and vitamin D supplementation reduces cardiovascular events. Renin-angiotensin system (RAS) suppression may be one of the mechanisms involved. However, there are no interventional prospective studies demonstrating a reduction in circulating RAS components after vitamin D treatment. Fifteen consecutive drug-free patients with essential hypertension and hypovitaminosis D underwent therapy with an oral dose of 25000 I.U. of cholecalciferol once a week for two months, while maintaining a constant-salt diet. In basal conditions and at the end of the study, RAS activity (plasma angiotensinogen, renin, PRA, angiotensin II, aldosterone and urinary angiotensinogen) was investigated, in addition to blood pressure and plasma vitamin D levels (25(OH)D). After cholecalciferol administration, all patients exhibited normalized plasma 25(OH)D values. At the end of the study, a reduction (p < 0.05) in plasma renin and aldosterone, and a decrement, although not significant, of PRA and angiotensin II, was observed. No difference was found in plasma and urinary angiotensinogen or blood pressure values. Our data indicate that in essential hypertensives with hypovitaminosis D, pharmacological correction of vitamin D levels can blunt systemic RAS activity.

  15. Budesonide, but not dexamethasone, blunted the response of aldosterone to renin elevation by suppressing angiotensin converting enzyme upon high-altitude exposure.

    PubMed

    Li, Hui-Jie; Zheng, Cheng-Rong; Chen, Guo-Zhu; Qin, Jun; Zhang, Ji-Hang; Yu, Jie; Zhang, En-Hao; Huang, Lan

    2016-01-01

    Inhaled budesonide is a novel approach to prevent acute mountain sickness (AMS). However, its mechanism is not completely understood. We aimed to investigate the effects of budesonide and dexamethasone on renin-angiotensin-aldosterone system in AMS prevention. Data were obtained from a randomised controlled trial including 138 participants. The participants were randomly assigned to receive budesonide, dexamethasone or placebo as prophylaxis before they travelled to 3450 m altitude from 400 m by car. Their plasma concentrations of renin, angiotensin-converting enzyme (ACE) and aldosterone were measured at both altitudes. All parameters were comparable among the three groups at 400 m. After high-altitude exposure of 3450, renin in all groups increased significantly; the ACE, aldosterone concentrations, as well as the aldosterone/renin ratio, rose markedly in the dexamethasone and placebo groups but not in the budesonide group. Moreover, the aldosterone/renin ratio correlated closely with ACE concentration. Upon acute high-altitude exposure, budesonide, but not dexamethasone, blunted the response of aldosterone to renin elevation by suppressing angiotensin converting enzyme. © The Author(s) 2016.

  16. Evaluation of Vasopressin for Septic Shock in Patients on Chronic Renin-Angiotensin-Aldosterone System Inhibitors.

    PubMed

    Erwin, Beth L; Denaburg, Michael A; Barker, Andrew B; McArdle, Philip J; Windham, Samuel T; Morgan, Charity J

    2017-12-01

    To compare the hemodynamic response in septic shock patients receiving vasopressin who were on chronic renin-angiotensin-aldosterone system inhibitor therapy with those who were not. Single-center, retrospective cohort study. Medical and surgical ICUs at a 1,100-bed academic medical center. Medical and surgical ICU patients with septic shock who received vasopressin infusion added to at least one concomitant vasopressor agent between January 2014 and December 2015, then divided into two cohorts: 1) patients who were on chronic renin-angiotensin-aldosterone system inhibitor therapy as outpatients and 2) patients who were not on chronic renin-angiotensin-aldosterone system inhibitor therapy as outpatients. None. Mean arterial pressure at 6 hours was 72.2 mm Hg in the renin-angiotensin-aldosterone system inhibitor group versus 69.7 mm Hg in the non-renin-angiotensin-aldosterone system inhibitor group (p = 0.298). There was no difference in mean arterial pressure at 1, 24, or 48 hours between groups. Total concomitant vasopressor requirements, based on norepinephrine equivalents excluding vasopressin, were significantly lower at 24 hours in the renin-angiotensin-aldosterone system inhibitor group versus the non-renin-angiotensin-aldosterone system inhibitor group (10.7 vs 18.1 µg/min, respectively; p = 0.007), but no significant differences were seen at the other time points assessed. There were no significant differences in ICU or hospital length of stay or mortality. There was no significant difference in the primary outcome of 6-hour mean arterial pressure in septic shock patients receiving vasopressin who were on chronic renin-angiotensin-aldosterone system inhibitor therapy versus those receiving vasopressin who were not on chronic renin-angiotensin-aldosterone system inhibitor therapy. Renin-angiotensin-aldosterone system inhibitor patients had lower total concomitant vasopressor requirements at 24 hours compared with non-renin-angiotensin-aldosterone system

  17. Urinary renin, but not angiotensinogen or aldosterone, reflects the renal renin-angiotensin-aldosterone system activity and the efficacy of renin-angiotensin-aldosterone system blockade in the kidney.

    PubMed

    van den Heuvel, Mieke; Batenburg, Wendy W; Jainandunsing, Sjaam; Garrelds, Ingrid M; van Gool, Jeanette M G; Feelders, Richard A; van den Meiracker, Anton H; Danser, A H Jan

    2011-11-01

    To study which renin-angiotensin-aldosterone system (RAAS) component best reflects renal RAAS activity. We measured urinary and plasma renin, prorenin, angiotensinogen, aldosterone, albumin and creatinine in 101 diabetic and nondiabetic patients with or without hypertension. Plasma prorenin was elevated in diabetic patients. Urinary prorenin was undetectable. Urinary albumin and renin were higher in diabetic patients. Men had higher plasma renin/prorenin levels, and lower plasma angiotensinogen levels than women. Plasma creatinine and albumin were also higher in men. Urinary RAAS components showed no sexual dimorphism, whereas urinary creatinine and albumin were higher in men. Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers increased plasma renin and decreased plasma angiotensinogen, without altering plasma aldosterone. In contrast, in urine, these drugs decreased renin and aldosterone without affecting angiotensinogen. When analyzing all patients together, urinary angiotensinogen excretion closely mimicked that of albumin, whereas urinary angiotensinogen and albumin levels both were 0.05% or less of their concomitant plasma levels. This may reflect the identical glomerular filtration and tubular handling of both proteins, which have a comparable molecular weight. In contrast, urinary renin excretion did not correlate with urinary albumin excretion, and the urinary/plasma concentration ratio of renin was more than 200 times the ratio of albumin, despite its comparable molecular weight. Urinary aldosterone excretion closely followed urinary creatinine excretion. The increased urinary renin levels in diabetes and the decreased urinary renin levels following RAAS blockade, occurring independently of changes in plasma renin, reflect the activated renal RAAS in diabetes and the success of RAAS blockade in the kidney, respectively. Urinary renin, therefore, more closely reflects renal RAAS activity than urinary angiotensinogen or

  18. Role of the renin-angiotensin system in cardiac hypertrophy induced in rats by hyperthyroidism

    PubMed Central

    KOBORI, HIROYUKI; ICHIHARA, ATSUHIRO; SUZUKI, HIROMICHI; TAKENAKA, TSUNEO; MIYASHITA, YUTAKA; HAYASHI, MATSUHIKO; SARUTA, TAKAO

    2008-01-01

    This study was conducted to examine whether the renin-angiotensin system contributes to hyperthyroidism-induced cardiac hypertrophy without involving the sympathetic nervous system. Sprague-Dawley rats were divided into control-innervated, control-denervated, hyperthyroid-innervated, and hyperthyroid-denervated groups using intraperitoneal injections of thyroxine and 6-hydroxydopamine. After 8 wk, the heart-to-body weight ratio increased in hyperthyroid groups (63%), and this increase was only partially inhibited by sympathetic denervation. Radioimmunoassays and reverse transcription-polymerase chain reaction revealed increased cardiac levels of renin (33%) and angiotensin II (53%) and enhanced cardiac expression of renin mRNA (225%) in the hyperthyroid groups. These increases were unaffected by sympathetic denervation or 24-h bilateral nephrectomy. In addition, losartan and nicardipine decreased systolic blood pressure to the same extent, but only losartan caused regression of thyroxine-induced cardiac hypertrophy. These results suggest that thyroid hormone activates the cardiac renin-angiotensin system without involving the sympathetic nervous system or the circulating renin-angiotensin system; the activated renin-angiotensin system contributes to cardiac hypertrophy in hyperthyroidism. PMID:9277473

  19. Role of the renin-angiotensin system in cardiac hypertrophy induced in rats by hyperthyroidism.

    PubMed

    Kobori, H; Ichihara, A; Suzuki, H; Takenaka, T; Miyashita, Y; Hayashi, M; Saruta, T

    1997-08-01

    This study was conducted to examine whether the renin-angiotensin system contributes to hyperthyroidism-induced cardiac hypertrophy without involving the sympathetic nervous system. Sprague-Dawley rats were divided into control-innervated, control-denervated, hyperthyroid-innervated, and hyperthyroid-denervated groups using intraperitoneal injections of thyroxine and 6-hydroxydopamine. After 8 wk, the heart-to-body weight ratio increased in hyperthyroid groups (63%), and this increase was only partially inhibited by sympathetic denervation. Radioimmunoassays and reverse transcription-polymerase chain reaction revealed increased cardiac levels of renin (33%) and angiotensin II (53%) and enhanced cardiac expression of renin mRNA (225%) in the hyperthyroid groups. These increases were unaffected by sympathetic denervation or 24-h bilateral nephrectomy. In addition, losartan and nicardipine decreased systolic blood pressure to the same extent, but only losartan caused regression of thyroxine-induced cardiac hypertrophy. These results suggest that thyroid hormone activates the cardiac renin-angiotensin system without involving the sympathetic nervous system or the circulating renin-angiotensin system; the activated renin-angiotensin system contributes to cardiac hypertrophy in hyperthyroidism.

  20. Renin-angiotensin-aldosterone system inhibition: overview of the therapeutic use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and direct renin inhibitors.

    PubMed

    Mercier, Kelly; Smith, Holly; Biederman, Jason

    2014-12-01

    Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy in hypertensive diabetic patients with macroalbuminuria, microalbuminuria, or normoalbuminuria has been repeatedly shown to improve cardiovascular mortality and reduce the decline in glomerular filtration rate. Renin-angiotensin-aldosterone system (RAAS) blockade in normotensive diabetic patients with normoalbuminuria or microalbuminuria cannot be advocated at present. Dual RAAS inhibition with ACE inhibitors plus ARBs or ACE inhibitors plus direct renin inhibitors has failed to improve cardiovascular or renal outcomes but has predisposed patients to serious adverse events. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. The evolution of renin-angiotensin blockade: angiotensin-converting enzyme inhibitors as the starting point.

    PubMed

    Sica, Domenic A

    2010-04-01

    The renin-angiotensin system has been a target in the treatment of hypertension for close to three decades. Several medication classes that block specific aspects of this system have emerged as useful therapies, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and, most recently, direct renin inhibitors. There has been a natural history to the development of each of these three drug classes, starting with their use as antihypertensive agents; thereafter, in each case they have been employed as end-organ protective agents. To date, there has been scant evidence to favor angiotensin receptor blockers or direct renin inhibitors over angiotensin-converting enzyme inhibitors in treating hypertension or in affording end-organ protection; thus, angiotensin-converting enzyme inhibitors remain the standard of care when renin-angiotensin system blockade is warranted.

  2. Effect of renin-angiotensin system on sodium intake.

    PubMed Central

    Chiaraviglio, E

    1976-01-01

    1. Water and saline intake was measured in rats depleted of Na by I.P. dialysis. Na intake was prevented 180 min but not 60-90 min after bilateral nephrectomy. Unilateral nephrectomy as well as ureteral ligature had no effect on Na intake. 2. Renin (3u.) injected I.P. re-established the Na appetite abolished by nephrectomy. 3. Angiotensin I (5 ng) or II (5-40 ng) injected into the 3rd ventricle, also restored the Na intake and this effect was dose-dependent. 4. The angiotensin converting-enzyme inhibitor Sq 20,881 (1 mg/kg) inhibited the effect of AI but not that of AII in restoring Na intake. 5. It is concluded that the kidneys might play a role in the regulation of Na intake through the renin-angiotensin system. PMID:1255521

  3. Inhibition of the renin-angiotensin-aldosterone system: is there room for dual blockade in the cardiorenal continuum?

    PubMed

    Volpe, Massimo; Danser, A H Jan; Menard, Joël; Waeber, Bernard; Mueller, Dominik N; Maggioni, Aldo P; Ruilope, Luis M

    2012-04-01

    Antagonism of renin-angiotensin-aldosterone system is exerted through angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, renin inhibitors and mineralocorticoid receptor antagonists. These drugs have been successfully tested in numerous trials and in different clinical settings. The original indications of renin-angiotensin-aldosterone system blockers have progressively expanded from the advanced stages to the earlier stages of cardiorenal continuum. To optimize the degree of blockade of renin-angiotensin-aldosterone system, dose uptitrations of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists or the use of a dual blockade, initially identified with the combination of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists, have been proposed. The data from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) study do not support this specific dual blockade approach. However, the dual blockade of angiotensin-converting enzyme inhibitors/angiotensin receptor antagonists with direct renin inhibitors is currently under investigation while that based on an aldosterone blocker with any of the previous three drugs requires more evidence beyond heart failure. In this review, we revisited potential advantages of dual blockade of renin-angiotensin-aldosterone system in arterial hypertension and diabetes.

  4. Budesonide, but not dexamethasone, blunted the response of aldosterone to renin elevation by suppressing angiotensin converting enzyme upon high-altitude exposure

    PubMed Central

    Li, Hui-Jie; Zheng, Cheng-Rong; Chen, Guo-Zhu; Qin, Jun; Zhang, Ji-Hang; Yu, Jie; Zhang, En-Hao; Huang, Lan

    2016-01-01

    Introduction: Inhaled budesonide is a novel approach to prevent acute mountain sickness (AMS). However, its mechanism is not completely understood. We aimed to investigate the effects of budesonide and dexamethasone on renin–angiotensin–aldosterone system in AMS prevention. Materials and methods: Data were obtained from a randomised controlled trial including 138 participants. The participants were randomly assigned to receive budesonide, dexamethasone or placebo as prophylaxis before they travelled to 3450 m altitude from 400 m by car. Their plasma concentrations of renin, angiotensin-converting enzyme (ACE) and aldosterone were measured at both altitudes. Results: All parameters were comparable among the three groups at 400 m. After high-altitude exposure of 3450, renin in all groups increased significantly; the ACE, aldosterone concentrations, as well as the aldosterone/renin ratio, rose markedly in the dexamethasone and placebo groups but not in the budesonide group. Moreover, the aldosterone/renin ratio correlated closely with ACE concentration. Conclusions: Upon acute high-altitude exposure, budesonide, but not dexamethasone, blunted the response of aldosterone to renin elevation by suppressing angiotensin converting enzyme. PMID:27317302

  5. Sequential changes in the human renin-angiotensin system following therapeutic termination of pregnancy.

    PubMed

    Broughton Pipkin, F; Oats, J J; Hunter, J C; Craven, D J; Symonds, E M

    1979-04-01

    Plasma renin and angiotensin II levels were measured in nine patients immediately before and at half-hourly intervals in the four hours following therapeutic termination of pregnancy. There was a small fall in renin and angiotensin II levels over the first 1 to 2 hours, followed by a slight increase. The magnitude of these effects was much smaller than those previously seen following normal delivery. It is concluded that in early pregnancy maternal, rather than feto-placental, factors are controlling the renin-angiotensin system.

  6. Drug discovery in renin-angiotensin system intervention: past and future.

    PubMed

    Williams, Bryan

    2016-06-01

    The renin-angiotensin system (RAS) plays a central role in the control of blood pressure in the body and the way this interacts with other systems is widely recognized. This has not always been the case and this review summarizes how our knowledge has evolved from the initial discovery of renin by Tigerstedt and Berman in 1898. This includes the identification of angiotensin in the 1950s to the proposed relationship between this system, hypertension and ultimately cardiovascular disease. While the RAS is far more complex than originally thought, much is now known about this system and the wide ranging effects of angiotensin in the body. This has enabled the development of therapies that target the various proteins in this pathway and hence are implicated in disease. The first of these treatments was the angiotensin converting enzyme inhibitors (ACE-Is), followed by the angiotensin receptor blockers (ARBs), and more recently the direct renin inhibitors (DRIs). Clinical outcome trials have shown these drugs to be effective, but as they act at contrasting points in the RAS, there are differences in their efficacy and safety profiles. RAS blockade is the foundation of modern combination therapy with a calcium channel blocker and/or a diuretic given to reduce blood pressure and limit the impact of RAS activation. Other options that complement these treatments may be available in the future and will offer more choice to clinicians. © The Author(s), 2016.

  7. Some Comparative Aspects of the Renin-Angiotensin System.

    ERIC Educational Resources Information Center

    Malvin, Richard L.

    1984-01-01

    The renin-angiotensin system (RAS) maintains salt and water balance. Discusses functions of the RAS as defined in mammalian species, considering how the system arose and what its original function was. Also discusses where some of the changes occurred in the system (and why) as well as other topics. (JN)

  8. [Pharmacological differences between inhibitor drugs of the renin-angiotensin aldosterone system].

    PubMed

    Méndez-Durán, Antonio

    2011-01-01

    The activation of the renin-angiotensin-aldosterone cascade is a mechanism that generates high blood pressure. The structure has been identified and can be blocked through specific enzymatic pathways or receptors. We have a diversity of medications that act on this system. It is useful to develop the skill in clinical practice for selecting a drug from a wide variety. Renin-angiotensin system inhibitors share many pharmacological and pharmacokinetic characteristics but not all them are equivalent. Knowledge based on scientific evidence allows the clinician to choose the ideal drug for each patient.

  9. Cholecalciferol treatment downregulates renin-angiotensin system and improves endothelial function in essential hypertensive patients with hypovitaminosid D.

    PubMed

    Carrara, Davide; Bruno, Rosa Maria; Bacca, Alessandra; Taddei, Stefano; Duranti, Emiliano; Ghiadoni, Lorenzo; Bernini, Giampaolo

    2016-11-01

    Vitamin D deficiency is related to an increased prevalence of cardiovascular disease. Renin-angiotensin-aldosterone system suppression and vascular dysfunction are considered among the main mechanisms implicated in this association. However, interventional studies demonstrating that vitamin D replacement reduces circulating renin-angiotensin-aldosterone components and improves vascular function in humans are still lacking. Thirty-three consecutive patients with essential hypertension and hypovitaminosis D underwent therapy with cholecalciferol 50 000 IU/week orally for 8 weeks. Thirty-three hypertensive patients with normal vitamin D levels and 20 normotensive individuals were also enrolled as control groups. At baseline and at the end of the study, we evaluated plasma renin activity, circulating renin, angiotensin II, aldosterone and plasma vitamin D levels. Endothelial function [flow-mediated dilation (FMD)], carotid-femoral pulse wave velocity and augmentation index, peripheral and central blood pressure were also acquired. After 8-week cholecalciferol administration, all treated patients normalized plasma 25(OH)D values. Furthermore, a reduction in plasma levels of plasma renin activity (1.17 ± 0.3 vs 1.51 ± 0.4 ng/ml per h, P = 0.02), renin (13.4 ± 1.7 vs 19.2 ± 2.9 pg/ml, P < 0.001), angiotensin II (11.6 ± 1.6 vs 15.8 ± 2.7 pg/ml, P = 0.02) was observed at the end of the study. FMD was significantly increased after cholecalciferol treatment (4.4 ± 2.6 vs 3.3 ± 2.1%, P < 0.05), in the absence of changes of brachial artery diameter and endothelium-independent vasodilation. Carotid-femoral pulse wave velocity and augmentation index were not modified, as well peripheral and central blood pressure. The restoration of normal vitamin D levels after 8-week cholecalciferol treatment is able to inhibit peripheral renin-angiotensin system and improve FMD in essential hypertensive patients with

  10. The Prorenin and (Pro)renin Receptor: New Players in the Brain Renin-Angiotensin System?

    PubMed Central

    Li, Wencheng; Peng, Hua; Seth, Dale M.; Feng, Yumei

    2012-01-01

    It is well known that the brain renin-angiotensin (RAS) system plays an essential role in the development of hypertension, mainly through the modulation of autonomic activities and vasopressin release. However, how the brain synthesizes angiotensin (Ang) II has been a debate for decades, largely due to the low renin activity. This paper first describes the expression of the vasoconstrictive arm of RAS components in the brain as well as their physiological and pathophysiological significance. It then focus on the (pro)renin receptor (PRR), a newly discovered component of the RAS which has a high level in the brain. We review the role of prorenin and PRR in peripheral organs and emphasize the involvement of brain PRR in the pathogenesis of hypertension. Some future perspectives in PRR research are heighted with respect to novel therapeutic target for the treatment of hypertension and other cardiovascular diseases. PMID:23316344

  11. Increased Dietary Salt Changes Baroreceptor Sensitivity and Intrarenal Renin-Angiotensin System in Goldblatt Hypertension.

    PubMed

    Shimoura, Caroline G; Lincevicius, Gisele S; Nishi, Erika E; Girardi, Adriana C C; Simon, Karin A; Bergamaschi, Cassia T; Campos, Ruy R

    2017-01-01

    Renovascular hypertension (2-kidney 1-clip model (2K1C)) is characterized by renin-angiotensin system (RAS) activation. Increased Angiotensin II (AngII) leads to sympathoexcitation, oxidative stress, and alterations in sodium and water balance. The aim of this study was to evaluate whether a discrete increase in sodium chloride intake in 2K1C rats leads to changes in cardiovascular and autonomic function, oxidative stress, and renin angiotensin aldosterone system. After 4 weeks of induction of hypertension, rats were fed a normal sodium diet (0.4% NaCl) or a high-sodium diet (2% NaCl) for 2 consecutive weeks. Experiments were carried out for 6 weeks after clipping. Mean arterial pressure (MAP), renal sympathetic nerve activity (rSNA), arterial baroreflex control of rSNA, and heart rate (HR) were assessed. Thiobarbituric acid reactive substances and glutathione were measured as indicators of systemic oxidative stress. Angiostensin-converting enzyme (ACE), ACE2, and angiotensinogen were evaluated in clipped and unclipped kidneys as also urinary angiotensinogen and plasma renin activity. Angiotensinogen, plasma renin activity (PRA) and angiotensin-converting enzyme (ACE) and ACE2 in clipped and unclipped kidneys were evaluated. High-sodium diet did not change systemic oxidative stress, and basal values of MAP, HR, or rSNA; however, increased renal (-0.7±0.2 vs. -1.5±0.1 spikes/s/mm Hg) and cardiac (-0.9±0.14 vs. -1.5±0.14 bpm/mm Hg) baroreceptor reflex sensitivity in 2K1C rats. Although there was no alteration in PRA, a high-salt diet significantly decreased urinary angiotensinogen, ACE, and ACE2 expressions in the clipped and unclipped kidneys. Increased arterial baroreceptor control associated with a suppression of the intrarenal RAS in the 2K1C rats on high-salt diet provide a salt-resistant effect on hypertension and sympathoexcitation in renovascular hypertensive rats. © American Journal of Hypertension, Ltd 2016. All rights reserved. For Permissions, please

  12. Comparative biochemistry of renins and angiotensins in the vertebrates.

    PubMed

    Nakajima, T; Khosla, M C; Sakakibara, S

    1978-09-01

    Comparative biochemistry of renins and angiotensins was discussed. Renin extracted from hog kidney was different from that from mouse submaxillary glands in immunoreactivity and carbohydrate content. Rat kidney renin was also different from hog kidney renin in the amino acid composition. The presence of big and big-big renins was pointed out immunochemically. These big renins were considered to be precursors of kidney renin. Angiotensins in mammalian and nonmammalian species produced by renal or extrarenal renin have been differentiated by some biochemical and pharmacological criteria. Some of these angiotensins were analyzed sequentially. The replacements of amino acid residues at positions 1, 5, and/or 9 of angiotensin I have been demonstrated in nonmammalian species. Specific pressor activities have been determined using synthetic angiotensins by a 4 point assay in rat. Specific pressor activities of various angiotensins were obtained from the dose-blood pressure-response curves using a single angiotensin sample per assay rat.

  13. Cardiac-specific suppression of NF-κB signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system.

    PubMed

    Thomas, Candice M; Yong, Qian Chen; Rosa, Rodolfo M; Seqqat, Rachid; Gopal, Shanthi; Casarini, Dulce E; Jones, W Keith; Gupta, Sudhiranjan; Baker, Kenneth M; Kumar, Rajesh

    2014-10-01

    Activation of NF-κB signaling in the heart may be protective or deleterious depending on the pathological context. In diabetes, the role of NF-κB in cardiac dysfunction has been investigated using pharmacological approaches that have a limitation of being nonspecific. Furthermore, the specific cellular pathways by which NF-κB modulates heart function in diabetes have not been identified. To address these questions, we used a transgenic mouse line expressing mutated IκB-α in the heart (3M mice), which prevented activation of canonical NF-κB signaling. Diabetes was developed by streptozotocin injections in wild-type (WT) and 3M mice. Diabetic WT mice developed systolic and diastolic cardiac dysfunction by the 12th week, as measured by echocardiography. In contrast, cardiac function was preserved in 3M mice up to 24 wk of diabetes. Diabetes induced an elevation in cardiac oxidative stress in diabetic WT mice but not 3M mice compared with nondiabetic control mice. In diabetic WT mice, an increase in the phospholamban/sarco(endo)plasmic reticulum Ca(2+)-ATPase 2 ratio and decrease in ryanodine receptor expression were observed, whereas diabetic 3M mice showed an opposite effect on these parameters of Ca(2+) handling. Significantly, renin-angiotensin system activity was suppressed in diabetic 3M mice compared with an increase in WT animals. In conclusion, these results demonstrate that inhibition of NF-κB signaling in the heart prevents diabetes-induced cardiac dysfunction through preserved Ca(2+) handling and inhibition of the cardiac renin-angiotensin system.

  14. Cardiac-specific suppression of NF-κB signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system

    PubMed Central

    Thomas, Candice M.; Yong, Qian Chen; Rosa, Rodolfo M.; Seqqat, Rachid; Gopal, Shanthi; Casarini, Dulce E.; Jones, W. Keith; Gupta, Sudhiranjan; Baker, Kenneth M.

    2014-01-01

    Activation of NF-κB signaling in the heart may be protective or deleterious depending on the pathological context. In diabetes, the role of NF-κB in cardiac dysfunction has been investigated using pharmacological approaches that have a limitation of being nonspecific. Furthermore, the specific cellular pathways by which NF-κB modulates heart function in diabetes have not been identified. To address these questions, we used a transgenic mouse line expressing mutated IκB-α in the heart (3M mice), which prevented activation of canonical NF-κB signaling. Diabetes was developed by streptozotocin injections in wild-type (WT) and 3M mice. Diabetic WT mice developed systolic and diastolic cardiac dysfunction by the 12th week, as measured by echocardiography. In contrast, cardiac function was preserved in 3M mice up to 24 wk of diabetes. Diabetes induced an elevation in cardiac oxidative stress in diabetic WT mice but not 3M mice compared with nondiabetic control mice. In diabetic WT mice, an increase in the phospholamban/sarco(endo)plasmic reticulum Ca2+-ATPase 2 ratio and decrease in ryanodine receptor expression were observed, whereas diabetic 3M mice showed an opposite effect on these parameters of Ca2+ handling. Significantly, renin-angiotensin system activity was suppressed in diabetic 3M mice compared with an increase in WT animals. In conclusion, these results demonstrate that inhibition of NF-κB signaling in the heart prevents diabetes-induced cardiac dysfunction through preserved Ca2+ handling and inhibition of the cardiac renin-angiotensin system. PMID:25085967

  15. The Intracrine Renin-Angiotensin System

    PubMed Central

    Kumar, Rajesh; Thomas, Candice M.; Yong, Qian Chen; Chen, Wen; Baker, Kenneth M.

    2014-01-01

    The renin-angiotensin system (RAS) is one of the earliest and most extensively studied hormonal systems. The RAS is an atypical hormonal system in several ways. The major bioactive peptide of the system, angiotensin (Ang) II, is neither synthesized in, nor targets one specific organ. New research has identified additional peptides with important physiological and pathological roles. More peptides also mean newer enzymatic cascades that generate these peptides and more receptors that mediate the function. In addition, completely different roles of components that constitute the RAS have been uncovered, such as that for prorenin via the prorenin receptor. Complexity of the RAS is further enhanced by the presence of sub-systems in tissues, which act in an autocrine/paracrine manner independent of the endocrine system. The RAS seems relevant at the cellular level, wherein individual cells have a complete system, termed the intracellular RAS. Thus, from cells to tissues to the entire organism, the RAS exhibits continuity while maintaining independent control at different levels. The intracellular RAS is a relatively new concept for the RAS. The current review presents a synopsis of the literature on this system in different tissues. PMID:22590974

  16. Azilsartan, aliskiren, and combination antihypertensives utilizing renin-angiotensin-aldosterone system antagonists.

    PubMed

    Lanier, Gregg; Sankholkar, Kedar; Aronow, Wilbert S

    2014-01-01

    Health care providers managing hypertension (HTN) have a large selection of pharmacologic agents to choose from, including several different classes of drugs and many similar drugs within each class. Antagonism of the renin-angiotensin-aldosterone system has been shown to be very effective for HTN, especially in patients with cardiovascular disease, diabetes, and heart failure. Within this group, there have been 2 new agents recently introduced to the US market and approved by the Food and Drug Administration. It is important for the HTN specialist to be familiar with the merits of these 2 drugs: the angiotensin receptor blocker Edarbi (azilsartan) and the renin inhibitor Tekturna (aliskiren). Additionally, there have been several new, fixed-dose combination antihypertensives introduced to the market since 2006 that use a renin-angiotensin-aldosterone antagonist. Seven of these combine 2 drugs together in a single pill: Edarbyclor (azilsartan/chlorthalidone), Exforge (amlodipine/valsartan), Azor (olmesartan/amlodipine), Twynsta (amlodipine/telmisartan), Tekturna HCT [aliskiren/hydrochlorothiazide (HCTZ)], Valturna (aliskiren/valsartan), Tekamlo (aliskiren/amlodipine). Three triple-drug combination medications have also been introduced recently: Exforge HCT (amlodipine/valsartan/HCTZ), Tribenzor (olmesartan/amlodipine/HCTZ), and Amturnide (aliskiren/amlodipine/hydrocholorothiazide). This review will summarize the trial data and important pharmacologic merits of these 2 new renin-angiotensin-aldosterone antagonists and the advantages of initiating treatment with one of the new fixed-dose, combination drugs approved over the last 5 years.

  17. Renin-angiotensin-aldosterone (RAAS): The ubiquitous system for homeostasis and pathologies.

    PubMed

    Patel, Seema; Rauf, Abdur; Khan, Haroon; Abu-Izneid, Tareq

    2017-10-01

    Renin-angiotensin-aldosterone system (RAAS) is a vital system of human body, as it maintains plasma sodium concentration, arterial blood pressure and extracellular volume. Kidney-secreted renin enzyme acts on its substrate to form angiotensin II, a versatile effector peptide hormone. Every organ is affected by RAAS activation and the resultant hypertension, cell proliferation, inflammation, and fibrosis. The imbalance of renin and angiotensin II can result in an overwhelming number of chronic and acute diseases. RAAS is influenced by other enzymes, hormones, pumps and signaling pathways, hence, this review discusses important facets of this system, its crosstalk with other crucial factors like estrogen, thyroid, cortisol, kallikrein-kinin system, Wnt/β-catenin signaling, and sodium-potassium pump. The nexus of RAAS with the above-discussed systems was scantily explored before. So, this review furnishes a new perspective in comprehension of inflammation diseases. It is followed by the formulation of hypotheses, which can contribute to better management of an array of pathologies plaguing mankind. Manipulation of RAAS, by bending it towards ACE2 expression can regulate endocrine functions, which can be critical for a number of pathological management. Dietary intervention can restore RAAS to normalcy. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  18. Characterization of renin-angiotensin system enzyme activities in cultured mouse podocytes.

    PubMed

    Velez, Juan Carlos Q; Bland, Alison M; Arthur, John M; Raymond, John R; Janech, Michael G

    2007-07-01

    Intraglomerular ANG II has been linked to glomerular injury. However, little is known about the contribution of podocytes (POD) to intraglomerular ANG II homeostasis. The aim of the present study was to examine the processing of angiotensin substrates by cultured POD. Our approach was to use matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry for peptide determination from conditioned cell media and customized AQUA peptides for quantification. Immortalized mouse POD were incubated with 1-2 microM ANG I, ANG II, or the renin substrate ANG-(1-14) for different time intervals and coincubated in parallel with various inhibitors. Human mesangial cells (MES) were used as controls. POD incubated with 1 microM ANG I primarily formed ANG-(1-9) and ANG-(1-7). In contrast, MES incubated with ANG I primarily generated ANG II. In POD, ANG-(1-7) was the predominant product, and its formation was inhibited by a neprilysin inhibitor. Modest angiotensin-converting enzyme (ACE) activity was also detected in POD, although only after cells were incubated with 2 microM ANG I. In addition, we observed that POD degraded ANG II into ANG III and ANG-(1-7). An aminopeptidase A inhibitor inhibited ANG III formation, and an ACE2 inhibitor led to ANG II accumulation. Furthermore, we found that POD converted ANG-(1-14) to ANG I and ANG-(1-7). This conversion was inhibited by a renin inhibitor. These findings demonstrate that POD express a functional intrinsic renin-angiotensin system characterized by neprilysin, aminopeptidase A, ACE2, and renin activities, which predominantly lead to ANG-(1-7) and ANG-(1-9) formation, as well as ANG II degradation. These findings may reflect a specific role of POD in maintenance of intraglomerular renin-angiotensin system balance.

  19. The Renin Angiotensin Aldosterone System and Insulin Resistance in Humans

    PubMed Central

    Underwood, Patricia C

    2012-01-01

    Alterations in the renin angiotensin aldosterone system (RAAS) contribute to the underlying pathophysiology of insulin resistance in humans; however, individual differences in the treatment response of insulin resistance to RAAS blockade persist. Thus, understanding inter-individual differences in the relationship between the RAAS and insulin resistance may provide insights into improved personalized treatments and improved outcomes. The effects of the systemic RAAS on blood pressure regulation and glucose metabolism have been studied extensively; however, recent discoveries on the influence of local tissue RAAS in the skeletal muscle, heart, vasculature, adipocytes, and pancreas have led to an improved understanding of how activated tissue RAAS influences the development of insulin resistance and diabetes in humans. Angiotensin II (ANGII) is the predominant RAAS component contributing to insulin resistance; however, other players such as aldosterone, renin, and ACE2 are also involved. This review examines the role of local ANGII activity on insulin resistance development in skeletal muscle, adipocytes, and pancreas, followed by a discussion of the other RAAS components implicated in insulin resistance, including ACE2, Ang1-7, renin, and aldosterone. PMID:23242734

  20. Local Renin Angiotensin Aldosterone Systems and Cardiovascular Diseases.

    PubMed

    De Mello, Walmor C

    2017-01-01

    The presence of local renin angiotensin aldosterone systems (RAAS) in the cardiovascular and renal tissues and their influence in cardiovascular and renal diseases are described. The fundamental role of ACE/Ang II/AT1 receptor axis activation as well the counterregulatory role of ACE2/Ang (1-7)/Mas receptor activation on cardiovascular and renal physiology and pathology are emphasized. The presence of a local RAS and its influence on hypertension is discussed, and finally, the hypothesis that epigenetic factors change the RAAS in utero and induce the expression of renin or Ang II inside the cells of the cardiovascular system is presented. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Brain-Targeted (Pro)Renin Receptor Knockdown attenuates Angiotensin II-Dependent Hypertension

    PubMed Central

    Li, Wencheng; Peng, Hua; Cao, Theresa; Sato, Ryosuke; McDaniels, Sarah. J.; Kobori, Hiroyuki; Navar, L. Gabriel; Feng, Yumei

    2012-01-01

    The (pro)renin receptor is a newly discovered member of the brain renin-angiotensin system. To investigate the role of brain (pro)renin receptor in hypertension, adeno-associated virus-mediated (pro)renin receptor shRNA was used to knockdown (pro)renin receptor expression in the brain of non-transgenic normotensive and human renin-angiotensinogen double transgenic hypertensive mice. Blood pressure was monitored using implanted telemetric probes in conscious animals. Real-time PCR and immunostaining were performed to determine (pro)renin receptor, angiotensin II type 1 receptor and vasopressin mRNA levels. Plasma vasopressin levels were determined by Enzyme-Linked Immuno Sorbent Assay. Double transgenic mice exhibited higher blood pressure, elevated cardiac and vascular sympathetic tone, and impaired spontaneous baroreflex sensitivity. Intracerebroventricular delivery of (pro)renin receptor shRNA significantly reduced blood pressure, cardiac and vasomotor sympathetic tone, and improved baroreflex sensitivity compared to the control virus treatment in double transgenic mice. (Pro)renin receptor knockdown significantly reduced angiotensin II type 1 receptor and vasopressin levels in double transgenic mice. These data indicate that (pro)renin receptor knockdown in the brain attenuates angiotensin II-dependent hypertension and is associated with a decrease insympathetic tone and an improvement of the baroreflex sensitivity. In addition, brain-targeted (pro)renin receptor knockdown is associated with down-regulation of angiotensin II type 1 receptor and vasopressin levels. We conclude that central (pro)renin receptor contributes to the pathogenesis of hypertension in human renin-angiotensinogen transgenic mice. PMID:22526255

  2. Vaccination: a novel strategy for inhibiting the renin-angiotensin-aldosterone system.

    PubMed

    Gradman, Alan H; Pinto, Rehka

    2008-12-01

    Immunologic approaches to renin-angiotensin-aldosterone system (RAAS) inhibition have been studied for more than 50 years. In animal models, vaccination against renin was effective but resulted in fatal autoimmune renal disease; vaccines directed at small peptides including angiotensin I and II and a segment of the AT(1) receptor reduced blood pressure (BP) without causing autoimmune disease. In humans, angiotensin I vaccination did not reduce BP. More promising is the AngQb vaccine, which uses an immunization technology involving conjugation of angiotensin II to virus-like particles. In a phase 2 trial, hypertensive patients vaccinated with 300 microg showed a difference of 9.0/4.0 mm Hg from baseline in mean daytime ambulatory BP after 14 weeks (P = 0.015 for systolic BP, P = 0.064 for diastolic BP), and a marked reduction in early morning BP. No serious adverse events were attributed to vaccine administration. Although questions remain regarding efficacy and safety, RAAS immunization represents an innovative and promising approach to hypertension treatment.

  3. Regulation of the renin-angiotensin-aldosterone system in fibromyalgia.

    PubMed

    Maliszewski, Anne M; Goldenberg, Don L; Hurwitz, Shelley; Adler, Gail K

    2002-07-01

    To assess the function of the renin-angiotensin-aldosterone (RAA) system in women with fibromyalgia (FM) compared to healthy women. Women with FM [n = 14, age 41.0+/-7.2 yrs, body mass index (BMI) 26.4+/-5.4 kg/m2] and healthy women (n = 13, age 40.0+/-7.7 yrs, BMI 25.0+/-5.0 kg/m2) were placed on a low sodium diet (10 mEq sodium/day) for 5 days. After being supine and fasting overnight, subjects received an intravenous infusion of angiotensin II at successive doses of 1, 3, and 10 ng/kg/min for 45 min per dose. Blood pressure (BP), plasma renin activity (PRA), aldosterone, and cortisol were measured at baseline and after each dose of angiotensin II. Prior to sodium restriction, women with FM completed the Hopkins Symptom Checklist-90, which included a question grading the extent of dizziness/faintness on a scale of 0 (none) to 4 (extremely). After dietary sodium restriction, baseline PRA, aldosterone, and supine BP were similar in healthy women and women with FM. Aldosterone and BP rose in response to infused angiotensin II; these responses did not differ significantly between healthy women and women with FM. In women with FM, symptoms of dizziness correlated inversely with BMI (r = -0.81, p < 0.001) and the systolic BP response to 10 ng/kg/min angiotensin II (r = -0.81, p < 0.001). The functioning of the RAA system, including the vascular response to angiotensin II, was intact in women with FM compared to healthy women. However, women with FM who complained of dizziness had a blunted vascular response to angiotensin II. This blunted vascular response may indicate intravascular volume depletion in women with symptoms of dizziness.

  4. Renal hemodynamics and renin-angiotensin system activity in humans with multifocal renal artery fibromuscular dysplasia.

    PubMed

    van Twist, Daan J L; Houben, Alphons J H M; de Haan, Michiel W; de Leeuw, Peter W; Kroon, Abraham A

    2016-06-01

    Fibromuscular dysplasia (FMD) is the second most common cause of renovascular hypertension. Nonetheless, knowledge on the renal microvasculature and renin-angiotensin system (RAS) activity in kidneys with FMD is scarce. Given the fairly good results of revascularization, we hypothesized that the renal microvasculature and RAS are relatively spared in kidneys with FMD. In 58 hypertensive patients with multifocal renal artery FMD (off medication) and 116 matched controls with essential hypertension, we measured renal blood flow (Xenon washout method) per kidney and drew blood samples from the aorta and both renal veins to determine renin secretion and glomerular filtration rate per kidney. We found that renal blood flow and glomerular filtration rate in FMD were comparable to those in controls. Although systemic renin levels were somewhat higher in FMD, renal renin secretion was not elevated. Moreover, in patients with unilateral FMD, no differences between the affected and unaffected kidney were observed with regard to renal blood flow, glomerular filtration rate, or renin secretion. In men, renin levels and renin secretion were higher as compared with women. The renal blood flow response to RAS modulation (by intrarenal infusion of angiotensin II, angiotensin-(1-7), an angiotensin II type 1 receptor blocker, or a nitric oxide synthase blocker) was also comparable between FMD and controls. Renal blood flow, glomerular filtration, and the response to vasoactive substances in kidneys with multifocal FMD are comparable to patients with essential hypertension, suggesting that microvascular function is relatively spared. Renin secretion was not increased and the response to RAS modulation was not affected in kidneys with FMD.

  5. [Renin-angiotensin-aldosteron system: evolution of views from renin discovery to nowadays. Perspectives of therapeutic block].

    PubMed

    Shestakova, M V

    2011-01-01

    Recent revolution in the knowledge about structure, physiological and pathophysiological effects of renin-angiotensin-aldosteron system (RAAS) took place recently when it was discovered that local synthesis of all the RAAS components occurs in target organs and their tissues (the heart, kidneys, vessels, brain tissues). It was found that besides classic RAAS acting via activation of angiotensin II (Ang-II) and its receptors, there is an alternative RAAS opposed to atherogenic potential of Ang-II. Renin and prorenin are shown to have both enzymatic and hormonal activities. Wider understanding appeared of extrarenal effects of aldosteron, its non-genomic activity. The above discoveries open new opportunities for pharmacological regulation of RAAS activity, which enables more effectively correct overactivity of this system in organs at risk of negativeAng-II impact.

  6. Renin inhibitor aliskiren exerts beneficial effect on trabecular bone by regulating skeletal renin-angiotensin system and kallikrein-kinin system in ovariectomized mice.

    PubMed

    Zhang, Y; Wang, L; Song, Y; Zhao, X; Wong, M S; Zhang, W

    2016-03-01

    The skeletal renin-angiotensin system contributes to the development of osteoporosis. The renin inhibitor aliskiren exhibited beneficial effects on trabecular bone of osteoporotic mice, and this action might be mediated through angiotensin and bradykinin receptor pathways. This study implies the potential application of renin inhibitor in the management for postmenopausal osteoporosis. The skeletal renin-angiotensin system plays key role in the pathological process of osteoporosis. The present study is designed to elucidate the effect of renin inhibitor aliskiren on trabecular bone and its potential action mechanism in ovariectomized (OVX) mice. The OVX mice were treated with low dose (5 mg/kg) or high dose (25 mg/kg) of aliskiren or its vehicle for 8 weeks. The bone turnover markers were measured by ELISA. The structural parameters of trabecular bone at lumbar vertebra (LV) and distal femoral metaphysis were measured by micro-CT. The expression of messenger RNA (mRNA) and protein was studied by RT-PCR and immunoblotting, respectively. Aliskiren treatment reduced urinary excretion of calcium and serum level of tartrate-resistant acid phosphatase in OVX mice. The treatment with aliskiren significantly increased bone volume (BV/TV) and connectivity density (Conn.D) of trabecular bone at LV-2 and LV-5 as well as dramatically enhanced BV/TV, Conn.D, bone mineral density (BMD/BV) and decreased bone surface (BS/BV) at the distal femoral end. Aliskiren significantly down-regulated the expression of angiotensinogen, angiotensin II (Ang II), Ang II type 1 receptor, bradykinin receptor (BR)-1, and osteocytic-specific gene sclerostin as well as the osteoclast-specific genes, including carbonic anhydrase II, matrix metalloproteinase-9, and cathepsin K. This study revealed that renin inhibitor aliskiren exhibited the beneficial effects on trabecular bone of ovariectomy-induced osteoporotic mice, and the underlying mechanism for this action might be mediated through Ang II and

  7. Hypertension: renin-angiotensin-aldosterone system alterations.

    PubMed

    Te Riet, Luuk; van Esch, Joep H M; Roks, Anton J M; van den Meiracker, Anton H; Danser, A H Jan

    2015-03-13

    Blockers of the renin-angiotensin-aldosterone system (RAAS), that is, renin inhibitors, angiotensin (Ang)-converting enzyme (ACE) inhibitors, Ang II type 1 receptor antagonists, and mineralocorticoid receptor antagonists, are a cornerstone in the treatment of hypertension. How exactly they exert their effect, in particular in patients with low circulating RAAS activity, also taking into consideration the so-called Ang II/aldosterone escape that often occurs after initial blockade, is still incompletely understood. Multiple studies have tried to find parameters that predict the response to RAAS blockade, allowing a personalized treatment approach. Consequently, the question should now be answered on what basis (eg, sex, ethnicity, age, salt intake, baseline renin, ACE or aldosterone, and genetic variance) a RAAS blocker can be chosen to treat an individual patient. Are all blockers equal? Does optimal blockade imply maximum RAAS blockade, for example, by combining ≥2 RAAS blockers or by simply increasing the dose of 1 blocker? Exciting recent investigations reveal a range of unanticipated extrarenal effects of aldosterone, as well as a detailed insight in the genetic causes of primary aldosteronism, and mineralocorticoid receptor blockers have now become an important treatment option for resistant hypertension. Finally, apart from the deleterious ACE-Ang II-Ang II type 1 receptor arm, animal studies support the existence of protective aminopeptidase A-Ang III-Ang II type 2 receptor and ACE2-Ang-(1 to 7)-Mas receptor arms, paving the way for multiple new treatment options. This review provides an update about all these aspects, critically discussing the many controversies and allowing the reader to obtain a full understanding of what we currently know about RAAS alterations in hypertension. © 2015 American Heart Association, Inc.

  8. Emerging drugs which target the renin-angiotensin-aldosterone system.

    PubMed

    Steckelings, Ulrike Muscha; Paulis, Ludovit; Unger, Thomas; Bader, Michael

    2011-12-01

    The renin-angiotensin-aldosterone system (RAAS) is already the most important target for drugs in the cardiovascular system. However, still new developments are underway to interfere with the system on different levels. The novel strategies to interfere with RAAS aim to reduce the synthesis of the two major RAAS effector hormones, angiotensin (Ang) II and aldosterone, or interfere with their receptors, AT1 and mineralocorticoid receptor, respectively. Moreover, novel targets have been identified in RAAS, such as the (pro)renin receptor, and molecules, which counteract the classical actions of Ang II and are therefore beneficial in cardiovascular diseases. These include the AT2 receptor and the ACE2/Ang-(1-7)/Mas axis. The search for drugs activating these tissue-protective arms of RAAS is therefore the most innovative field in RAAS pharmacology. Most of the novel pharmacological strategies to inhibit the classical RAAS need to prove their superiority above the existing treatment in clinical trials and then have to compete against these now quite cheap drugs in a competitive market. The newly discovered targets have functions beyond the cardiovascular system opening up novel therapeutic areas for drugs interfering with RAAS components.

  9. Targeting renin-angiotensin system in malignant hypertension in atypical hemolytic uremic syndrome

    PubMed Central

    Raghunathan, V.; Sethi, S. K.; Dragon-Durey, M. A.; Dhaliwal, M.; Raina, R.; Jha, P.; Bansal, S. B.; Kher, V.

    2017-01-01

    Hypertension is common in hemolytic uremic syndrome (HUS) and often difficult to control. Local renin-angiotensin activation is believed to be an important part of thrombotic microangiopathy, leading to a vicious cycle of progressive renal injury and intractable hypertension. This has been demonstrated in vitro via enhanced tissue factor expression on glomerular endothelial cells which is enhanced by angiotensin II. We report two pediatric cases of atypical HUS with severe refractory malignant hypertension, in which we targeted the renin-angiotensin system by using intravenous (IV) enalaprilat, oral aliskiren, and oral enalapril with quick and dramatic response of blood pressure. Both drugs, aliskiren and IV enalaprilat, were effective in controlling hypertension refractory to multiple antihypertensive medications. These appear to be promising alternatives in the treatment of severe atypical HUS-induced hypertension and hypertensive emergency. PMID:28356668

  10. Exercise training modulates the hepatic renin-angiotensin system in fructose-fed rats.

    PubMed

    Frantz, Eliete Dalla Corte; Medeiros, Renata Frauches; Giori, Isabele Gomes; Lima, Juliana Bittencourt Silveira; Bento-Bernardes, Thais; Gaique, Thaiane Gadioli; Fernandes-Santos, Caroline; Fernandes, Tiago; Oliveira, Edilamar Menezes; Vieira, Carla Paulo; Conte-Junior, Carlos Adam; Oliveira, Karen Jesus; Nobrega, Antonio Claudio Lucas

    2017-09-01

    What is the central question of this study? What are the effects of exercise training on the hepatic renin-angiotensin system and their contribution to damage resulting from fructose overload in rats? What is the main finding and its importance? Exercise training attenuated the deleterious actions of the angiotensin-converting enzyme/angiotensin II/angiotensin II type 1 receptor axis and increased expression of the counter-regulatory (angiotensin-converting enzyme 2/angiotensin (1-7)/Mas receptor) axis in the liver. Therefore, our study provides evidence that exercise training modulates the hepatic renin-angiotensin system, which contributes to reducing the progression of metabolic dysfunction and non-alcoholic fatty liver disease in fructose-fed rats. The renin-angiotensin system (RAS) has been implicated in the development of metabolic syndrome. We investigated whether the hepatic RAS is modulated by exercise training and whether this modulation improves the deleterious effects of fructose overload in rats. Male Wistar rats were divided into (n = 8 each) control (CT), exercise control (CT-Ex), high-fructose (HFr) and exercise high-fructose (HFr-Ex) groups. Fructose-drinking rats received d-fructose (100 g l -1 ). After 2 weeks, CT-Ex and HFr-Ex rats were assigned to a treadmill training protocol at moderate intensity for 8 weeks (60 min day -1 , 4 days per week). We assessed body mass, glucose and lipid metabolism, hepatic histopathology, angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activity, the angiotensin concentration and the expression profile of proteins affecting the hepatic RAS, gluconeogenesis and inflammation. Neither fructose overload nor exercise training influenced body mass gain and serum ACE and ACE2 activity. The HFr group showed hyperinsulinaemia, but exercise training normalized this parameter. Exercise training was effective in preventing hepatic steatosis and in preventing triacylglycerol and

  11. Role of the renin-angiotensin system, renal sympathetic nerve system, and oxidative stress in chronic foot shock-induced hypertension in rats.

    PubMed

    Dong, Tao; Chen, Jing-Wei; Tian, Li-Li; Wang, Lin-Hui; Jiang, Ren-Di; Zhang, Zhe; Xu, Jian-Bing; Zhao, Xiao-Dong; Zhu, Wei; Wang, Guo-Qing; Sun, Wan-Ping; Zhang, Guo-Xing

    2015-01-01

    The renin-angiotensin system (RAS) and renal sympathetic nerve system (RSNS) are involved in the development of hypertension. The present study is designed to explore the possible roles of the RAS and the RSNS in foot shock-induced hypertension. Male Sprague-Dawley rats were divided into six groups: control, foot shock, RSNS denervation, denervation plus foot shock, Captopril (angiotensin I converting enzyme inhibitor, ACE inhibitor) plus foot shock, and Tempol (superoxide dismutase mimetic) plus foot shock. Rats received foot shock for 14 days. We measured the quantity of thiobarbituric acid reactive substances (TBARS), corticosterone, renin, and angiotensin II (Ang II) in plasma, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and renal noradrenaline content. RAS component mRNA and protein levels were quantified in the cerebral cortex and hypothalamus. The two week foot shock treatment significantly increased systolic blood pressure, which was accompanied by an increase in angiotensinogen, renin, ACE1, and AT1a mRNA and protein expression in the cerebral cortex and hypothalamus, an increase of the plasma concentrations of renin, Ang II, corticosterone, and TBARS, as well as a decrease in plasma SOD and GSH-Px activities. Systolic blood pressure increase was suppressed by denervation of the RSNS or treatment with Captopril or Tempol. Interestingly, denervation or Tempol treatment both decreased main RAS components not only in the circulatory system, but also in the central nervous system. In addition, decreased antioxidant levels and increased TBARS and corticosterone levels were also partially restored by denervation or treatment with Tempol or Captopril. RAS, RSNS and oxidative stress reciprocally potentiate to play important roles in the development of foot shock-induced hypertension.

  12. 21 CFR 862.1085 - Angiotensin I and renin test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Angiotensin I and renin test system. 862.1085 Section 862.1085 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test...

  13. 21 CFR 862.1085 - Angiotensin I and renin test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Angiotensin I and renin test system. 862.1085 Section 862.1085 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test...

  14. 21 CFR 862.1085 - Angiotensin I and renin test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Angiotensin I and renin test system. 862.1085 Section 862.1085 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test...

  15. 21 CFR 862.1085 - Angiotensin I and renin test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Angiotensin I and renin test system. 862.1085 Section 862.1085 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test...

  16. 21 CFR 862.1085 - Angiotensin I and renin test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Angiotensin I and renin test system. 862.1085 Section 862.1085 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test...

  17. Renin angiotensin aldosterone system altered in resistant hypertension in Sub-Saharan African diabetes patients without evidence of primary hyperaldosteronism.

    PubMed

    Edinga-Melenge, Bertille Elodie; Ama Moor, Vicky J; Nansseu, Jobert Richie N; Nguetse Djoumessi, Romance; Mengnjo, Michel K; Katte, Jean-Claude; Noubiap, Jean Jacques N; Sobngwi, Eugene

    2017-01-01

    The renin-angiotensin-aldosterone system may be altered in patients with resistant hypertension. This study aimed to evaluate the relation between renin-angiotensin-aldosterone system activity and resistant hypertension in Cameroonian diabetes patients with resistant hypertension. We carried out a case-control study including 19 diabetes patients with resistant hypertension and 19 diabetes patients with controlled hypertension matched to cases according to age, sex and duration of hypertension since diagnosis. After collection of data, fasting blood was collected for measurement of sodium, potassium, chloride, active renin and plasma aldosterone of which the aldosterone-renin ratio was derived to assess the activity of renin-angiotensin-aldosterone system. Then, each participant received 2000 ml infusion of saline solution after which plasma aldosterone was re-assayed. Potassium levels were lower among cases compared to controls (mean: (4.10 ± 0.63 mmol/l vs. 4.47 ± 0.58 mmol/l), though nonsignificant (p = 0.065). Active renin, plasma aldosterone both before and after the dynamic test and aldosterone-renin ratio were comparable between cases and controls (all p values > 0.05). Plasma aldosterone significantly decreased after the dynamic test in both groups (p < 0.001), but no participant exhibited a post-test value>280 pmol/l. We found a significant negative correlation between potassium ion and plasma aldosterone (ρ = -0.324; p  = 0.047), the other correlations being weak and unsignificant. Although this study failed to show an association between RH and primary hyperaldosteronism in our context, there was a hyperactivity of renin-angiotensin-aldosterone system. Moreover, this study confirms the importance of potassium dosage when screening the renin-angiotensin-aldosterone system.

  18. Interaction of renin-angiotensin system and adenosine monophosphate-activated protein kinase signaling pathway in renal carcinogenesis of uninephrectomized rats.

    PubMed

    Yang, Ke-Ke; Sui, Yi; Zhou, Hui-Rong; Zhao, Hai-Lu

    2017-05-01

    Renin-angiotensin system and adenosine monophosphate-activated protein kinase signaling pathway both play important roles in carcinogenesis, but the interplay of renin-angiotensin system and adenosine monophosphate-activated protein kinase in carcinogenesis is not clear. In this study, we researched the interaction of renin-angiotensin system and adenosine monophosphate-activated protein kinase in renal carcinogenesis of uninephrectomized rats. A total of 96 rats were stratified into four groups: sham, uninephrectomized, and uninephrectomized treated with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Renal adenosine monophosphate-activated protein kinase and its downstream molecule acetyl coenzyme A carboxylase were detected by immunohistochemistry and western blot at 10 months after uninephrectomy. Meanwhile, we examined renal carcinogenesis by histological transformation and expressions of Ki67 and mutant p53. During the study, fasting lipid profiles were detected dynamically at 3, 6, 8, and 10 months. The results indicated that adenosine monophosphate-activated protein kinase expression in uninephrectomized rats showed 36.8% reduction by immunohistochemistry and 89.73% reduction by western blot. Inversely, acetyl coenzyme A carboxylase expression increased 83.3% and 19.07% in parallel to hyperlipidemia at 6, 8, and 10 months. The histopathology of carcinogenesis in remnant kidneys was manifested by atypical proliferation and carcinoma in situ, as well as increased expressions of Ki67 and mutant p53. Intervention with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker significantly prevented the inhibition of adenosine monophosphate-activated protein kinase signaling pathway and renal carcinogenesis in uninephrectomized rats. In conclusion, the novel findings suggest that uninephrectomy-induced disturbance in adenosine monophosphate-activated protein kinase signaling pathway resulted in hyperlipidemia and

  19. Role of the Renin-Angiotensin System, Renal Sympathetic Nerve System, and Oxidative Stress in Chronic Foot Shock-Induced Hypertension in Rats

    PubMed Central

    Dong, Tao; Chen, Jing-Wei; Tian, Li-Li; Wang, Lin-Hui; Jiang, Ren-Di; Zhang, Zhe; Xu, Jian-Bing; Zhao, Xiao-Dong; Zhu, Wei; Wang, Guo-Qing; Sun, Wan-Ping; Zhang, Guo-Xing

    2015-01-01

    Objective: The renin-angiotensin system (RAS) and renal sympathetic nerve system (RSNS) are involved in the development of hypertension. The present study is designed to explore the possible roles of the RAS and the RSNS in foot shock-induced hypertension. Methods: Male Sprague-Dawley rats were divided into six groups: control, foot shock, RSNS denervation, denervation plus foot shock, Captopril (angiotensin I converting enzyme inhibitor, ACE inhibitor) plus foot shock, and Tempol (superoxide dismutase mimetic) plus foot shock. Rats received foot shock for 14 days. We measured the quantity of thiobarbituric acid reactive substances (TBARS), corticosterone, renin, and angiotensin II (Ang II) in plasma, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and renal noradrenaline content. RAS component mRNA and protein levels were quantified in the cerebral cortex and hypothalamus. Results: The two week foot shock treatment significantly increased systolic blood pressure, which was accompanied by an increase in angiotensinogen, renin, ACE1, and AT1a mRNA and protein expression in the cerebral cortex and hypothalamus, an increase of the plasma concentrations of renin, Ang II, corticosterone, and TBARS, as well as a decrease in plasma SOD and GSH-Px activities. Systolic blood pressure increase was suppressed by denervation of the RSNS or treatment with Captopril or Tempol. Interestingly, denervation or Tempol treatment both decreased main RAS components not only in the circulatory system, but also in the central nervous system. In addition, decreased antioxidant levels and increased TBARS and corticosterone levels were also partially restored by denervation or treatment with Tempol or Captopril. Conclusions: RAS, RSNS and oxidative stress reciprocally potentiate to play important roles in the development of foot shock-induced hypertension. PMID:25999788

  20. Retinal vasculopathy is reduced by dietary salt restriction: involvement of Glia, ENaCα, and the renin-angiotensin-aldosterone system.

    PubMed

    Deliyanti, Devy; Armani, Roksana; Casely, David; Figgett, William A; Agrotis, Alex; Wilkinson-Berka, Jennifer L

    2014-09-01

    Neovascularization and vaso-obliteration are vision-threatening events that develop by interactions between retinal vascular and glial cells. A high-salt diet is causal in cardiovascular and renal disease, which is linked to modulation of the renin-angiotensin-aldosterone system. However, it is not known whether dietary salt influences retinal vasculopathy and if the renin-angiotensin-aldosterone system is involved. We examined whether a low-salt (LS) diet influenced vascular and glial cell injury and the renin-angiotensin-aldosterone system in ischemic retinopathy. Pregnant Sprague Dawley rats were fed LS (0.03% NaCl) or normal salt (0.3% NaCl) diets, and ischemic retinopathy was induced in the offspring. An LS diet reduced retinal neovascularization and vaso-obliteration, the mRNA and protein levels of the angiogenic factors, vascular endothelial growth factor, and erythropoietin. Microglia, which influence vascular remodeling in ischemic retinopathy, were reduced by LS as was tumor necrosis factor-α. Macroglial Müller cells maintain the integrity of the blood-retinal barrier, and in ischemic retinopathy, LS reduced their gliosis and also vascular leakage. In retina, LS reduced mineralocorticoid receptor, angiotensin type 1 receptor, and renin mRNA levels, whereas, as expected, plasma levels of aldosterone and renin were increased. The aldosterone/mineralocorticoid receptor-sensitive epithelial sodium channel alpha (ENaCα), which is expressed in Müller cells, was increased in ischemic retinopathy and reduced by LS. In cultured Müller cells, high salt increased ENaCα, which was prevented by mineralocorticoid receptor and angiotensin type 1 receptor blockade. Conversely, LS reduced ENaCα, angiotensin type 1 receptor, and mineralocorticoid receptor expression. An LS diet reduced retinal vasculopathy, by modulating glial cell function and the retinal renin-angiotensin-aldosterone system. © 2014 American Heart Association, Inc.

  1. Acute renal haemodynamic and renin-angiotensin system responses to graded renal artery stenosis in the dog.

    PubMed Central

    Anderson, W P; Johnston, C I; Korner, P I

    1979-01-01

    1. The acute renal haemodynamic and renin-angiotensin system responses to graded renal artery stenosis were studied in chronically instrumented, unanaesthetized dogs. 2. Stenosis was induced over 30 sec by inflation of a cuff around the renal artery to lower distal pressure to 60, 40 or 20 mmHg, with stenosis maintained for 1 hr. This resulted in an immediate fall in renal vascular resistance, but over the next 5--30 min both resistance and renal artery pressure were restored back towards prestenosis values. Only transient increases in systemic arterial blood pressure and plasma renin and angiotensin levels were seen with the two milder stenoses. Despite restoration of renal artery pressure, renal blood flow remained reduced at all grades of stenosis. 3. Pre-treatment with angiotensin I converting enzyme inhibitor or sarosine1, isoleucone8 angiotensin II greatly attenuated or abolished the restoration of renal artery pressure and renal vascular resistance after stenosis, and plasma renin and angiotensin II levels remained high. Renal dilatation was indefinitely maintained, but the normal restoration of resistance and pressure could be simulated by infusing angiotensin II into the renal artery. 4. The effective resistance to blood flow by the stenosis did not remain constant but varied with changes in the renal vascular resistance. PMID:219182

  2. Hesperidin Suppresses Renin-Angiotensin System Mediated NOX2 Over-Expression and Sympathoexcitation in 2K-1C Hypertensive Rats.

    PubMed

    Wunpathe, Chutamas; Potue, Prapassorn; Maneesai, Putcharawipa; Bunbupha, Sarawoot; Prachaney, Parichat; Kukongviriyapan, Upa; Kukongviriyapan, Veerapol; Pakdeechote, Poungrat

    2018-05-13

    Hesperidin, a flavonoid derived from citrus fruits, possesses several beneficial effects including anti-oxidation and anti-inflammation. The aim of this study was to investigate the effects of hesperidin on the renin-angiotensin system (RAS) cascade that mediated oxidative stress and sympathoexcitation in two-kidney, one-clipped (2K-1C) hypertensive rats. 2K-1C hypertension was induced in male Sprague-Dawley rats. Hypertensive rats were treated with hesperidin at 20[Formula: see text]mg/kg or 40[Formula: see text]mg/kg or losartan at 10[Formula: see text]mg/kg beginning at three weeks after surgery and then continued for four weeks ([Formula: see text]/group). Hesperidin reduced blood pressure in a dose-dependent manner in hypertensive rats compared to untreated rats ([Formula: see text]). Increased plasma angiotensin converting enzyme (ACE) activity and angiotensin II levels, as well as, upregulated AT 1 receptor protein expression in aortic tissues were attenuated in hypertensive rats treated with hesperidin. Hesperidin suppressed oxidative stress markers and NADPH oxidase over-expression, and restored plasma nitric oxide metabolites in 2K-1C rats. This was associated with improvement of the vascular response to acetylcholine in isolated mesenteric vascular beds and aortic rings from 2K-1C rats treated with hesperidin ([Formula: see text]). Enhancement of nerve-mediated vasoconstriction related to high plasma noradrenaline in the 2K-1C group was alleviated by hesperidin treatment ([Formula: see text]). Furthermore, losartan exhibited antihypertensive effects by suppressing the RAS cascade and oxidative stress and improved vascular dysfunction observed in 2K-1C rats ([Formula: see text]). Based on these results, it can be presumed that hesperidin is an antihypertensive agent. Its antihypertensive action might be associated with reducing RAS cascade-induced NOX2 over-expression and sympathoexcitation in 2K-1C hypertensive rats.

  3. [Angiotensin converting enzyme 2 and its emerging role in the regulation of the renin angiotensin system].

    PubMed

    Soler, María José; Lloveras, Josep; Batlle, Daniel

    2008-07-12

    The renin-angiotensin system (RAS) plays a key role in the regulation of cardiovascular and renal function. Thus, RAS blockade with an angiotensin-converting enzyme (ACE) and/or angiotensin receptor blocker decreases blood pressure, cardiovascular events, and delays the progression of kidney disease. The discovery of ACE2, a homologue of ACE, capable of degrading angiotensin II to angiotensin 1-7, may offer new insights into the RAS. In this review we discuss the possible protective role of ACE2 in different organs, namely heart, lungs and kidneys. The role of this enzyme is inferred from recent studies performed using genetically manipulated mice that lack the ACE2 gene and also mice treated with pharmacological ACE2 inhibitors. These results suggest that ACE2 might be a new therapeutic target within the RAS.

  4. Renin-angiotensin system within the diabetic podocyte.

    PubMed

    Márquez, Eva; Riera, Marta; Pascual, Julio; Soler, María José

    2015-01-01

    Diabetic kidney disease is the leading cause of end-stage renal disease. Podocytes are differentiated cells necessary for the development and maintenance of the glomerular basement membrane and the capillary tufts, as well as the function of the glomerular filtration barrier. The epithelial glomerular cells express a local renin-angiotensin system (RAS) that varies in different pathological situations such as hyperglycemia or mechanical stress. RAS components have been shown to be altered in diabetic podocytopathy, and their modulation may modify diabetic nephropathy progression. Podocytes are a direct target for angiotensin II-mediated injury by altered expression and distribution of podocyte proteins. Furthermore, angiotensin II promotes podocyte injury indirectly by inducing cellular hypertrophy, increased apoptosis, and changes in the anionic charge of the glomerular basement membrane, among other effects. RAS blockade has been shown to decrease the level of proteinuria and delay the progression of chronic kidney disease. This review summarizes the local intraglomerular RAS and its imbalance in diabetic podocytopathy. A better understanding of the intrapodocyte RAS might provide a new approach for diabetic kidney disease treatment. Copyright © 2015 the American Physiological Society.

  5. Renin Angiotensin Aldosterone System Inhibitors in Hypertension: Is There Evidence for Benefit Independent of Blood Pressure Reduction?

    PubMed

    Bavishi, Chirag; Bangalore, Sripal; Messerli, Franz H

    The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the pathogenesis of hypertension (HTN). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are first line anti-HTN drug classes that are potent, effective and largely safe. Direct renin inhibitors (DRIs) have shown similar blood pressure (BP) reduction but more side effects. The efficacy of ACEIs and ARBs (for cardiovascular, cerebrovascular and renal protection) has been promoted to extend beyond what could be explained by BP reduction alone. In the current review, we will briefly discuss the (1) pathophysiology of renin-angiotensin-aldosterone system (RAAS) system, (2) clinical evidence for ACEIs, ARBs and DRIs in HTN, (3) comparison of ACEIs vs. ARBs and combination therapy, (4) role of RAAS inhibitors in specific patient populations, (5) safety profile of RAAS inhibitors, and (6) guideline recommendations and future perspectives. Closer scrutiny of outcome data shows little, if any, evidence that the efficacy of RAAS blockers in HTN extends beyond BP reduction. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Renal Atp6ap2/(Pro)renin Receptor Is Required for Normal Vacuolar H+-ATPase Function but Not for the Renin-Angiotensin System.

    PubMed

    Trepiccione, Francesco; Gerber, Simon D; Grahammer, Florian; López-Cayuqueo, Karen I; Baudrie, Véronique; Păunescu, Teodor G; Capen, Diane E; Picard, Nicolas; Alexander, R Todd; Huber, Tobias B; Chambrey, Regine; Brown, Dennis; Houillier, Pascal; Eladari, Dominique; Simons, Matias

    2016-11-01

    ATPase H + -transporting lysosomal accessory protein 2 (Atp6ap2), also known as the (pro)renin receptor, is a type 1 transmembrane protein and an accessory subunit of the vacuolar H + -ATPase (V-ATPase) that may also function within the renin-angiotensin system. However, the contribution of Atp6ap2 to renin-angiotensin-dependent functions remains unconfirmed. Using mice with an inducible conditional deletion of Atp6ap2 in mouse renal epithelial cells, we found that decreased V-ATPase expression and activity in the intercalated cells of the collecting duct impaired acid-base regulation by the kidney. In addition, these mice suffered from marked polyuria resistant to desmopressin administration. Immunoblotting revealed downregulation of the medullary Na + -K + -2Cl - cotransporter NKCC2 in these mice compared with wild-type mice, an effect accompanied by a hypotonic medullary interstitium and impaired countercurrent multiplication. This phenotype correlated with strong autophagic defects in epithelial cells of medullary tubules. Notably, cells with high accumulation of the autophagosomal substrate p62 displayed the strongest reduction of NKCC2 expression. Finally, nephron-specific Atp6ap2 depletion did not affect angiotensin II production, angiotensin II-dependent BP regulation, or sodium handling in the kidney. Taken together, our results show that nephron-specific deletion of Atp6ap2 does not affect the renin-angiotensin system but causes a combination of renal concentration defects and distal renal tubular acidosis as a result of impaired V-ATPase activity. Copyright © 2016 by the American Society of Nephrology.

  7. The renin-angiotensin-aldosterone system (RAAS) - physiology and molecular mechanisms of functioning.

    PubMed

    Chaszczewska-Markowska, Monika; Sagan, Maria; Bogunia-Kubik, Katarzyna

    2016-09-13

    Secretion of renin juxtaglomerular cells into bloodstream initiates activation of an enzymatic-hormonal cascade known as the RAAS (renin - angiotensin - aldosterone system). As a result, blood pressure is increased by the means several interrelated mechanisms. Mechanism of Zjednoczoaction of this system has been known for decades, but a few previously unknown components were recently added, such as ACE-2 and Ang(1-7), and their role often seems to be opposite to that of the conventional components. Local tissue systems also have important biological functions. They operate largely independently of the systemic activity, and their activity is observed primarily in the kidney, heart, in blood vessels, adrenal gland and nervous system. Angiotensin-2 (Ang-2), the main RAAS effector, has a wide scope of action, and thus abnormalities in its functioning have many consequences. Excessive activation is accompanied by chronic inflammation, as Ang-2 stimulates inflammatory mediators. As a result, degenerative processes and atherosclerosis are initiated. RAAS imbalance is associated with the most common diseases of civilization, such as cardio-vascular diseases, diabetes, kidney diseases, preeclampsia, osteoporosis and even neurodegenerative diseases. Many of these pathological processes are attributed to the excessive activation of tissue RA system. Therapeutic strategies based on inhibition of the RAAS are commonly used mainly in the treatment of hypertension and other cardiovascular disorders. The benefits of this class of drugs is primarily a decrease in blood pressure, but also the suppression of inflammatory processes and other pathological phenomena resulting from excessive activation of the RAAS. For that reason, some consider to use RAAS inhibitors in other diseases, e.g. Parkinson's disease. Further studies give hope for the improvement of RAAS inhibitor therapy and the development of new therapeutic strategies.

  8. Living high training low induces physiological cardiac hypertrophy accompanied by down-regulation and redistribution of the renin-angiotensin system

    PubMed Central

    Shi, Wei; Meszaros, J Gary; Zeng, Shao-ju; Sun, Ying-yu; Zuo, Ming-xue

    2013-01-01

    Aim: Living high training low” (LHTL) is an exercise-training protocol that refers living in hypoxia stress and training at normal level of O2. In this study, we investigated whether LHTL caused physiological heart hypertrophy accompanied by changes of biomarkers in renin-angiotensin system in rats. Methods: Adult male SD rats were randomly assigned into 4 groups, and trained on living low-sedentary (LLS, control), living low-training low (LLTL), living high-sedentary (LHS) and living high-training low (LHTL) protocols, respectively, for 4 weeks. Hematological parameters, hemodynamic measurement, heart hypertrophy and plasma angiotensin II (Ang II) level of the rats were measured. The gene and protein expression of angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II receptor I (AT1) in heart tissue was assessed using RT-PCR and immunohistochemistry, respectively. Results: LLTL, LHS and LHTL significantly improved cardiac function, increased hemoglobin concentration and RBC. At the molecular level, LLTL, LHS and LHTL significantly decreased the expression of ACE, AGT and AT1 genes, but increased the expression of ACE and AT1 proteins in heart tissue. Moreover, ACE and AT1 protein expression was significantly increased in the endocardium, but unchanged in the epicardium. Conclusion: LHTL training protocol suppresses ACE, AGT and AT1 gene expression in heart tissue, but increases ACE and AT1 protein expression specifically in the endocardium, suggesting that the physiological heart hypertrophy induced by LHTL is regulated by region-specific expression of renin-angiotensin system components. PMID:23377552

  9. Renin-Angiotensin-Aldosterone System Inhibition Increases Podocyte Derivation from Cells of Renin Lineage

    PubMed Central

    Lichtnekert, Julia; Kaverina, Natalya V.; Eng, Diana G.; Gross, Kenneth W.; Kutz, J. Nathan; Pippin, Jeffrey W.

    2016-01-01

    Because adult podocytes cannot proliferate and are therefore unable to self-renew, replacement of these cells depends on stem/progenitor cells. Although podocyte number is higher after renin-angiotensin-aldosterone system (RAAS) inhibition in glomerular diseases, the events explaining this increase are unclear. Cells of renin lineage (CoRL) have marked plasticity, including the ability to acquire a podocyte phenotype. To test the hypothesis that RAAS inhibition partially replenishes adult podocytes by increasing CoRL number, migration, and/or transdifferentiation, we administered tamoxifen to Ren1cCreERxRs-tdTomato-R CoRL reporter mice to induce permanent labeling of CoRL with red fluorescent protein variant tdTomato. We then induced experimental FSGS, typified by abrupt podocyte depletion, with a cytopathic antipodocyte antibody. RAAS inhibition by enalapril (angiotensin-converting enzyme inhibitor) or losartan (angiotensin-receptor blocker) in FSGS mice stimulated the proliferation of CoRL, increasing the reservoir of these cells in the juxtaglomerular compartment (JGC). Compared with water or hydralazine, RAAS inhibition significantly increased the migration of CoRL from the JGC to the intraglomerular compartment (IGC), with more glomeruli containing RFP+CoRL and, within these glomeruli, more RFP+CoRL. Moreover, RAAS inhibition in FSGS mice increased RFP+CoRL transdifferentiation in the IGC to phenotypes, consistent with those of podocytes (coexpression of synaptopodin and Wilms tumor protein), parietal epithelial cells (PAX 8), and mesangial cells (α8 integrin). These results show that in the context of podocyte depletion in FSGS, RAAS inhibition augments CoRL proliferation and plasticity toward three different glomerular cell lineages. PMID:27080979

  10. Complement 3 activates the renal renin-angiotensin system by induction of epithelial-to-mesenchymal transition of the nephrotubulus in mice.

    PubMed

    Zhou, Xueli; Fukuda, Noboru; Matsuda, Hiroyuki; Endo, Morito; Wang, Xiaofei; Saito, Kosuke; Ueno, Takahiro; Matsumoto, Taro; Matsumoto, Koichi; Soma, Masayoshi; Kobayashi, Naohiko; Nishiyama, Akira

    2013-10-01

    We have demonstrated that mesenchymal cells from spontaneously hypertensive rats genetically express complement 3 (C3). Mature tubular epithelial cells can undergo epithelial-to-mesenchymal transition (EMT) that is linked to the pathogenesis of renal fibrosis and injury. In this study, we investigated the contribution of C3 in EMT and in the renal renin-angiotensin (RA) systems associated with hypertension. C3a induced EMT in mouse TCMK-1 epithelial cells, which displayed increased expression of renin and Krüppel-like factor 5 (KLF5) and nuclear localization of liver X receptor α (LXRα). C3 and renin were strongly stained in the degenerated nephrotubulus and colocalized with LXRα and prorenin receptor in unilateral ureteral obstruction (UUO) kidneys from wild-type mice. In C3-deficient mice, hydronephrus and EMT were suppressed, with no expression of renin and C3. After UUO, systolic blood pressure was increased in wild-type but not C3-deficient mice. In wild-type mice, intrarenal angiotensin II (ANG II) levels were markedly higher in UUO kidneys than normal kidneys and decreased with aliskiren. There were no increases in intrarenal ANG II levels after UUO in C3-deficient mice. Thus C3 induces EMT and dedifferentiation of epithelial cells, which produce renin through induction of LXRα. These data indicate for the first time that C3 may be a primary factor to activate the renal RA systems to induce hypertension.

  11. Renin-angiotensin-aldosterone system in normal and hypertensive pregnancy. Response to postural stimuli.

    PubMed

    Fagundes, V G; Lamas, C C; Francischetti, E A

    1992-02-01

    Most studies that have attempted to distinguish pregnancy-induced hypertension from chronic hypertension in pregnancy include arbitrary clinical definitions and morphological reports based on renal biopsy. To evaluate whether these conditions have different responses to stimuli to the renin-angiotensin-aldosterone system, we studied four normal nonpregnant women, eight normal pregnant women, 10 women with pregnancy-induced hypertension, and 14 with chronic hypertension in pregnancy, in the third trimester of pregnancy, after they had sequentially adopted the supine, the left lateral recumbent, and the orthostatic positions for 90 minutes each. Postural maneuvers did not significantly change mean arterial pressure in pregnancy-induced hypertensive or in normal pregnant women, although in chronic hypertensive women, a significant reduction in this parameter was observed in left lateral recumbency. The renin-angiotensin-aldosterone system was significantly less activated with women in the supine position in pregnancy-induced hypertensive and chronic hypertensive women; however, as opposed to pregnancy-induced hypertensive women, those with chronic hypertension reassumed their humoral response to upright posture, which was accompanied by a significant reduction in sodium excretion. The parallelism between plasma renin activity and aldosterone levels, absent in normal pregnancy, returned in pregnancy-induced hypertensive and chronic hypertensive women in the erect posture (r = 0.73, p less than 0.01; r = 0.68, p less than 0.01, respectively). These data suggest that the adoption of the left lateral recumbent position in pregnancy reduces mean arterial pressure only in chronic hypertensive women. Moreover, in chronic hypertension, the upright position provoked a significant response of the renin-angiotensin-aldosterone system. This effect was not observed in women with pregnancy-induced hypertension.

  12. Low Response of Renin-Angiotensin System to Sodium Intake Intervention in Chinese Hypertensive Patients.

    PubMed

    Feng, Weijing; Cai, Qingqing; Yuan, Woliang; Liu, Yu; Bardeesi, Adham Sameer A; Wang, Jingfeng; Chen, Jie; Huang, Hui

    2016-02-01

    The interactions of sodium balance and response of renin-angiotensin-aldosterone system are important for maintaining the hemodynamic stability in physiological conditions. However, the influence of short-term sodium intake intervention in the response of renin-angiotensin system (RAS) on hypertensive patients is still unclear. Thus, we conducted a clinical trial to investigate the effects of short-term sodium intake intervention on the response of RAS in hypertensive patients.One hundred twenty-five primary Chinese hypertensive patients were divided into high, moderate, and low sodium groups by 24-hour urinary sodium excretion (UNa). All the patients received a 10-day dietary sodium intake intervention with standardized sodium (173.91mmol/day) and potassium (61.53mmol/day). Blood pressure, urinary sodium, urinary potassium, plasma sodium, potassium, creatinine, the levels of plasma renin activity, plasma angiotensin II concentrations (AT-II), and plasma aldosterone concentrations were detected before and after the intervention.Before the intervention, no differences were found in blood pressure and RAS among 3 groups. After standardized dietary sodium intake intervention, both UNa excretion and systolic pressure decreased in high-sodium group, while they increased in moderate and low-sodium groups. Intriguingly, there were no changes in the levels of plasma renin activity, AT-II, and plasma aldosterone concentrations among 3 groups during the intervention.The present study demonstrated that the influenced sodium excretion and blood pressure by short-term sodium intake intervention were independent of RAS quick response in Chinese hypertensive patients.

  13. Excessively low salt diet damages the heart through activation of cardiac (pro) renin receptor, renin-angiotensin-aldosterone, and sympatho-adrenal systems in spontaneously hypertensive rats.

    PubMed

    Okamoto, Chihiro; Hayakawa, Yuka; Aoyama, Takuma; Komaki, Hisaaki; Minatoguchi, Shingo; Iwasa, Masamitsu; Yamada, Yoshihisa; Kanamori, Hiromitsu; Kawasaki, Masanori; Nishigaki, Kazuhiko; Mikami, Atsushi; Minatoguchi, Shinya

    2017-01-01

    A high salt intake causes hypertension and leads to cardiovascular disease. Therefore, a low salt diet is now recommended to prevent hypertension and cardiovascular disease. However, it is still unknown whether an excessively low salt diet is beneficial or harmful for the heart. Wistar Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) received normal salt chow (0.9% salt diet) and excessively low salt chow (0.01% salt diet referred to as saltless diet) for 8 weeks from 8 to 16 weeks of age. The effects of the excessively low salt diet on the cardiac (pro) renin receptor, renin-angiotensin-aldosterone, and sympatho-adrenal systems were investigated. The excessively low salt diet did not affect the systolic blood pressure but significantly increased the heart rate both in WKYs and SHRs. The excessively low salt diet significantly elevated plasma renin activity, plasma angiotensin I, II and aldosterone concentrations, and plasma noradrenaline and adrenaline concentrations both in WKYs and SHRs. Cardiac expressions of renin, prorenin, (P)RR, angiotensinogen, and angiotensin II AT1 receptor and phosphorylated (p)-ERK1/2, p-HSP27, p-38MAPK, and TGF-ß1 were significantly enhanced by the excessively low salt diet in both WKYs and SHRs. The excessively low salt diet accelerated cardiac interstitial and perivascular fibrosis and increased the cardiomyocyte size and interventricular septum thickness in WKYs and SHRs but the extent was greater in SHRs. An excessively low salt diet damages the heart through activation of plasma renin-angiotensin-aldosterone and sympatho-adrenal systems and activation of cardiac (P)RR and angiotensin II AT1 receptor and their downstream signals both in WKYs and SHRs.

  14. Common genetic variations of the renin-angiotensin-aldosterone system and response to acute angiotensin I-converting enzyme inhibition in essential hypertension.

    PubMed

    Hannila-Handelberg, Tuula; Kontula, Kimmo K; Paukku, Kirsi; Lehtonen, Jukka Y; Virtamo, Jarmo; Tikkanen, Ilkka; Hiltunen, Timo P

    2010-04-01

    In order to get insight into possible genetic determinants of antihypertensive drug action, we analysed the relations between polymorphisms of the genes of the renin-angiotensin-aldosterone system and acute effects of ACE inhibition on blood pressure as well as circulating renin and aldosterone levels in hypertensive patients. A total of 315 hypertensive patients referred for problems in drug treatment were given a single 50 mg dose of captopril. Plasma renin and aldosterone were measured before and 60 min after the drug administration. Four DNA variants, including angiotensin type I receptor (AGTR1) 1166 A/C, angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and AGT -217 G/A, were genotyped in the patients and normotensive men (n = 175). A replication study on the relation between AGTR1 1166 A/C and plasma renin and aldosterone levels was carried out in the 244 hypertensive men of the pharmacogenetic GENRES Study. Referred hypertensive patients with the AGTR1 CC genotype had higher aldosterone at baseline (P = 0.02) and after 60 min of captopril administration (P = 0.01) compared with the AA genotype. Replicate analysis in the GENRES patients showed a similar trend. When the two studies were combined (315 and 244 patients, respectively), plasma aldosterone level (P = 0.007) as well as aldosterone/renin ratio (P = 0.04) were significantly higher in the CC genotype (n = 13) than in the AA genotype (n = 370). Transfection studies in cultured HEK293 cells indicated that the 1166C allele was associated with higher mRNA levels than the 1166A allele. The AGTR1 1166C allele when present in homozygous form may be associated with a form of essential hypertension characterized by high plasma aldosterone and low plasma renin levels, possibly due to increased AGTR1 mRNA levels and augmented angiotensin II action.

  15. Autonomic, locomotor and cardiac abnormalities in a mouse model of muscular dystrophy: targeting the renin-angiotensin system.

    PubMed

    Sabharwal, Rasna; Chapleau, Mark W

    2014-04-01

    New Findings What is the topic of this review? This symposium report summarizes autonomic, cardiac and skeletal muscle abnormalities in sarcoglycan-δ-deficient mice (Sgcd-/-), a mouse model of limb girdle muscular dystrophy, with emphasis on the roles of autonomic dysregulation and activation of the renin-angiotensin system at a young age. What advances does it highlight? The contributions of the autonomic nervous system and the renin-angiotensin system to the pathogenesis of muscular dystrophy are highlighted. Results demonstrate that autonomic dysregulation precedes and predicts later development of cardiac dysfunction in Sgcd-/- mice and that treatment of young Sgcd-/- mice with the angiotensin type 1 receptor antagonist losartan or with angiotensin-(1-7) abrogates the autonomic dysregulation, attenuates skeletal muscle pathology and increases spontaneous locomotor activity. Muscular dystrophies are a heterogeneous group of genetic muscle diseases characterized by muscle weakness and atrophy. Mutations in sarcoglycans and other subunits of the dystrophin-glycoprotein complex cause muscular dystrophy and dilated cardiomyopathy in animals and humans. Aberrant autonomic signalling is recognized in a variety of neuromuscular disorders. We hypothesized that activation of the renin-angiotensin system contributes to skeletal muscle and autonomic dysfunction in mice deficient in the sarcoglycan-δ (Sgcd) gene at a young age and that this early autonomic dysfunction contributes to the later development of left ventricular (LV) dysfunction and increased mortality. We demonstrated that young Sgcd-/- mice exhibit histopathological features of skeletal muscle dystrophy, decreased locomotor activity and severe autonomic dysregulation, but normal LV function. Autonomic regulation continued to deteriorate in Sgcd-/- mice with age and was accompanied by LV dysfunction and dilated cardiomyopathy at older ages. Autonomic dysregulation at a young age predicted later development of

  16. The Renin-Angiotensin-Aldosterone System (RAAS) and Cardiac Arrhythmias

    PubMed Central

    Iravanian, Shahriar; Dudley, Samuel C.

    2008-01-01

    The role of the renin-angiotensin-aldosterone system (RAAS) in many cardiovascular disorders, including hypertension, cardiac hypertrophy, and atherosclerosis is well established, whereas its relationship with cardiac arrhythmias is a new area of investigation. Atrial fibrillation and malignant ventricular tachyarrhythmias, especially in the setting of cardiac hypertrophy or failure, appear to be examples of RAAS-related arrhythmias, since treatment with RAAS modulators, including angiotensin converting enzyme inhibitors, angiotensin receptor blockers and mineralocorticoid receptor blockers, reduces the incidence of these arrhythmias. RAAS has a multitude of electrophysiological effects and can potentially cause arrhythmia through a variety of mechanisms. We review new experimental results that suggest RAAS has pro-arrhythmic effects on membrane and sarcoplasmic reticulum ion channels and that increased oxidative stress is likely contributing to the increased arrhythmic incidence. A summary of ongoing clinical trials that will address the clinical usefulness of RAAS modulators for prevention or treatment of arrhythmias is presented. PMID:18456194

  17. The renin-angiotensin-aldosterone system (RAAS) and cardiac arrhythmias.

    PubMed

    Iravanian, Shahriar; Dudley, Samuel C

    2008-06-01

    The role of the renin-angiotensin-aldosterone system (RAAS) in many cardiovascular disorders, including hypertension, cardiac hypertrophy, and atherosclerosis, is well established, whereas its relationship with cardiac arrhythmias is a new area of investigation. Atrial fibrillation and malignant ventricular tachyarrhythmias, especially in the setting of cardiac hypertrophy or failure, seem to be examples of RAAS-related arrhythmias because treatment with RAAS modulators, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor blockers, reduces the incidence of these arrhythmias. RAAS has a multitude of electrophysiological effects and can potentially cause arrhythmia through a variety of mechanisms. We review new experimental results that suggest that RAAS has proarrhythmic effects on membrane and sarcoplasmic reticulum ion channels and that increased oxidative stress is likely contributing to the increased arrhythmic incidence. A summary of ongoing clinical trials that will address the clinical usefulness of RAAS modulators for prevention or treatment of arrhythmias is presented.

  18. Chronobiology and Pharmacologic Modulation of the Renin-Angiotensin-Aldosterone System in Dogs: What Have We Learned?

    PubMed

    Mochel, Jonathan P; Danhof, Meindert

    2015-01-01

    Congestive heart failure (CHF) is a primary cause of morbidity and mortality with an increasing prevalence in human and canine populations. Recognition of the role of renin-angiotensin-aldosterone system (RAAS) overactivation in the pathophysiology of CHF has led to significant medical advances. By decreasing systemic vascular resistance and angiotensin II (AII) production, angiotensin-converting enzyme (ACE) inhibitors such as benazepril improve cardiac hemodynamics and reduce mortality in human and dog CHF patients. Although several experiments have pointed out that efficacy of ACE inhibitors depends on the time of administration, little attention is paid to the optimum time of dosing of these medications. A thorough characterization of the chronobiology of the renin cascade has the potential to streamline the therapeutic management of RAAS-related diseases and to help determining the optimal time of drug administration that maximizes efficacy of ACE inhibitors, while minimizing the occurrence of adverse effects. We have developed an integrated pharmacokinetic-pharmacodynamic model that adequately captures the disposition kinetics of the paradigm drug benazeprilat, as well as the time-varying changes of systemic renin-angiotensin-aldosterone biomarkers, without and with ACE inhibition therapy. Based on these chronobiological investigations, the optimal efficacy of ACE inhibitors is expected with bedtime dosing. The data further show that benazepril influences the dynamics of the renin-angiotensin-aldosterone cascade, resulting in a profound decrease in AII and aldosterone (ALD), while increasing renin activity for about 24 h. From the results of recent investigations in human, it is hypothesized that reduction of AII and ALD is one of the drivers of increased survival and improved quality of life in dogs receiving ACE inhibitors. To support and consolidate this hypothesis, additional efforts should be directed toward the collection of circulating RAAS peptides

  19. [The changes in renin-angiotensin-aldosterone-system in different subtypes of Cushing's syndrome].

    PubMed

    Cui, Jia; Dou, Jingtao; Yang, Guoqing; Zang, Li; Jin, Nan; Chen, Kang; Du, Jin; Gu, Weijun; Wang, Xianling; Yang, Lijuan; Lyu, Zhaohui; Ba, Jianming; Mu, Yiming; Lu, Juming; Li, Jiangyuan; Pan, Changyu

    2015-07-01

    Cushing's syndrome is a clinical condition resulting from chronic exposure to excess glucocorticoid. As a consequence, long-term hypercortisolism contributes significantly to the development of systemic disorders by direct and/or indirect effects. The present study was to analyze the changes of renin-angiotensin-aldosterone-system in different subtypes of Cushing's syndrome on the standard posture test. We retrospectively reviewed 150 patients with histologically confirmed Cushing's syndrome treated at the PLA General Hospital between 2002 and 2014. Among them, 128 patients were diagnosed as adreno-cortico-tropic-hormone (ACTH)-independent Cushing's syndrome, and 22 were ACTH-dependent Cushing's syndrome. All patients were undertaken the posture test. Plasma renin activity (PRA), angiotensin II, plasma aldosterone concertration (PAC) levels were measured before and after the test. Basal plasma PRA [0.5 (0.2,1.3)µg·L(-1)·h(-1), angiotensin II [(48.9±20.1) ng/L] and PAC [(285.0±128.1) pmol/L] levels were within the normal range in supine position. Compared with the subjects with ACTH-independent Cushing's syndrome, the basal PAC levels were higher in subjects with ACTH-dependent Cushing's syndrome [(348.0±130.4) pmol/L vs (274.2±125.0) pmol/L, P<0.05]. However, the PAC response in subjects with ACTH-dependent Cushing's syndrome [(49.7±26.4)%] was significantly lower than that in those with ACTH-independent Cushing's syndrome [(81.2±69.3)%] upon upright posture stimulation (P<0.05). There were no statistical significances in PRA and angiotensin II levels between the two groups. The basal PAC and PRA levels were positively correlated with ACTH, whereas PAC response was negatively correlated with ACTH. The renin-angiotensin-aldosterone-system activity in subjects with Cushing's syndrome was similar to that in normal control. The basal PAC level and its response to upright posture are differently associated with ACTH level in Cushing's syndrome.

  20. Biomarkers of activation of renin-angiotensin-aldosterone system in heart failure: how useful, how feasible?

    PubMed

    Emdin, Michele; Fatini, Cinzia; Mirizzi, Gianluca; Poletti, Roberta; Borrelli, Chiara; Prontera, Concetta; Latini, Roberto; Passino, Claudio; Clerico, Aldo; Vergaro, Giuseppe

    2015-03-30

    Renin-angiotensin-aldosterone system (RAAS), participated by kidney, liver, vascular endothelium, and adrenal cortex, and counter-regulated by cardiac endocrine function, is a complex endocrine system regulating systemic functions, such as body salt and water homeostasis and vasomotion, in order to allow the accomplishment of physiological tasks, such as orthostasis, physical and emotional stimuli, and to react towards the hemorrhagic insult, in tight conjunction with other neurohormonal axes, namely the sympathetic nervous system, the endothelin and vasopressin systems. The systemic as well as the tissue RAAS are also dedicated to promote tissue remodeling, particularly relevant after damage, when chronic activation may configure as a maladaptive response, leading to fibrosis, hypertrophy and apoptosis, and organ dysfunction. RAAS activation is a fingerprint of systemic arterial hypertension, kidney dysfunction, vascular atherosclerotic disease, and is definitely an hallmark of heart failure, which rapidly shifts from organ disease to a disorder of neurohormonal regulatory systems. Chronic RAAS activation is an indirect or direct target of most effective pharmacological treatments in heart failure, such as beta-blockers, inhibitors of angiotensin converting enzyme, angiotensin receptor blockers, direct renin inhibitors, and mineralocorticoid receptor blockers. Biomarkers of RAAS activation are available, with different feasibility and accuracy, such as plasma renin activity, renin, angiotensin II, and aldosterone, which all accompany the increasing clinical severity of heart failure disease, and are well recognized prognostic factors, even in patients with optimal therapy. Polymorphisms influencing the expression and activity of RAAS pathways have been recognized as clinically relevant biomarkers, likely influencing either the individual clinical phenotype, or the response to drugs. This solid, growing evidence strongly suggests the rationale for the use of

  1. High maternal sodium intake alters sex-specific renal renin-angiotensin system components in newborn Wistar offspring.

    PubMed

    Maia, D R R; Lopes, K L; Heimann, J C; Furukawa, L N S

    2016-01-28

    This study aimed to evaluate the systemic and renal renin-angiotensin-aldosterone system (RAAS) at birth in male and female offspring and in mothers fed a high sodium diet (HSD) before and during gestation. Female Wistar rats were fed a HSD (8.0% NaCl) or a normal sodium diet (1.3% NaCl) from 8 weeks of age until delivery of their first litter. Maternal body weight, tail blood pressure, and food and water intake were evaluated. The litter sizes were assessed, and the body and kidney weights of the offspring were measured. Both mothers and offspring were euthanized immediately following the birth of the pups to evaluate plasma renin activity (PRA), renal renin content (RRC), renal angiotensin-converting enzyme (ACE) activity, renal angiotensin (Ang) II content, serum aldosterone (ALDO) levels, and renal cortical and medullary renin messenger RNA expression. In mothers in the HSD group, water intake and kidney mass were higher, whereas renal ACE activity, Ang II, PRA, ALDO and RRC were decreased. In the offspring of HSD-fed dams, the body and kidney mass were lower in both genders, renal ACE activity was lower in females and renal Ang II was lower in males. PRA, RRC, renin gene expression and ALDO levels did not differ between the groups of offspring. The data presented herein showed that a maternal HSD during pregnancy induces low birth weight and a sex-specific response in the RAAS in offspring.

  2. Intrarenal renin-angiotensin system mediates fatty acid-induced ER stress in the kidney

    PubMed Central

    Li, Chunling; Lin, Yu; Luo, Renfei; Chen, Shaoming; Zheng, Peili; Levi, Moshe; Yang, Tianxin; Wang, Weidong

    2015-01-01

    Obesity-related kidney disease is related to caloric excess promoting deleterious cellular responses. Accumulation of saturated free fatty acids in tubular cells produces lipotoxicity involving significant cellular dysfunction and injury. The objectives of this study were to elucidate the role of renin-angiotensin system (RAS) activation in saturated fatty acid-induced endoplasmic reticulum (ER) stress in cultured human proximal tubule epithelial cells (HK2) and in mice fed with a high-fat diet. Treatment with saturated fatty acid palmitic acid (PA; 0.8 mM) for 24 h induced ER stress in HK2, leading to an unfolded protein response as reflected by increased expressions of the ER chaperone binding immunoglobulin protein (BiP) and proapoptotic transcription factor C/EBP homologous protein (CHOP) protein as evaluated by immunoblotting. PA treatment also induced increased protein expression of inositol requiring protein 1α (IRE1α), phosphorylated eukaryotic initiation factor-α (eIF2α), and activating transcription factor 4 (ATF4) as well as activation of caspase-3. PA treatment was associated with increased angiotensin II levels in cultured medium. The angiotensin II type 1 receptor (AT1R) blocker valsartan or renin inhibitor aliskiren dramatically suppressed PA-induced upregulation of BiP, CHOP, IRE1α, p-eIF2α, and ATF4 in HK2 cells. In contrast, valsartan or aliskiren did not prevent ER stress induced by tunicamycin. C57BL/6 mice fed with a high-fat diet for 14 wk exhibited increased protein expressions of BiP and CHOP compared with control mice, which were significantly attenuated by the valsartan treatment. Increased angiotensin II levels in serum and urine were observed in mice fed with a high-fat diet when compared with controls. It is suggested that the intrarenal RAS activation may play an important role in diabetic kidney injury via mediating ER stress induced by saturated fatty acid. PMID:26672616

  3. Collecting Duct Nitric Oxide Synthase 1ß Activation Maintains Sodium Homeostasis During High Sodium Intake Through Suppression of Aldosterone and Renal Angiotensin II Pathways.

    PubMed

    Hyndman, Kelly A; Mironova, Elena V; Giani, Jorge F; Dugas, Courtney; Collins, Jessika; McDonough, Alicia A; Stockand, James D; Pollock, Jennifer S

    2017-10-24

    During high sodium intake, the renin-angiotensin-aldosterone system is downregulated and nitric oxide signaling is upregulated in order to remain in sodium balance. Recently, we showed that collecting duct nitric oxide synthase 1β is critical for fluid-electrolyte balance and subsequently blood pressure regulation during high sodium feeding. The current study tested the hypothesis that high sodium activation of the collecting duct nitric oxide synthase 1β pathway is critical for maintaining sodium homeostasis and for the downregulation of the renin-angiotensin-aldosterone system-epithelial sodium channel axis. Male control and collecting duct nitric oxide synthase 1β knockout (CDNOS1KO) mice were placed on low, normal, and high sodium diets for 1 week. In response to the high sodium diet, plasma sodium was significantly increased in control mice and to a significantly greater level in CDNOS1KO mice. CDNOS1KO mice did not suppress plasma aldosterone in response to the high sodium diet, which may be partially explained by increased adrenal AT1R expression. Plasma renin concentration was appropriately suppressed in both genotypes. Furthermore, CDNOS1KO mice had significantly higher intrarenal angiotensin II with high sodium diet, although intrarenal angiotensinogen levels and angiotensin-converting enzyme activity were similar between knockout mice and controls. In agreement with inappropriate renin-angiotensin-aldosterone system activation in the CDNOS1KO mice on a high sodium diet, epithelial sodium channel activity and sodium transporter abundance were significantly higher compared with controls. These data demonstrate that high sodium activation of collecting duct nitric oxide synthase 1β signaling induces suppression of systemic and intrarenal renin-angiotensin-aldosterone system, thereby modulating epithelial sodium channel and other sodium transporter abundance and activity to maintain sodium homeostasis. © 2017 The Authors. Published on behalf of the

  4. Effector peptides of the renin-angiotensin system in the central mechanisms of acquired and innate behavior in thirst in rats.

    PubMed

    Vlasenko, R Ya; Kotov, A V

    2007-03-01

    We report here a comparative analysis of the involvement of a number of components of the renin-angiotensin system in the performance of simple and complex forms of drinking behavior and thirst-associated non-drinking types of behavior. On central (intracerebroventricular) microinjection, [des-Asp1]-angiotensin I at doses equieffective to those of angiotensins II and III was found to be involved only in the performance of simple (taking water from the bowl) and linked forms of activity (comfort behavior, stress grooming, orientational-investigative, and feeding behavior). Angiotensin II was involved in the central mechanisms of complex acquired drinking behavior, selectively modulating its key stages (initial, final), while angiotensin III was involved only in the mechanisms of reproduction of the complex skill. All three substances induced "innate patterns of behavior" specific for each compound, these occurring at fixed periods of time after intracerebral microinjection. The effects of these substances were selectively suppressed by the AT1 receptor blocker losartan potassium.

  5. [Renin-angiotensin-aldosterone system (RAAS) and its pharmacologic modulation].

    PubMed

    Giestas, Anabela; Palma, Isabel; Ramos, Maria Helena

    2010-01-01

    The renin-angiotensin-aldosterone system (RAAS) is a neuroendocrine complex system that regulates the modulation of salt and water homeostasis, and regulation of blood pressure. Through its multiple interactions it protects the endothelium, heart, brain and kidney. In addition, the RAAS regulates the vascular response to injury and inflammation. Chronic activation/dysregulation of the RAAS leads to hypertension and perpetuates a cascade of proinflammatory, prothrombotic and atherogenic effects associated with endorgan damage (heart, brain, kidney, endothelium). Consequently, the RAAS is an important therapeutic target in these situations. This article presents an overview of physiology, pathophysiology and pharmacologic modulation of the RAAS.

  6. Fenoterol stimulates human erythropoietin production via activation of the renin angiotensin system.

    PubMed

    Freudenthaler, S M; Schenck, T; Lucht, I; Gleiter, C H

    1999-10-01

    The present study assessed the hypothesis that the beta2 sympathomimetic fenoterol influences the production of erythropoietin (EPO) by activation of the renin angiotensin system (RAS), i.e. angiotensin II. In an open, parallel, randomized study healthy volunteers received i.v. either placebo (electrolyte solution), fenoterol or fenoterol in combination with an oral dose of the AT1-receptor antagonist losartan. Compared with placebo treatment AUCEPO(0,24 h) was significantly increased after fenoterol application by 48% whereas no increase in the group receiving fenoterol and losartan could be detected. The rise of PRA was statistically significant under fenoterol and fenoterol plus lorsartan. Stimulation of EPO production during fenoterol infusion appears to be angiotensin II-mediated. Thus, angiotensin II may be considered as one important physiological modulator of EPO production in humans.

  7. Success and failure of vaccines against renin-angiotensin system components.

    PubMed

    Brown, Morris J

    2009-10-01

    Therapeutic vaccination pre-dated modern drugs as a possible strategy for treating hypertension. This approach is now being rediscovered, through use of modified angiotensins as immunogens together with carriers and adjuvants. Effective blockade of the renin-angiotensin system (RAS) with treatment twice a year might suit patients who dislike taking drugs on a daily basis and would also be an attractive option for those who have blood pressures in the prehypertensive range, if it can prevent hypertension itself from developing. Proof of concept with a vaccine whose efficacy is easy to measure will encourage development of further vaccines directed against targets such as aldosterone or other pathways where alternative treatments are scarce or absent. Two angiotensin-based vaccines are currently in development: PMD3117 comprises modified angiotensin I coupled to keyhole limpet hemocyanin, and Cyt006-AngQb is a conjugate of angiotensin II linked to virus particles. Early phase II studies in patients with hypertension demonstrated some efficacy, but the vaccines are not as effective as existing inhibitors of the RAS. Large studies now in progress will establish whether further modification of the immunogen or adjuvant is required to boost antibody titers.

  8. Dual renin-angiotensin system blockade plus oral methylprednisone for the treatment of proteinuria in IgA nephropathy.

    PubMed

    Trimarchi, Hernán; Muryan, Alexis; Young, Pablo; Forrester, Mariano; Iotti, Alejandro; Pereyra, Horacio; Lombi, Fernando; Seminario, Omar; Alonso, Mirta; Iotti, Roberto

    2007-01-01

    Renin-angiotensin system inhibition is a widely accepted approach to initially deal with proteinuria in IgA nephropathy, while the role of immunosuppressants remains controversial in many instances. A prospective, uncontrolled, open-label trial was undertaken in patients with biopsy-proven IgA nephropathy with proteinuria > 0.5 g/day and normal renal function to assess the efficacy of a combination treatment of angiotensin converting enzyme inhibitors plus angiotensin receptor blockers enalapril valsartan coupled with methylprednisone to decrease proteinuria to levels below 0.5 g/day. Twenty patients were included: Age 37.45 +/- 13.26 years (50% male); 7 patients (35%) were hypertensive; proteinuria 2.2 +/- 1.86 g/day; serum creatinine 1.07 +/- 0.29 mg/dl; mean follow-up 60.10 +/- 31.47 months. IgA nephropathy was subclassified according to Haas criteria. Twelve patients (60%) were class II; seven (35%) were class III and one (5%) class V. All patients received dual renin-angiotensin system blockade as tolerated. Oral methylprednisone was started at 0.5 mg/kg/day for the initial 8 weeks and subsequently tapered bi-weekly until the maintenance dose of 4 mg was reached. Oral steroids were discontinued after 24 weeks (6 months) of therapy but renin-angiotensin inhibition remained unchanged. At 10 weeks of therapy proteinuria decreased to 0.15 +/- 0.07 g/day (P < 0.001) while serum creatinine did not vary: 1.07 +/- 0.28 mg/dl (P = ns). After a mean follow-up of 42.36 +/- 21.56 months urinary protein excretion (0.12 +/- 0.06 g/day) and renal function (serum creatinine 1.06 +/- 0.27 mg/dl) remained stable. No major side effects were reported during the study. Renin-angiotensin blockade plus oral steroids proved useful to significantly decrease proteinuria to < 0.5 g/day in patients with IgA nephropathy without changes in renal function.

  9. Effect of all-trans retinoic acid treatment on prohibitin and renin-angiotensin-aldosterone system expression in hypoxia-induced renal tubular epithelial cell injury.

    PubMed

    Zhou, Tian-Biao; Ou, Chao; Rong, Liang; Drummen, Gregor P C

    2014-09-01

    All-trans retinoic acid (ATRA) exerts various effects on physiological processes such as cell growth, differentiation, apoptosis and inflammation. Prohibitins (PHB), including prohibitin 1 (PHB1) and prohibitin 2 (PHB2), are evolutionary conserved and pleiotropic proteins implicated in various cellular functions, including proliferation, tumor suppression, apoptosis, transcription, and mitochondrial protein folding. The renin-angiotensin-aldosterone system plays a pivotal role in the regulation of blood pressure and volume homeostasis. All these factors and systems have been implicated in renal interstitial fibrosis. Therefore, the objective of this study was to investigate the effect of ATRA treatment on the renin-angiotensin-aldosterone system and expression of prohibitins to further understand its role in the processes leading to renal interstitial fibrosis. The hypoxic and oxidative stress conditions in obstructive renal disease were simulated in a hypoxia/reoxygenation model with renal tubular epithelial cells (RTEC) as a model system. Subsequently, the effect of ATRA on mRNA and protein expression levels was determined and correlations were established between factors involved in the renin-angiotensin-aldosterone system, the prohibitins, cellular redox status, renal interstitial fibrosis and ATRA treatment. Correlation analysis showed that both PHB1 and PHB2 protein levels were negatively correlated with angiotensin I, ACE1, angiotensin II, TGF-β1, Col-IV, FN, ROS, and MDA (PHB1: r = -0.792, -0.834, -0.805, -0.795, -0.778, -0.798, -0.751, -0.682; PHB2: r = -0.872, -0.799, -0.838, -0.773, -0.769, -0.841, -0.794, -0.826; each p < 0.05), but positively correlated with ACE2, SOD, and GSH (PHB1: r = 0.796, 0.879, 0.824; PHB2: r = 0.785, 0.914, 0.849; each p < 0.05). ACE1 was positively correlated with angiotensin I, angiotensin II, TGF-β1, Col-IV, FN, ROS, and MDA, and negatively correlated with ACE2, SOD, and GSH (each p < 0.05). ACE2 was negatively correlated

  10. [Estimation of the renin-angiotensin-aldosterone system, water and electrolyte imbalance and endothelial function in newborns of women with chronic hypertension].

    PubMed

    Chistiakova, G N; Gazieva, I A; Rmizova, I I

    2015-01-01

    The aim of this study was to evaluate the parameters of renin-angiotensin-aldosterone system, natriuretic peptides, and markers of endothelial function in the early neonatal period and at the age of 3 months in 83 full-term infants of women with chronic hypertension, there were: 60 newborns from women with chronic hypertension of mild to moderate severity (main group) and 23 newborns from women without hypertension (comparison group). The levels of the renin angiotensin-II, aldosterone, natriuretic peptides, endothelin-1, in cord and peripheral blood were determined by immunoassay, the metabolites of stable oxide nitric--by Griess method. The newborn of women with chronic hypertension showed a significant elevation of renin, angiotensin II and brain natriuretic peptide at birth. A statistically significant increase in concentration of atrial natriuretic peptide (aANP1-28) was determined to the 3-5 days of life. Significantly high levels of renin, angiotensin II, endothelin-1 and decreased levels of endogenous nitrite at the age of 3 months of life was found. The results findings suggest that prenatal activation of the renin-angiotensin-aldosterone system of the fetus, continuing to be in the newborn of women with chronic hypertension during the first three months of life. The same infants have the violation of endothelial function to 3 months of age.

  11. The Non-Classical Renin-Angiotensin System and Renal Function

    PubMed Central

    Chappell, Mark C.

    2014-01-01

    The renin-angiotensin-system (RAS) constitutes one of the most important hormonal systems in the physiological regulation of blood pressure through renal and non-renal mechanisms. Indeed, dysregulation of the RAS is considered a major factor in the development of cardiovascular pathologies including kidney injury and blockade of this system by the inhibition of angiotensin converting enzyme (ACE) or blockade of the angiotensin type 1 receptor (AT1R) by selective antagonists constitutes an effective therapeutic regimen. It is now apparent with the identification of multiple components of the RAS within the kidney and other tissues that the system is actually composed of different angiotensin peptides with diverse biological actions mediated by distinct receptor subtypes. The classic RAS can be defined as the ACE-Ang II AT1R axis that promotes vasoconstriction, water intake, sodium retention and other mechanisms to maintain blood pressure, as well as increase oxidative stress, fibrosis, cellular growth and inflammation in pathological conditions. In contrast, the non-classical RAS composed primarily of the AngII/Ang III–AT2R pathway and the ACE2-Ang-(1-7)-AT7R axis generally opposes the actions of a stimulated Ang II-AT1R axis through an increase in nitric oxide and prostaglandins and mediates vasodilation, natriuresis, diuresis, and a reduced oxidative stress. Moreover, increasing evidence suggests that these non-classical RAS components contribute to the therapeutic blockade of the classical system to reduce blood pressure and attenuate various indices of renal injury, as well as contribute to normal renal function. PMID:23720263

  12. The Adipose Renin-Angiotensin System Modulates Systemic Markers of Insulin Sensitivity and Activates the Intrarenal Renin-Angiotensin System

    DOE PAGES

    Kim, Suyeon; Soltani-Bejnood, Morvarid; Quignard-Boulange, Annie; ...

    2006-01-01

    Background . The adipose tissue renin-angiotensin system (RAS) contributes to regulation of fat mass and may also impact systemic functions such as blood pressure and metabolism. Methods and results . A panel of mouse models including mice lacking angiotensinogen, Agt ( Agt -KO), mice expressing Agt solely in adipose tissue (aP2- Agt/Agt -KO), and mice overexpressing Agt in adipose tissue (aP2- Agt ) was studied. Total body weight, epididymal fat pad weight, and circulating levels of leptin, insulin, and resistin were significantly decreased in Agt -KO mice, while plasma adiponectin levels were increased. aP2- Agt mice exhibited increased adiposity andmore » plasma leptin and insulin levels compared to wild type (WT) controls. Angiotensinogen and type I Ang II receptor protein levels were also elevated in kidney of aP2- Agt mice. Conclusion . These findings demonstrate that alterations in adipose RAS activity significantly impact both local and systemic physiology in a way that may contribute to the detrimental health effects of obesity.« less

  13. Prorenin induces ERK activation in endothelial cells to enhance neovascularization independently of the renin-angiotensin system

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Uraoka, Maki; Ikeda, Koji, E-mail: ikedak@koto.kpu-m.ac.jp; Nakagawa, Yusuke

    Prorenin is an enzymatically inactive precursor of renin, and its biological function in endothelial cells (ECs) is unknown despite its relevance with the incidence of diabetic microvascular complications. Recently, (pro)renin receptor was identified, and the receptor-associated prorenin system has been discovered, whereas its expression as well as function in ECs remain unclear. In the present study, we found that ECs express the (pro)renin receptor, and that prorenin provoked ERK activation through (pro)renin receptor independently of the renin-angiotensin system (RAS). Prorenin stimulated the proliferation, migration and tube-formation of ECs, while it inhibited endothelial apoptosis induced by serum and growth factor depletion.more » MEK inhibitor abrogated these proangiogenic effects of prorenin, while AT1 receptor antagonist or angiotensin-converting enzyme inhibitor failed to block them. In vivo neovascularization in the Matrigel-plugs implanted into mouse flanks was significantly enhanced by prorenin, in which significant ERK activation was detected in ECs. Furthermore, tumor xenografts stably transfected with prorenin demonstrated the significantly accelerated growth rate concomitantly with enhanced intratumoral neovascularization. Our data demonstrated that the RAS-independent (pro)renin receptor-mediated signal transduction plays a pivotal role in the regulation of ECs function as well as in the neovascularization, and thus prorenin is potentially involved in the pathophysiology of diabetic microvascular complications as well as cancers.« less

  14. Fenoterol stimulates human erythropoietin production via activation of the renin angiotensin system

    PubMed Central

    Freudenthaler, S M; Schenck, T; Lucht, I; Gleiter, C H

    1999-01-01

    Aims The present study assessed the hypothesis that the β2 sympathomimetic fenoterol influences the production of erythropoietin (EPO) by activation of the renin angiotensin system (RAS), i.e. angiotensin II. Methods In an open, parallel, randomized study healthy volunteers received i.v. either placebo (electrolyte solution), fenoterol or fenoterol in combination with an oral dose of the AT1-receptor antagonist losartan. Results Compared with placebo treatment AUCEPO(0,24 h) was significantly increased after fenoterol application by 48% whereas no increase in the group receiving fenoterol and losartan could be detected. The rise of PRA was statistically significant under fenoterol and fenoterol plus lorsartan. Conclusions Stimulation of EPO production during fenoterol infusion appears to be angiotensin II-mediated. Thus, angiotensin II may be considered as one important physiological modulator of EPO production in humans. PMID:10583037

  15. New approaches to hyperkalemia in patients with indications for renin angiotensin aldosterone inhibitors: Considerations for trial design and regulatory approval.

    PubMed

    Zannad, Faiez; Rossignol, Patrick; Stough, Wendy Gattis; Epstein, Murray; Alonso Garcia, Maria de Los Angeles; Bakris, George L; Butler, Javed; Kosiborod, Mikhail; Berman, Lance; Mebazaa, Alexandre; Rasmussen, Henrik S; Ruilope, Luis M; Stockbridge, Norman; Thompson, Aliza; Wittes, Janet; Pitt, Bertram

    2016-08-01

    Hyperkalemia is a common clinical problem, especially in patients with chronic kidney disease, diabetes mellitus, or heart failure. Treatment with renin angiotensin aldosterone system inhibitors exacerbates the risk of hyperkalemia in these patients. Concern about hyperkalemia can result in the failure to initiate, suboptimal dosing, or discontinuation of renin angiotensin aldosterone system inhibitor therapy in patients; effective treatments for hyperkalemia might mitigate such undertreatment. New treatments for hyperkalemia in development may offer better efficacy, tolerability and safety profiles than do existing approved treatments. These compounds might enable more eligible patients to receive renin angiotensin aldosterone system inhibitor therapy or to receive renin angiotensin aldosterone system inhibitors at target doses. The evidence needed to support a treatment claim (reduction in serum potassium) differs from that needed to support a prevention claim (preventing hyperkalemia to allow renin angiotensin aldosterone system inhibitor treatment). Thus, several issues related to clinical trial design and drug development need to be considered. This paper summarizes and expands upon a discussion at the Global Cardiovascular Clinical Trialists 2014 Forum and examines methodologic considerations for trials of new potassium binders for the prevention and management of hyperkalemia in patients with renin angiotensin aldosterone system inhibitor indications. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. Treatment with patiromer decreases aldosterone in patients with chronic kidney disease and hyperkalemia on renin-angiotensin system inhibitors.

    PubMed

    Weir, Matthew R; Bakris, George L; Gross, Coleman; Mayo, Martha R; Garza, Dahlia; Stasiv, Yuri; Yuan, Jinwei; Berman, Lance; Williams, Gordon H

    2016-09-01

    Elevated serum aldosterone can be vasculotoxic and facilitate cardiorenal damage. Renin-angiotensin system inhibitors reduce serum aldosterone levels and/or block its effects but can cause hyperkalemia. Patiromer, a nonabsorbed potassium binder, decreases serum potassium in patients with chronic kidney disease on renin-angiotensin system inhibitors. Here we examined the effect of patiromer treatment on serum aldosterone, blood pressure, and albuminuria in patients with chronic kidney disease on renin-angiotensin system inhibitors with hyperkalemia (serum potassium 5.1-6.5 mEq/l). We analyzed data from the phase 3 OPAL-HK study (4-week initial treatment phase of 243 patients; 8-week randomized withdrawal phase of 107 patients). In the treatment phase, the (mean ± standard error) serum potassium was decreased concordantly with the serum aldosterone (-1.99 ± 0.51 ng/dl), systolic/diastolic blood pressure (-5.64 ± 1.04 mm Hg/-3.84 ± 0.69 mm Hg), and albumin-to-creatinine ratio (-203.7 ± 54.7 mg/g), all in a statistically significant manner. The change in the plasma renin activity (-0.44 ± 0.63 μg/l/hr) was not significant. In the withdrawal phase, mean aldosterone levels were sustained with patiromer (+0.23 ± 1.07 ng/dl) and significantly increased with placebo (+2.78 ± 1.25 ng/dl). Patients on patiromer had significant reductions in mean systolic/diastolic blood pressure (-6.70 ± 1.59/-2.15 ± 1.06 mm Hg), whereas those on placebo did not (-1.21 ± 1.89 mm Hg/+1.72 ± 1.26 mm Hg). Significant changes in plasma renin activity were found only in the placebo group (-3.90 ± 1.41 μg/l/hr). Thus, patiromer reduced serum potassium and aldosterone levels independent of plasma renin activity in patients with chronic kidney disease and hyperkalemia on renin-angiotensin system inhibitors. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  17. Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin-angiotensin system inhibitors in the community increases the risk of acute kidney injury.

    PubMed

    Dreischulte, Tobias; Morales, Daniel R; Bell, Samira; Guthrie, Bruce

    2015-08-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of acute kidney injury (AKI) when used in triple combination with renin-angiotensin system inhibitors and diuretics, but previous research reported that NSAIDs in dual combinations with either renin-angiotensin system inhibitors or diuretics alone were not. However, earlier studies relied on hospital coding to define AKI, which may underestimate true risk. This nested case-control study characterized the risk of community-acquired AKI associated with NSAID use among 78,379 users of renin-angiotensin system inhibitors and/or diuretics, where AKI was defined as a 50% or greater increase in creatinine from baseline. The AKI incidence was 68/10,000 person-years. The relative increase in AKI risk was similar for NSAID use in both triple (adjusted rate ratio 1.64 (95% CI 1.25-2.14)) and dual combinations with either renin-angiotensin system inhibitors (1.60 (1.18-2.17)) or diuretics (1.64 (1.17-2.29)). However, the absolute increase in AKI risk was higher for NSAIDs used in triple versus dual combinations with renin-angiotensin system inhibitors or diuretics alone (numbers needed to harm for 1 year treatment with NSAID of 158 vs. over 300). AKI risk was highest among users of loop diuretic/aldosterone antagonist combinations, in those over 75 years of age, and in those with renal impairment. Thus, the nephrotoxic potential of both dual and triple combinations of NSAIDs with renin-angiotensin system inhibitors and/or diuretics yields a higher incidence of AKI than previously thought.

  18. Long-term systemic angiotensin II type 1 receptor blockade regulates mRNA expression of dorsomedial medulla renin-angiotensin system components.

    PubMed

    Gilliam-Davis, Shea; Gallagher, Patricia E; Payne, Valerie S; Kasper, Sherry O; Tommasi, Ellen N; Westwood, Brian M; Robbins, Michael E; Chappell, Mark C; Diz, Debra I

    2011-07-14

    In Fischer 344 (F344) rats, renin-angiotensin system (RAS) blockade for 1 yr with the angiotensin II type 1 (AT(1)) receptor blocker L-158,809 prevents age-related impairments in metabolic function, similar to transgenic rats with low glial angiotensinogen (Aogen). Brain RAS regulation may contribute to the benefits of long-term systemic AT(1) antagonism. We assessed the mRNA of RAS components in the dorsomedial medulla of F344 rats at 3 (young; n = 8) or 15 mo of age (old; n = 7) and in rats treated from 3 to 15 mo of age with 20 mg/l of the AT(1) receptor antagonist L-158,809 (Old+L; n = 6). Aogen and renin mRNA were lower in the young compared with old group. Angiotensin-converting enzyme (ACE) mRNA was lower in the old and Old+L compared with the young group. ACE2 and neprilysin expression were significantly higher in Old+L compared with young or old rats. AT(1b), AT(2), and Mas receptor mRNA were higher with treatment. Leptin receptor mRNA was lower in the old rats and this was prevented by L-158,809 treatment. Dual-specificity phosphatase 1 (DUSP1) mRNA was highest in the Old+L group. Aggregate correlate summation revealed a positive relationship for Mas receptor mRNA with food intake. The findings provide evidence for regulation of dorsomedial medullary renin and Aogen mRNA during aging. Long-term AT(1) receptor blockade increases the mRNA of the enzymes ACE2 and neprilysin and the MAS receptor, which could potentially shift the balance from ANG II to ANG-(1-7) and prevent age-related declines in the leptin receptor and its signaling pathway.

  19. Long-term systemic angiotensin II type 1 receptor blockade regulates mRNA expression of dorsomedial medulla renin-angiotensin system components

    PubMed Central

    Gilliam-Davis, Shea; Gallagher, Patricia E.; Payne, Valerie S.; Kasper, Sherry O.; Tommasi, Ellen N.; Westwood, Brian M.; Robbins, Michael E.; Chappell, Mark C.

    2011-01-01

    In Fischer 344 (F344) rats, renin-angiotensin system (RAS) blockade for 1 yr with the angiotensin II type 1 (AT1) receptor blocker L-158,809 prevents age-related impairments in metabolic function, similar to transgenic rats with low glial angiotensinogen (Aogen). Brain RAS regulation may contribute to the benefits of long-term systemic AT1 antagonism. We assessed the mRNA of RAS components in the dorsomedial medulla of F344 rats at 3 (young; n = 8) or 15 mo of age (old; n = 7) and in rats treated from 3 to 15 mo of age with 20 mg/l of the AT1 receptor antagonist L-158,809 (Old+L; n = 6). Aogen and renin mRNA were lower in the young compared with old group. Angiotensin-converting enzyme (ACE) mRNA was lower in the old and Old+L compared with the young group. ACE2 and neprilysin expression were significantly higher in Old+L compared with young or old rats. AT1b, AT2, and Mas receptor mRNA were higher with treatment. Leptin receptor mRNA was lower in the old rats and this was prevented by L-158,809 treatment. Dual-specificity phosphatase 1 (DUSP1) mRNA was highest in the Old+L group. Aggregate correlate summation revealed a positive relationship for Mas receptor mRNA with food intake. The findings provide evidence for regulation of dorsomedial medullary renin and Aogen mRNA during aging. Long-term AT1 receptor blockade increases the mRNA of the enzymes ACE2 and neprilysin and the MAS receptor, which could potentially shift the balance from ANG II to ANG-(1–7) and prevent age-related declines in the leptin receptor and its signaling pathway. PMID:21540301

  20. The adipose renin-angiotensin system modulates sysemic markers of insulin sensitivity activates the intrarenal renin-angiotensin system

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kim, Suyeon; Soltani-Bejnood, Morvarid; Quignard-Boulange, Annie

    2006-07-01

    BACKGROUND: A growing body of data provides increasing evidence that the adipose tissue renin-angiotensin system (RAS) contributes to regulation of fat mass. Beyond its paracrine actions within adipose tissue, adipocyte-derived angiotensin II (Ang II) may also impact systemic functions such as blood pressure and metabolism. METHODS AND RESULTS: We used a genetic approach to manipulate adipose RAS activity in mice and then study the consequences on metabolic parameters and on feedback regulation of the RAS. The models included deletion of the angiotensinogen (Agt) gene (Agt-KO), its expression solely in adipose tissue under the control of an adipocyte-specific promoter (aP2-Agt/ Agt-KO),more » and overexpression in adipose tissue of wild type mice (aP2-Agt). Total body weight, epididymal fat pad weight, and circulating levels of leptin, insulin and resistin were significantly decreased in Agt-KO mice, while plasma adiponectin levels were increased. Overexpression of Agt in adipose tissue resulted in increased adiposity and plasma leptin and insulin levels compared to wild type (WT) controls. Angiotensinogen and type I Ang II receptor protein levels were also markedly elevated in kidney of aP2-Agt mice, suggesting that hypertension in these animals may be in part due to stimulation of the intrarenal RAS. CONCLUSIONS: Taken together, the results from this study demonstrate that alterations in adipose RAS activity significantly alter both local and systemic physiology in a way that may contribute to the detrimental health effects of obesity.« less

  1. Local bone marrow renin-angiotensin system in the genesis of leukemia and other malignancies.

    PubMed

    Haznedaroglu, I C; Malkan, U Y

    2016-10-01

    The existence of a local renin-angiotensin system (RAS) specific to the hematopoietic bone marrow (BM) microenvironment had been proposed two decades ago. Most of the RAS molecules including ACE, ACE2, AGT, AGTR1, AGTR2, AKR1C4, AKR1D1, ANPEP, ATP6AP2, CMA1, CPA3, CTSA, CTSD, CTSG, CYP11A1, CYP11B1, CYP11B2, CYP17A1, CYP21A2, DPP3, EGFR, ENPEP, GPER, HSD11B1, HSD11B2, IGF2R, KLK1, LNPEP, MAS1, MME, NR3C1, NR3C2, PREP, REN, RNPEP, and THOP1 are locally present in the BM microenvironment. Local BM RAS peptides control the hematopoietic niche, myelopoiesis, erythropoiesis, thrombopoiesis and the development of other cellular lineages. Local BM RAS is important in hematopoietic stem cell biology and microenvironment. Angiotensin II regulates the proliferation, differentiation, and engraftment of hematopoietic stem cells. Activation of Mas receptor or ACE2 promotes proliferation of CD34+ cells. BM contains a progenitor that expresses renin throughout development. Angiotensin II attenuates the migration and proliferation of CD34+ Cells and promotes the adhesion of both MNCs and CD34+ cells. Renin cells in hematopoietic organs are precursor B cells. The renin cell requires RBP-J to differentiate. Mutant renin-expressing hematopoietic precursors can cause leukemia. Deletion of RBP-J in the renin-expressing progenitors enriches the precursor B-cell gene programme. Mutant cells undergo a neoplastic transformation, and mice develop a highly penetrant B-cell leukemia with multi-organ infiltration and early death. Many biological conditions during the development and function of blood cells are mediated by RAS, such as apoptosis, cellular proliferation, intracellular signaling, mobilization, angiogenesis, and fibrosis. The aim of this paper is to review recent developments regarding the actions of local BM RAS in the genesis of leukemia and other malignancies molecules.

  2. Intramuscular renin-angiotensin system is activated in human muscular dystrophy.

    PubMed

    Sun, Guilian; Haginoya, Kazuhiro; Dai, Hongmei; Chiba, Yoko; Uematsu, Mitsugu; Hino-Fukuyo, Naomi; Onuma, Akira; Iinuma, Kazuie; Tsuchiya, Shigeru

    2009-05-15

    To investigate the role of the muscular renin-angiotensin system (RAS) in human muscular dystrophy, we used immunohistochemistry and Western blotting to examine the cellular localization of angiotensin-converting enzyme (ACE), the angiotensin II type 1 receptor (AT1) and the angiotensin II type 2 receptor (AT2) in muscle biopsies from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and congenital muscular dystrophy (CMD). In normal muscle, ACE was expressed in vascular endothelial cells and neuromuscular junctions (NMJs), whereas AT1 was immunolocalized to the smooth muscle cells of blood vessels and intramuscular nerve twigs. AT2 was immunolocalized in the smooth muscle cells of blood vessels. These findings suggest that the RAS has a functional role in peripheral nerves and NMJs. ACE and AT1, but AT2 immunoreactivity were increased markedly in dystrophic muscle as compared to controls. ACE and the AT1 were strongly expressed in the cytoplasm and nuclei of regenerating muscle fibers, fibroblasts, and in macrophages infiltrating necrotic fibers. Double immunolabeling revealed that activated fibroblasts in the endomysium and perimysium of DMD and CMD muscle were positive for ACE and AT1. Triple immunolabeling demonstrated that transforming growth factor-beta1 (TGF-beta1) and ACE were colocalized on the cytoplasm of activated fibroblasts in dystrophic muscle. Furthermore, Western blotting showed increases in the expression of AT1 and TGF-beta1 protein in dystrophic muscle, which coincided with our immunohistochemical results. The overexpression of ACE and AT1 in dystrophic muscle would likely result in the increased production of Ang II, which may act on these cells in an autocrine manner via AT1. The activation of AT1 may induce fibrous tissue formation through overexpression of TGF-beta1, which potently activates fibrogenesis and suppresses regeneration. In conclusion, our results imply that the intramuscular RAS-TGF-beta1 pathway

  3. Acute change in glomerular filtration rate with inhibition of the renin-angiotensin system does not predict subsequent renal and cardiovascular outcomes.

    PubMed

    Clase, Catherine M; Barzilay, Joshua; Gao, Peggy; Smyth, Andrew; Schmieder, Roland E; Tobe, Sheldon; Teo, Koon K; Yusuf, Salim; Mann, Johannes F E

    2017-03-01

    Initiation of blockade of the renin-angiotensin system may cause an acute decrease in glomerular filtration rate (GFR): the prognostic significance of this is unknown. We did a post hoc analysis of patients with, or at risk for, vascular disease, in two randomized controlled trials: Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND), whose median follow-up was 56 months. In 9340 patients new to renin-angiotensin system blockade, who were then randomized to renin-angiotensin system blockade, a fall in GFR of 15% or more at 2 weeks after starting renin-angiotensin system blockade was seen in 1480 participants (16%), with persistence at 8 weeks in 700 (7%). Both acute increases and decreases in GFR after initiation of renin-angiotensin system blockade were associated with tendencies, mostly not statistically significant, to increased risk of cardiovascular outcomes, which occurred in 1280 participants, and of microalbuminuria, which occurred in 864. Analyses of creatinine-based outcomes were suggestive of regression to the mean. In more than 3000 patients randomized in TRANSCEND to telmisartan or placebo, there was no interaction between acute change in GFR and renal or cardiovascular benefit from telmisartan. Thus, both increases and decreases in GFR on initiation of renin-angiotensin system blockade are common, and may be weakly associated with increased risk of cardiovascular and renal outcomes. Changes do not predict increased benefit from therapy. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  4. Increased methylglyoxal formation with upregulation of renin angiotensin system in fructose fed Sprague Dawley rats.

    PubMed

    Dhar, Indu; Dhar, Arti; Wu, Lingyun; Desai, Kaushik M

    2013-01-01

    The current epidemic of obesity and type 2 diabetes is attributed to a high carbohydrate diet, containing mainly high fructose corn syrup and sucrose. More than two thirds of diabetic patients have hypertension. Methylglyoxal is a highly reactive dicarbonyl generated during glucose and fructose metabolism, and a major precursor of advanced glycation end products (AGEs). Plasma methylglyoxal levels are increased in hypertensive rats and diabetic patients. Our aim was to examine the levels of methylglyoxal, mediators of the renin angiotensin system and blood pressure in male Sprague-Dawley rats treated with a high fructose diet (60% of total calories) for 4 months. The thoracic aorta and kidney were used for molecular studies, along with cultured vascular smooth muscle cells (VSMCs). HPLC, Western blotting and Q-PCR were used to measure methylglyoxal and reduced glutathione (GSH), proteins and mRNA, respectively. Fructose treated rats developed a significant increase in blood pressure. Methylglyoxal level and protein and mRNA for angiotensin II, AT1 receptor, adrenergic α1D receptor and renin were significantly increased, whereas GSH levels were decreased, in the aorta and/or kidney of fructose fed rats. The protein expression of the receptor for AGEs (RAGE) and NF-κB were also significantly increased in the aorta of fructose fed rats. MG treated VSMCs showed increased protein for angiotensin II, AT1 receptor, and α1D receptor. The effects of methylglyoxal were attenuated by metformin, a methylglyoxal scavenger and AGEs inhibitor. In conclusion, we report a strong association between elevated levels of methylglyoxal, RAGE, NF-κB, mediators of the renin angiotensin system and blood pressure in high fructose diet fed rats.

  5. Are "functionally related polymorphisms" of renin-angiotensin-aldosterone system gene polymorphisms associated with hypertension?

    PubMed

    Hahntow, Ines N; Mairuhu, Gideon; van Valkengoed, Irene Gm; Koopmans, Richard P; Michel, Martin C

    2010-06-02

    Genotype-phenotype association studies are typically based upon polymorphisms or haplotypes comprised of multiple polymorphisms within a single gene. It has been proposed that combinations of polymorphisms in distinct genes, which functionally impact the same phenotype, may have stronger phenotype associations than those within a single gene. We have tested this hypothesis using genes encoding components of the renin-angiotensin-aldosterone system and the high blood pressure phenotype. Our analysis is based on 1379 participants of the cross-sectional SUNSET study randomly selected from the population register of Amsterdam. Each subject was genotyped for the angiotensinogen M235T, the angiotensin-converting enzyme insertion/deletion and the angiotensin II type 1 receptor A1166C polymorphism. The phenotype high blood pressure was defined either as a categorical variable comparing hypertension versus normotension as in most previous studies or as a continuous variable using systolic, diastolic and mean blood pressure in a multiple regression analysis with gender, ethnicity, age, body-mass-index and antihypertensive medication as covariates. Genotype-phenotype relationships were explored for each polymorphism in isolation and for double and triple polymorphism combinations. At the single polymorphism level, only the A allele of the angiotensin II type 1 receptor was associated with a high blood pressure phenotype. Using combinations of polymorphisms of two or all three genes did not yield stronger/more consistent associations. We conclude that combinations of physiologically related polymorphisms of multiple genes, at least with regard to the renin-angiotensin-aldosterone system and the hypertensive phenotype, do not necessarily offer additional benefit in analyzing genotype/phenotype associations.

  6. Metabolic Rate Regulation by the Renin-Angiotensin System: Brain vs. Body

    PubMed Central

    Grobe, Justin L.; Rahmouni, Kamal; Liu, Xuebo; Sigmund, Curt D.

    2013-01-01

    Substantial evidence supports a role for the renin-angiotensin system (RAS) in the regulation of metabolic function, but an apparent paradox exists where genetic or pharmacological inhibition of the RAS occasionally have similar physiological effects as chronic angiotensin infusion. Similarly, while RAS targeting in animal models has robust metabolic consequences, effects in humans are more subtle. Here we review the data supporting a role for the RAS in metabolic rate regulation and propose a model where the local brain RAS works in opposition to the peripheral RAS, thus helping to explain the paradoxically similar effects of RAS supplementation and inhibition. Selectively modulating the peripheral RAS or brain RAS may thus provide a more effective treatment paradigm for obesity and obesity-related disorders. PMID:22491893

  7. Antihypertensive effect of caffeic acid and its analogs through dual renin-angiotensin-aldosterone system inhibition.

    PubMed

    Bhullar, Khushwant S; Lassalle-Claux, Grégoire; Touaibia, Mohamed; Rupasinghe, H P Vasantha

    2014-05-05

    Hypertension is a crucial risk factor for cardiovascular diseases and contributes to one third of global mortality. In addition to conventional antihypertensive drugs such as captopril, naturally occurring phytochemicals and their analogs are used for reducing the risk and occurrence of hypertension. Herein, we demonstrate the possible use of caffeic acid and its derivatives in the treatment of hypertension through multi-target modulation of renin-angiotensin-aldosterone system (RAAS). Caffeic acid along with its nineteen novel derivatives, chlorogenic acid, quercetin and captopril were all investigated for the inhibition of renin and angiotensin converting enzyme (ACE) activities and production of aldosterone. Compound 22 with CH2CH(Ph)2 moiety exhibited the strongest renin inhibition (IC50=229µM) among all compounds tested (P≤0.05). Caffeic acid was the weakest renin inhibitor (IC50=5704µM) among all the compounds assayed. Similar to renin inhibition, compound 22 (IC50=9.1µM) also exhibited about 47 times stronger ACE inhibition compared to the parent compound. Analysis of aldosterone revealed that compound 8 with n-Pr moiety was the strongest modulator of aldosterone production among all the derivatives (P≤0.05). Toxicity analysis using human fibroblasts (WI-38 cells) confirmed the non-toxic manifestations of caffeic acid and its derivatives in comparison to clinically used drug captopril. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Human vascular renin-angiotensin system and its functional changes in relation to different sodium intakes.

    PubMed

    Boddi, M; Poggesi, L; Coppo, M; Zarone, N; Sacchi, S; Tania, C; Neri Serneri, G G

    1998-03-01

    A growing body of evidence supports the existence of a tissue-based renin-angiotensin system (RAS) in the vasculature, but the functional capacity of vascular RAS was not investigated in humans. In 28 normotensive healthy control subjects, the metabolism of angiotensins through vascular tissue was investigated in normal, low, and high sodium diets by the measurement of arterial-venous gradient of endogenous angiotensin (Ang) I and Ang II in two different vascular beds (forearm and leg), combined with the study of 125I-Ang I and 125I-Ang II kinetics. In normal sodium diet subjects, forearm vascular tissue extracted 36+/-6% of 125I-Ang I and 30+/-5% of 125I-Ang II and added 14.9+/-5.1 fmol x 100 mL(-1) x min(-1) of de novo formed Ang I and 6.2+/-2.8 fmol x 100 mL(-1) x min(-1) of Ang II to antecubital venous blood. Fractional conversion of 125I-Ang I through forearm vascular tissue was about 12%. Low sodium diet increased (P<.01) plasma renin activity, whereas de novo Ang I and Ang II formation by forearm vascular tissue became undetectable. Angiotensin degradation (33+/-7% for Ang I and 30+/-7% for Ang II) was unchanged, and vascular fractional conversion of 125I-Ang I decreased from 12% to 6% (P<.01). In high sodium diet subjects, plasma renin activity decreased, and de novo Ang I and Ang II formation by forearm vascular tissue increased to 22 and 14 fmol x 100 mL(-1) x min(-1), respectively (P<.01). Angiotensin degradation did not significantly change, whereas fractional conversion of 125I-Ang I increased from 12% to 20% (P<.01). Leg vascular tissue functional activities of RAS paralleled those of forearm vascular tissue both at baseline and during different sodium intake. These results provide consistent evidence for the existence of a functional tissue-based RAS in vascular tissue of humans. The opposite changes of plasma renin activity and vascular angiotensin formation indicate that vascular RAS is independent from but related to circulating RAS.

  9. Expression of classical components of the renin-angiotensin system in the human eye.

    PubMed

    White, Andrew J R; Cheruvu, Sarat C; Sarris, Maria; Liyanage, Surabhi S; Lumbers, Eugenie; Chui, Jeanie; Wakefield, Denis; McCluskey, Peter J

    2015-03-01

    The purpose of this study was to determine the relative expression of clinically-relevant components of the renin-angiotensin system (RAS) in the adult human eye. We obtained 14 post-mortem enucleated human eyes from patients whom had no history of inflammatory ocular disease nor pre-mortem ocular infection. We determined the gene expression for prorenin, renin, prorenin receptor, angiotensin-converting enzyme, angiotensinogen and angiotensin II Type 1 receptor, on tissue sections and in cultured human primary retinal pigment epithelial and iris pigment epithelial (RPE/IPE) cell lines, using both qualitative and quantitative reverse transcription polymerase chain reaction (RT-PCR). Protein expression was studied using indirect immunofluorescence (IF). Almost all components of the classical RAS were found at high levels, at both the transcript and protein level, in the eyes' uvea and retina; and at lower levels in the cornea, conjunctiva and sclera. There was a much lower level of expression in the reference cultured RPE/IPE cells lines. This study describes the distribution of RAS in the normal adult human eye and demonstrates the existence of an independent ocular RAS, with uveal and retinal tissues showing the highest expression of RAS components. These preliminary findings provide scope for examination of additional components of this system in the human eye, as well as possible differential expression under pathological conditions. © The Author(s) 2014.

  10. Local bone marrow renin-angiotensin system in primitive, definitive and neoplastic haematopoiesis.

    PubMed

    Haznedaroglu, Ibrahim C; Beyazit, Yavuz

    2013-03-01

    The locally active ligand peptides, mediators, receptors and signalling pathways of the haematopoietic BM (bone marrow) autocrine/paracrine RAS (renin-angiotensin system) affect the essential steps of definitive blood cell production. Haematopoiesis, erythropoiesis, myelopoiesis, formation of monocytic and lymphocytic lineages, thrombopoiesis and other stromal cellular elements are regulated by the local BM RAS. The local BM RAS is present and active even in primitive embryonic haematopoiesis. ACE (angiotensin-converting enzyme) is expressed on the surface of the first endothelial and haematopoietic cells, forming the marrow cavity in the embryo. ACE marks early haematopoietic precursor cells and long-term blood-forming CD34(+) BM cells. The local autocrine tissue BM RAS may also be active in neoplastic haematopoiesis. Critical RAS mediators such as renin, ACE, AngII (angiotensin II) and angiotensinogen have been identified in leukaemic blast cells. The local tissue RAS influences tumour growth and metastases in an autocrine and paracrine fashion via the modulation of numerous carcinogenic events, such as angiogenesis, apoptosis, cellular proliferation, immune responses, cell signalling and extracellular matrix formation. The aim of the present review is to outline the known functions of the local BM RAS within the context of primitive, definitive and neoplastic haematopoiesis. Targeting the actions of local RAS molecules could represent a valuable therapeutic option for the management of neoplastic disorders.

  11. The protective arm of the renin-angiotensin system may counteract the intense inflammatory process in fetuses with posterior urethral valves.

    PubMed

    Rocha, Natalia P; Bastos, Fernando M; Vieira, Érica L M; Prestes, Thiago R R; Silveira, Katia D da; Teixeira, Mauro M; Simões E Silva, Ana Cristina

    2018-03-11

    Posterior urethral valve is the most common lower urinary tract obstruction in male children. A high percentage of patients with posterior urethral valve evolve to end-stage renal disease. Previous studies showed that cytokines, chemokines, and components of the renin-angiotensin system contribute to the renal damage in obstructive uropathies. The authors recently found that urine samples from fetuses with posterior urethral valve have increased levels of inflammatory molecules. The aim of this study was to measure renin-angiotensin system molecules and to investigate their correlation with previously detected inflammatory markers in the same urine samples of fetuses with posterior urethral valve. Urine samples from 24 fetuses with posterior urethral valve were collected and compared to those from 22 healthy male newborns at the same gestational age (controls). Renin-angiotensin system components levels were measured by enzyme-linked immunosorbent assay. Fetuses with posterior urethral valve presented increased urinary levels of angiotensin (Ang) I, Ang-(1-7) and angiotensin-converting enzyme 2 in comparison with controls. ACE levels were significantly reduced and Ang II levels were similar in fetuses with posterior urethral valve in comparison with controls. Increased urinary levels of angiotensin-converting enzyme 2 and of Ang-(1-7) in fetuses with posterior urethral valve could represent a regulatory response to the intense inflammatory process triggered by posterior urethral valve. Copyright © 2018 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  12. Intermittent hypoxia increases arterial blood pressure in humans through a Renin-Angiotensin system-dependent mechanism.

    PubMed

    Foster, Glen E; Hanly, Patrick J; Ahmed, Sofia B; Beaudin, Andrew E; Pialoux, Vincent; Poulin, Marc J

    2010-09-01

    Intermittent hypoxia (IH) is believed to contribute to the pathogenesis of hypertension in obstructive sleep apnea through mechanisms that include activation of the renin-angiotensin system. The objective of this study was to assess the role of the type I angiotensin II receptor in mediating an increase in arterial pressure associated with a single 6-hour IH exposure. Using a double-blind, placebo-controlled, randomized, crossover study design, we exposed 9 healthy male subjects to sham IH, IH with placebo medication, and IH with the type I angiotensin II receptor antagonist losartan. We measured blood pressure, cerebral blood flow, and ventilation at baseline and after exposure to 6 hours of IH. An acute isocapnic hypoxia experimental protocol was conducted immediately before and after exposure to IH. IH with placebo increased resting mean arterial pressure by 7.9+/-1.6 mm Hg, but mean arterial pressure did not increase with sham IH (1.9+/-1.5 mm Hg) or with losartan IH (-0.2+/-2.4 mm Hg; P<0.05). Exposure to IH prevented the diurnal decrease in the cerebral blood flow response to hypoxia, independently of the renin-angiotensin system. Finally, in contrast to other models of IH, the acute hypoxic ventilatory response did not change throughout the protocol. IH increases arterial blood pressure through activation of the type I angiotensin II receptor, without a demonstrable impact on the cerebrovascular or ventilatory response to acute hypoxia.

  13. Renin Angiotensin Aldosterone System (RAAS): its biology and drug targets for treating diabetic nephropathy.

    PubMed

    Zain, Maryam; Awan, Fazli Rabbi

    2014-09-01

    Diabetes mellitus is a multifactorial disorder of hyperglycemia caused by a combination of biochemical, molecular and genetic factors, which leads to the dysfunction of various organs including kidneys. Diabetic nephropathy (DN) is one of the microvascular complications of diabetes that results due to poor glycemic control. Several molecular and biochemical pathways have been implicated in the pathogenesis of DN. Of these, the Renin Angiotensin Aldosterone System (RAAS) is considered as a key pathway. RAAS involves various subsystems which contribute to the development of DN. Mutations in several genes of the RAAS pathway have been associated with the development of DN. These genes or their products present them as therapeutic targets for potent drugs to control or prevent DN, and development of new drugs for targeting the RAAS. Drugs in use for DN are mainly the Angiotensin Converting Enzyme (ACE) inhibitors, Angiotensin Receptors Blockers (ARB) and renin inhibitors which play important roles in reducing DN. Hence, the present review is focused on the pathophysiology and genetic factors for DN by exploring the RAAS pathway and emphasizing the benefits of blocking this pathway to control and prevent DN.

  14. Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension

    PubMed Central

    De Man, Frances; Tu, Ly; Handoko, Louis; Rain, Silvia; Ruiter, Gerrina; François, Charlène; Schalij, Ingrid; Dorfmüller, Peter; Simonneau, Gérald; Fadel, Elie; Perros, Frederic; Boonstra, Anco; Postmus, Piet; Van Der Velden, Jolanda; Vonk-Noordegraaf, Anton; Humbert, Marc; Eddahibi, Saadia; Guignabert, Christophe

    2012-01-01

    Rationale Patients with idiopathic pulmonary arterial hypertension (iPAH) often have a low cardiac output. To compensate, neurohormonal systems like renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system are upregulated but this may have long-term negative effects on the progression of iPAH. Objectives Assess systemic and pulmonary RAAS-activity in iPAH-patients and determine the efficacy of chronic RAAS-inhibition in experimental PAH. Measurements and Main Results We collected 79 blood samples from 58 iPAH-patients in the VU University Medical Center Amsterdam (between 2004–2010), to determine systemic RAAS-activity. We observed increased levels of renin, angiotensin (Ang) I and AngII, which was associated with disease progression (p<0.05) and mortality (p<0.05). To determine pulmonary RAAS-activity, lung specimens were obtained from iPAH-patients (during lung transplantation, n=13) and controls (during lobectomy or pneumonectomy for cancer, n=14). Local RAAS-activity in pulmonary arteries of iPAH-patients was increased, demonstrated by elevated ACE-activity in pulmonary endothelial cells and increased AngII type 1 (AT1) receptor expression and signaling. In addition, local RAAS- upregulation was associated with increased pulmonary artery smooth muscle cell proliferation via enhanced AT1-receptor signaling in iPAH-patients compared to controls. Finally, to determine the therapeutic potential of RAAS-activity, we assessed the chronic effects of an AT1-receptor antagonist (losartan) in the monocrotaline PAH-rat model (60 mg/kg). Losartan delayed disease progression, decreased RV afterload and pulmonary vascular remodeling and restored right ventricular-arterial coupling in PAH-rats. Conclusions Systemic and pulmonary RAAS-activities are increased in iPAH-patients and associated with increased pulmonary vascular remodeling. Chronic inhibition of RAAS by losartan is beneficial in experimental PAH. PMID:22859525

  15. Expression of genes of the cardiac and renal renin-angiotensin systems in preterm piglets: is this system a suitable target for therapeutic intervention?

    PubMed

    Kim, Eleanor; Eiby, Yvonne; Lumbers, Eugenie; Boyce, Amanda; Gibson, Karen; Lingwood, Barbara

    2015-10-01

    The newborn circulating, cardiac and renal renin-angiotensin systems (RASs) are essential for blood pressure control, and for cardiac and renal development. If cardiac and renal RASs are immature this may contribute to cardiovascular compromise in preterm infants. This study measured mRNA expression of cardiac and renal RAS components in preterm, glucocorticoid (GC) exposed preterm, and term piglets. Renal and cardiac RAS mRNA levels were measured using real-time polymerase chain reaction (PCR). Genes studied were: (pro)renin receptor, renin, angiotensinogen, angiotensin converting enzyme (ACE), ACE2, angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptor (AT2R). All the genes studied were expressed in the kidney; neither renin nor AT2R mRNA were detected in the heart. There were no gestational changes in (pro)renin receptor, renin, ACE or AT1R mRNA levels. Right ventricular angiotensinogen mRNA levels in females were lower in preterm animals than at term, and GC exposure increased levels in male piglets. Renal angiotensinogen mRNA levels in female term piglets were lower than females from both preterm groups, and lower than male term piglets. Left ventricular ACE2 mRNA expression was lower in GC treated preterm piglets. Renal AT2R mRNA abundance was highest in GC treated preterm piglets, and the AT1R/AT2R ratio was increased at term. Preterm cardiac and renal RAS mRNA levels were similar to term piglets, suggesting that immaturity of these RASs does not contribute to preterm cardiovascular compromise. Since preterm expression of both renal and cardiac angiotensin II-AT1R is similar to term animals, cardiovascular dysfunction in the sick preterm human neonate might be effectively treated by agents acting on their RASs. © The Author(s), 2015.

  16. Renin-angiotensin-aldosterone system (RAAS) pharmacogenomics: implications in heart failure management.

    PubMed

    Beitelshees, Amber L; Zineh, Issam

    2010-05-01

    Blockade of the renin-angiotensin-aldosterone system (RAAS) with ACE inhibitors has been a cornerstone of heart failure therapy for over 15 years. More recently, further blockade of RAAS with aldosterone antagonists and angiotensin receptor blockers (ARBs) has been studied. While these therapies have certainly improved outcomes in the treatment of heart failure, morbidity and mortality remain extremely high. Furthermore, polypharmacy and complex regimens of seven medications on average is the norm for management of heart failure. This results in increased costs, patient burden, and uncertainty as to the best course of therapy. The ability to personalize patients' therapeutic regimens using pharmacogenomics has the potential of providing more effective and efficient use of RAAS-modulating medications. This review highlights the implications of major RAAS pharmacogenetic studies, while outlining future directions for translation to practice.

  17. Current status of renin-aldosterone angiotensin system-targeting anti-hypertensive drugs as therapeutic options for Alzheimer's disease.

    PubMed

    Ashby, Emma Louise; Kehoe, Patrick G

    2013-10-01

    Hypertension is a modifiable risk factor for Alzheimer's disease (AD) and other dementias. Yet, despite this well-documented association, few of the current strategies to treat AD are directed at this possible target. The renin-aldosterone angiotensin system (RAAS) is a centrally active modifiable pathway that is involved in cerebral blood flow regulation. Currently, three classes of RAAS-targeting drugs are licensed for treatment of peripheral hypertension--angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin II receptor blockers (ARBs) and direct renin inhibitors (DRIs). All of these are generally well tolerated and have been shown to offer varying degrees of protection on aspects of cognition and dementia, thus making them an attractive therapeutic option for AD. This review summarises existing evidence regarding the plausibility of using RAAS-targeting drugs as a strategy to treat AD and highlights unresolved aspects to such approaches, namely the potential impact of altering angiotensin II-mediated processes in the central nervous system. Continued biochemical research of the RAAS pathway in combination with formal investigation of current RAAS-modifying drugs in randomised clinical trials is now necessary to determine their therapeutic value in AD.

  18. Abnormal regulation of renin angiotensin aldosterone system is associated with right ventricular dysfunction in hypertension.

    PubMed

    Gregori, Mario; Tocci, Giuliano; Giammarioli, Benedetta; Befani, Alberto; Ciavarella, Giuseppino Massimo; Ferrucci, Andrea; Paneni, Francesco

    2014-02-01

    Right ventricular dysfunction (RVD) is a major predictor of cardiovascular mortality. Inadequate suppression of the renin-angiotensin-aldosterone system (RAAS) after postural manoeuvres favours alterations of left ventricular (LV) function. The effects of RAAS dysregulation on RV performance remain elusive. The present study investigated RV function in hypertensive patients with or without altered RAAS activation. Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured in 104 newly diagnosed hypertensive patients after both supine and upright positioning to assess dynamic changes of RAAS induced by antigravitational stress. Twenty-four-hour ambulatory blood pressure monitoring and echocardiographic evaluation of the right ventricle including tissue Doppler imaging (TDI) were performed. Patients were divided as follows: (1) normal PRA and PAC (N group [n = 58]), (2) suppressible RAAS after supine positioning (SR group [n = 24]), and (3), nonsuppressible RAAS (NSR group [n = 22]). RVD was identified by the TDI-derived myocardial performance index (MPI) calculated with a multisegmental approach. Patients in the NSR group had reduced indices of RV function compared with patients in the N and SR groups. MPI of the right ventricle as well as prevalence of RVD were also significantly higher in the NSR group. Regression models showed that inadequate RAAS suppression was independently associated with RVD, regardless of blood pressure values and LV dysfunction (LVD). Patients without supine normalization of RAAS display a significant impairment of RV function. Our findings suggest that a dynamic RAAS evaluation may help to identify hypertensive patients at higher risk of RVD. Copyright © 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  19. High-salt diets during pregnancy affected fetal and offspring renal renin-angiotensin system.

    PubMed

    Mao, Caiping; Liu, Rong; Bo, Le; Chen, Ningjing; Li, Shigang; Xia, Shuixiu; Chen, Jie; Li, Dawei; Zhang, Lubo; Xu, Zhice

    2013-07-01

    Intrauterine environments are related to fetal renal development and postnatal health. Influence of salty diets during pregnancy on renal functions and renin-angiotensin system (RAS) was determined in the ovine fetuses and offspring. Pregnant ewes were fed high-salt diet (HSD) or normal-salt diet (NSD) for 2 months during middle-to-late gestation. Fetal renal functions, plasma hormones, and mRNA and protein expressions of the key elements of renal RAS were measured in the fetuses and offspring. Fetal renal excretion of sodium was increased while urine volume decreased in the HSD group. Fetal blood urea nitrogen was increased, while kidney weight:body weight ratio decreased in the HSD group. The altered ratio was also observed in the offspring aged 15 and 90 days. Maternal and fetal plasma antidiuretic hormone was elevated without changes in plasma renin activity and Ang I levels, while plasma Ang II was decreased. The key elements of local renal RAS, including angiotensinogen, angiotensin converting enzyme (ACE), ACE2, AT1, and AT2 receptor expression in both mRNA and protein, except renin, were altered following maternal high salt intake. The results suggest that high intake of salt during pregnancy affected fetal renal development associated with an altered expression of the renal key elements of RAS, some alterations of fetal origins remained after birth as possible risks in developing renal or cardiovascular diseases.

  20. Discordant orthostatic reflex renin-angiotensin and sympathoneural responses in premenopausal exercising-hypoestrogenic women.

    PubMed

    O'Donnell, Emma; Goodman, Jack M; Mak, Susanna; Murai, Hisayoshi; Morris, Beverley L; Floras, John S; Harvey, Paula J

    2015-05-01

    Our prior observations in normotensive postmenopausal women stimulated the hypotheses that compared with eumenorrheic women, active hypoestrogenic premenopausal women with functional hypothalamic amenorrhea would demonstrate attenuated reflex renin-angiotensin-aldosterone system responses to an orthostatic challenge, whereas to defend blood pressure reflex increases in muscle, sympathetic nerve activity would be augmented. To test these hypotheses, we assessed, in recreationally active women, 12 with amenorrhea (ExFHA; aged 25 ± 1 years; body mass index 20.7 ± 0.7 kg/m(2); mean ± SEM) and 17 with eumenorrhea (ExOv; 24 ± 1 years; 20.9 ± 0.5 kg/m(2)), blood pressure, heart rate, plasma renin, angiotensin II, aldosterone, and muscle sympathetic nerve activity at supine rest and during graded lower body negative pressure (-10, -20, and -40 mm Hg). At baseline, heart rate and systolic blood pressure were lower (P<0.05) in ExFHA (47 ± 2 beats/min and 94 ± 2 mm Hg) compared with ExOv (56 ± 2 beats/min and 105 ± 2 mm Hg), but muscle sympathetic nerve activity and renin-angiotensin-aldosterone system constituents were similar (P>0.05). In response to graded lower body negative pressure, heart rate increased (P<0.05) and systolic blood pressure decreased (P<0.05) in both groups, but these remained consistently lower in ExFHA (P<0.05). Lower body negative pressure elicited increases (P<0.05) in renin, angiotensin II, and aldosterone in ExOv, but not in ExFHA (P>0.05). Muscle sympathetic nerve activity burst incidence increased reflexively in both groups, but more so in ExFHA (P<0.05). Otherwise, healthy hypoestrogenic ExFHA women demonstrate low blood pressure and disruption of the normal circulatory response to an orthostatic challenge: plasma renin, angiotensin II, and aldosterone fail to increase and blood pressure is defended by an augmented sympathetic vasoconstrictor response. © 2015 American Heart Association, Inc.

  1. New drug therapies interfering with the renin-angiotensin-aldosterone system for resistant hypertension.

    PubMed

    Monge, Matthieu; Lorthioir, Aurélien; Bobrie, Guillaume; Azizi, Michel

    2013-12-01

    There is a persistent need for the development of new antihypertensive drugs, because the control of blood pressure is still not achievable in a significant proportion of hypertensive patients. Since the approval in 2007 of aliskiren, no other new antihypertensive based on new mechanism(s) of action have been approved. In fact, the development of promising novel drugs has been stopped for safety, efficacy or marketing reasons. Despite these difficulties, the pipeline is not dry and different new antihypertensive strategies targeting the renin-angiotensin-aldosterone pathway, are in clinical development stage. The dual angiotensin II receptor-neprilysin inhibitor LCZ696, a single molecule synthetized by cocrystallisation of valsartan and the neprilysin inhibitor prodrug AHU377 is in development for resistant hypertension and for heart failure. Daglutril is a dual neprylisin-endothelin converting enzyme inhibitor which was shown to decrease BP in patients with type 2 diabetic nephropathy. Aldosterone synthase inhibitors and the third and fourth generation non-steroidal dihydropyridine based mineralocorticoid receptors blockers are new ways to target the multiple noxious effects of aldosterone in the kidney, vessels and heart. Centrally acting aminopeptidase A inhibitors block brain angiotensin III formation, one of the main effector peptides of the brain renin angiotensin system. However, a long time will be still necessary to evaluate extensively the efficacy and safety of these new approaches. In the mean time, using appropriate and personalized daily doses of available drugs, decreasing physician inertia, improving treatment adherence, improving access to healthcare and reducing treatment costs remain major objectives to reduce the incidence of resistant hypertension.

  2. Recombinant erythropoietin acutely decreases renal perfusion and decouples the renin-angiotensin-aldosterone system.

    PubMed

    Aachmann-Andersen, Niels J; Christensen, Soren J; Lisbjerg, Kristian; Oturai, Peter; Johansson, Pär I; Holstein-Rathlou, Niels-Henrik; Olsen, Niels V

    2018-03-01

    The effect of recombinant erythropoietin (rhEPO) on renal and systemic hemodynamics was evaluated in a randomized double-blinded, cross-over study. Sixteen healthy subjects were tested with placebo, or low-dose rhEPO for 2 weeks, or high-dose rhEPO for 3 days. Subjects refrained from excessive salt intake, according to instructions from a dietitian. Renal clearance studies were done for measurements of renal plasma flow, glomerular filtration rate (GFR) and the segmentel tubular handling of sodium and water (lithium clearance). rhEPO increased arterial blood pressure, total peripheral resistance, and renal vascular resistance, and decreased renal plasma flow in the high-dose rhEPO intervention and tended to decrease GFR. In spite of the decrease in renal perfusion, rhEPO tended to decrease reabsorption of sodium and water in the proximal tubule and induced a prompt decrease in circulating levels of renin and aldosterone, independent of changes in red blood cell mass, blood volumes, and blood pressure. We also found changes in biomarkers showing evidence that rhEPO induced a prothrombotic state. Our results suggest that rhEPO causes a direct downregulation in proximal tubular reabsorption that seems to decouple the activity of the renin-angiotensin-aldosterone system from changes in renal hemodynamics. This may serve as a negative feed-back mechanism on endogenous synthesis of EPO when circulating levels of EPO are high. These results demonstrates for the first time in humans a direct effect of rhEPO on renal hemodynamics and a decoupling of the renin-angiotensin-aldosterone system. © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  3. Low LBNP Tolerance in Men is Associated With Attenuated Activation of The Renin-Angiotensin System

    NASA Technical Reports Server (NTRS)

    Greenleaf, J. E.; Petersen, T. W.; Gabrielsen, A.; Pump, B.; Bie, P.; Christensen, N.-J.; Warberg, J.; Videbaeck, R.; Simonson, S. R.; Norsk, P.

    1999-01-01

    Vasoactive hormone concentrations [epinephrine (pE), norepinephrine (pNE), angiotensin II (pATII), vasopressin (pVP), endothelin 1 (pET1)] and plasma renin activity (pRA) were measured during lower body negative pressure (LBNP) to test the hypothesis that responsiveness of the renin-angiotensin system is related to LBNP tolerance. Healthy men (2,822 cal/day(exp -1), 2 mmol*kg(exp -1)*day(exp -1)) Na(+)) were exposed to 30 minutes of progressive LBNP to -50 mmHg. LBNP was uneventful for seven men (25 +/- 2 years, HiTol group), but eight men (26 +/- 3 years) reached pre-syncope after 11 +/- 1 minutes (P < 0.001, LoTol group). Mean arterial pressure was unchanged. Central venous pressure and left atrial diameter decreased in both groups (5-6 mmHg by approx. 30%, P < 0.05). Control [hormone] were similar but, pRA differed between groups (LoTol 0.6 +/- 0.1, HiTol 1.2 +/- 0.1 ng Ang1/(ml(exp -1)*h(exp -1)), P < 0.05). LBNP increased (P < 0.05) pRA and pATII more in HiTol (9.9 +/- 2.2 ng Ang1/(ml(exp -1)*h(exp -1)) and 58 +/- 12 pg/ml(exp -1)) than LoTol (4.3 +/- 0.9 ng Ang1/(ml*h) and 28 +/- 6 pg/ml(exp -1)). In contrast, pVP was higher (P < 0.05) in LoTol than in HiTol. The response of the renin-angiotensin system seems linked to the occurrence of pre-syncope, and measurement of resting pRA may be predictive.

  4. Renin-angiotensin system: an old player with novel functions in skeletal muscle.

    PubMed

    Cabello-Verrugio, Claudio; Morales, María Gabriela; Rivera, Juan Carlos; Cabrera, Daniel; Simon, Felipe

    2015-05-01

    Skeletal muscle is a tissue that shows the most plasticity in the body; it can change in response to physiological and pathological stimuli. Among the diseases that affect skeletal muscle are myopathy-associated fibrosis, insulin resistance, and muscle atrophy. A common factor in these pathologies is the participation of the renin-angiotensin system (RAS). This system can be functionally separated into the classical and nonclassical RAS axis. The main components of the classical RAS pathway are angiotensin-converting enzyme (ACE), angiotensin II (Ang-II), and Ang-II receptors (AT receptors), whereas the nonclassical axis is composed of ACE2, angiotensin 1-7 [Ang (1-7)], and the Mas receptor. Hyperactivity of the classical axis in skeletal muscle has been associated with insulin resistance, atrophy, and fibrosis. In contrast, current evidence supports the action of the nonclassical RAS as a counter-regulator axis of the classical RAS pathway in skeletal muscle. In this review, we describe the mechanisms involved in the pathological effects of the classical RAS, advances in the use of pharmacological molecules to inhibit this axis, and the beneficial effects of stimulation of the nonclassical RAS pathway on insulin resistance, atrophy, and fibrosis in skeletal muscle. © 2015 Wiley Periodicals, Inc.

  5. Methylglyoxal, a reactive glucose metabolite, increases renin angiotensin aldosterone and blood pressure in male Sprague-Dawley rats.

    PubMed

    Dhar, Indu; Dhar, Arti; Wu, Lingyun; Desai, Kaushik M

    2014-03-01

    The majority of people with diabetes develop hypertension along with increased activity of the renin-angiotensin system. Methylglyoxal, a reactive glucose metabolite, is elevated in diabetic patients. We investigated the effects of methylglyoxal on the renin-angiotensin system and blood pressure. Male Sprague-Dawley rats were treated with a continuous infusion of methylglyoxal with a minipump for 4 weeks. Organs/tissues and cultured vascular smooth muscle cells (VSMCs) were used for molecular studies. High-performance liquid chromatography, Western blotting, and quantitative real-time polymerase chain reaction were used to measure methylglyoxal, proteins, and mRNA, respectively. Small interfering RNA for angiotensinogen and the receptor for advanced glycation endproducts (RAGE) were used to study mechanisms. Methylglyoxal-treated rats developed a significant increase in blood pressure and plasma levels of aldosterone, renin, angiotensin, and catecholamines. Methylglyoxal level and protein and mRNA for angiotensin, AT1 receptor, adrenergic α1D receptor, and renin were significantly increased in the aorta and/or kidney of methylglyoxal-treated rats, a novel finding. Alagebrium attenuated the above effects of methylgloyxal. Treatment of cultured VSMCs with methylglyoxal or high glucose (25 mM) significantly increased cellular methylglyoxal and protein and mRNA for nuclear factor kappa B (NF-κB), angiotensin, AT1 receptor, and α1D receptor, which were prevented by inhibition of NF-κB, and by alagebrium. Silencing of mRNA for RAGE prevented the increase in NF-kB induced by methylglyoxal. Silencing of mRNA for angiotensinogen prevented the increase in NF-κB, angiotensin, AT1 receptor, and α1D receptor. Methylglyoxal activates NF-κB through RAGE and thereby increases renin-angiotensin levels, a novel finding, and a probable mechanism of increase in blood pressure.

  6. Renin-Angiotensin System Blockade Improves Cardiac Indices in Acromegaly Patients.

    PubMed

    Thomas, Julia D J; Dattani, Abhishek; Zemrak, Filip; Burchell, Thomas; Akker, Scott A; Kaplan, Felicity J L; Khoo, Bernard; Aylwin, Simon; Grossman, Ashley B; Davies, L Ceri; Korbonits, Márta

    2017-06-01

    Blockade of the angiotensin-renin system, with angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), has been shown to improve cardiac outcomes following myocardial infarction and delay progression of heart failure. Acromegaly is associated with a disease-specific cardiomyopathy, the pathogenesis of which is poorly understood.The cardiac indices of patients with active acromegaly with no hypertension (Group A, n=4), established hypertension not taking ACEi/ARBs (Group B, n=4) and established hypertension taking ACEi/ARBs (Group C, n=4) were compared using cardiac magnetic imaging.Patients taking ACEi/ARBs had lower end diastolic volume index (EDVi) and end systolic volume index (ESVi) than the other 2 groups ([C] 73.24 vs. [A] 97.92 vs. [B] 101.03 ml/m 2 , ANOVA p=0.034, B vs. C p<0.01). Groups A and B had EDVi and ESVi values at the top of published reference range values; Group C had values in the middle of the range.Acromegaly patients on ACEi/ARBs for hypertension demonstrate improved cardiac indices compared to acromegaly patients with hypertension not taking these medications. Further studies are needed to determine if these drugs have a beneficial cardiac effect in acromegaly in the absence of demonstrable hypertension. © Georg Thieme Verlag KG Stuttgart · New York.

  7. Role of the Renin-Angiotensin-Aldosterone System beyond Blood Pressure Regulation: Molecular and Cellular Mechanisms Involved in End-Organ Damage during Arterial Hypertension

    PubMed Central

    Muñoz-Durango, Natalia; Fuentes, Cristóbal A.; Castillo, Andrés E.; González-Gómez, Luis Martín; Vecchiola, Andrea; Fardella, Carlos E.; Kalergis, Alexis M.

    2016-01-01

    Arterial hypertension is a common condition worldwide and an important predictor of several complicated diseases. Arterial hypertension can be triggered by many factors, including physiological, genetic, and lifestyle causes. Specifically, molecules of the renin-angiotensin-aldosterone system not only play important roles in the control of blood pressure, but they are also associated with the genesis of arterial hypertension, thus constituting a need for pharmacological interventions. Chronic high pressure generates mechanical damage along the vascular system, heart, and kidneys, which are the principal organs affected in this condition. In addition to mechanical stress, hypertension-induced oxidative stress, chronic inflammation, and the activation of reparative mechanisms lead to end-organ damage, mainly due to fibrosis. Clinical trials have demonstrated that renin-angiotensin-aldosterone system intervention in hypertensive patients lowers morbidity/mortality and inflammatory marker levels as compared to placebo patients, evidencing that this system controls more than blood pressure. This review emphasizes the detrimental effects that a renin-angiotensin-aldosterone system (RAAS) imbalance has on health considerations above and beyond high blood pressure, such as fibrotic end-organ damage. PMID:27347925

  8. Role of the Renin-Angiotensin-Aldosterone System beyond Blood Pressure Regulation: Molecular and Cellular Mechanisms Involved in End-Organ Damage during Arterial Hypertension.

    PubMed

    Muñoz-Durango, Natalia; Fuentes, Cristóbal A; Castillo, Andrés E; González-Gómez, Luis Martín; Vecchiola, Andrea; Fardella, Carlos E; Kalergis, Alexis M

    2016-06-23

    Arterial hypertension is a common condition worldwide and an important predictor of several complicated diseases. Arterial hypertension can be triggered by many factors, including physiological, genetic, and lifestyle causes. Specifically, molecules of the renin-angiotensin-aldosterone system not only play important roles in the control of blood pressure, but they are also associated with the genesis of arterial hypertension, thus constituting a need for pharmacological interventions. Chronic high pressure generates mechanical damage along the vascular system, heart, and kidneys, which are the principal organs affected in this condition. In addition to mechanical stress, hypertension-induced oxidative stress, chronic inflammation, and the activation of reparative mechanisms lead to end-organ damage, mainly due to fibrosis. Clinical trials have demonstrated that renin-angiotensin-aldosterone system intervention in hypertensive patients lowers morbidity/mortality and inflammatory marker levels as compared to placebo patients, evidencing that this system controls more than blood pressure. This review emphasizes the detrimental effects that a renin-angiotensin-aldosterone system (RAAS) imbalance has on health considerations above and beyond high blood pressure, such as fibrotic end-organ damage.

  9. Cushing's disease and hypertension: in vivo and in vitro study of the role of the renin-angiotensin-aldosterone system and effects of medical therapy.

    PubMed

    van der Pas, R; van Esch, J H M; de Bruin, C; Danser, A H J; Pereira, A M; Zelissen, P M; Netea-Maier, R; Sprij-Mooij, D M; van den Berg-Garrelds, I M; van Schaik, R H N; Lamberts, S W J; van den Meiracker, A H; Hofland, L J; Feelders, R A

    2014-02-01

    Cushing's disease (CD) is often accompanied by hypertension. CD can be treated surgically and, given the expression of somatostatin subtype 5 and dopamine 2 receptors by corticotroph pituitary adenomas, pharmacologically. Indeed, we recently observed that stepwise medical combination therapy with the somatostatin-analog pasireotide, the dopamine-agonist cabergoline, and ketoconazole (which directly suppresses steroidogenesis) biochemically controlled CD patients and lowered their blood pressure after 80 days. Glucocorticoids (GC) modulate the renin-angiotensin-aldosterone system (RAAS) among others by increasing hepatic angiotensinogen expression and stimulating mineralocorticoid receptors (MR). This study therefore evaluated plasma RAAS components in CD patients before and after drug therapy. In addition, we studied whether cabergoline/pasireotide have direct relaxant effects in angiotensin II (Ang II)-constricted iliac arteries of spontaneously hypertensive rats, with and without concomitant GR/MR stimulation with dexamethasone or hydrocortisone. Baseline concentrations of angiotensinogen were elevated, while renin and aldosterone were low and suppressed, respectively, even in patients treated with RAAS-blockers. This pattern did not change after 80 days of treatment, despite blood pressure normalization, nor after 4 years of remission. In the presence of dexamethasone, pasireotide inhibited Ang II-mediated vasoconstriction. The low plasma renin concentrations, even under RAAS blockade, in CD may be the consequence of increased GC-mediated MR stimulation and/or the elevated angiotensinogen levels in such patients. The lack of change in RAAS-parameters despite blood pressure and cortisol normalization suggests persisting consequences of long-term exposure to cortisol excess. Finally, pasireotide may have a direct vasodilating effect contributing to blood pressure lowering.

  10. Skeletal muscle wasting: new role of nonclassical renin-angiotensin system.

    PubMed

    Cabello-Verrugio, Claudio; Rivera, Juan C; Garcia, Dominga

    2017-05-01

    Skeletal muscle can be affected by many physiological and pathological conditions that contribute to the development of muscle weakness, including skeletal muscle loss, inflammatory processes, or fibrosis. Therefore, research into therapeutic treatment alternatives or alleviation of these effects on skeletal muscle is of great importance. Recent studies have shown that angiotensin (1-7) [Ang-(1-7)] - a vasoactive peptide of the nonclassical axis in the renin-angiotensin system (RAS) - and its Mas receptor are expressed in skeletal muscle. Ang-(1-7), through its Mas receptor, prevents or diminishes deleterious effects induced by skeletal muscle disease or injury. Specifically, the Ang-(1-7)-Mas receptor axis modulates molecular mechanisms involved in muscle mass regulation, such as the ubiquitin proteasome pathway, the insulin-like growth factor type 1/Akt (protein kinase B) pathway, or myonuclear apoptosis, and also inflammation and fibrosis pathways. Although further research into this topic and the possible side effects of Ang-(1-7) is necessary, these findings are promising, and suggest that the Ang-(1-7)-Mas axis can be considered a possible therapeutic target for treating patients with muscular disorders.

  11. Role of the renin-angiotensin system in hepatic fibrosis and portal hypertension.

    PubMed

    Shim, Kwang Yong; Eom, Young Woo; Kim, Moon Young; Kang, Seong Hee; Baik, Soon Koo

    2018-05-01

    The renin-angiotensin system (RAS) is an important regulator of cirrhosis and portal hypertension. As hepatic fibrosis progresses, levels of the RAS components angiotensin (Ang) II, Ang-(1-7), angiotensin-converting enzyme (ACE), and Ang II type 1 receptor (AT1R) are increased. The primary effector Ang II regulates vasoconstriction, sodium homoeostasis, fibrosis, cell proliferation, and inflammation in various diseases, including liver cirrhosis, through the ACE/Ang II/AT1R axis in the classical RAS. The ACE2/Ang-(1-7)/Mas receptor and ACE2/Ang-(1-9)/AT2R axes make up the alternative RAS and promote vasodilation, antigrowth, proapoptotic, and anti-inflammatory effects; thus, countering the effects of the classical RAS axis to reduce hepatic fibrogenesis and portal hypertension. Patients with portal hypertension have been treated with RAS antagonists such as ACE inhibitors, Ang receptor blockers, and aldosterone antagonists, with very promising hemodynamic results. In this review, we examine the RAS, its roles in hepatic fibrosis and portal hypertension, and current therapeutic approaches based on the use of RAS antagonists in patients with portal hypertension.

  12. The retinal renin-angiotensin system: implications for therapy in diabetic retinopathy.

    PubMed

    Sjølie, A K; Chaturvedi, N

    2002-08-01

    Retinopathy is the most common complication of diabetes, and a leading cause of blindness in people of working age. Optimal blood pressure and metabolic control can reduce the risk of diabetic retinopathy, but are difficult to achieve in clinical practice. In the EUCLID Study, the angiotensin converting enzyme (ACE) inhibitor lisinopril reduced the risk of progression of retinopathy by approximately 50%, and also significantly reduced the risk of progression to proliferative retinopathy. These findings are consistent with extensive evidence that the renin-angiotensin system is expressed in the eye, and that adverse effects of angiotensin II on retinal angiogenesis and function can be inhibited by ACE inhibitors or angiotensin II-receptor blockers. However, in the EUCLID Study retinopathy was not a primary end-point and the study was not sufficiently powered for the eye-related outcomes. Hence, the Diabetic Retinopathy Candesartan Trials (DIRECT) programme has been established to determine whether AT(1)-receptor blockade with candesartan can prevent the incidence and progression of diabetic retinopathy. This programme comprises three studies, involving a total of 4500 patients recruited from about 300 centres worldwide. The patients are normotensive or treated hypertensive individuals, and so the DIRECT programme should assess the potential of an AT(1)-receptor blocker to protect against the pathological changes in the eye following diabetes.

  13. Local renin–angiotensin system contributes to hyperthyroidism-induced cardiac hypertrophy

    PubMed Central

    Kobori, H; Ichihara, A; Miyashita, Y; Hayashi, M; Saruta, T

    2008-01-01

    We have reported previously that thyroid hormone activates the circulating and tissue renin–angiotensin systems without involving the sympathetic nervous system, which contributes to cardiac hypertrophy in hyperthyroidism. This study examined whether the circulating or tissue renin–angiotensin system plays the principal role in hyperthyroidism-induced cardiac hypertrophy. The circulating renin–angiotensin system in Sprague–Dawley rats was fixed by chronic angiotensin II infusion (40 ng/ min, 28 days) via mini-osmotic pumps. Daily i.p. injection of thyroxine (0·1 mg/kg per day, 28 days) was used to mimic hyperthyroidism. Serum free tri-iodothyronine, plasma renin activity, plasma angiotensin II, cardiac renin and cardiac angiotensin II were measured with RIAs. The cardiac expression of renin mRNA was evaluated by semiquantitative reverse transcriptase-polymerase chain reaction. Plasma renin activity and plasma angiotensin II were kept constant in the angiotensin II and angiotensin II+thyroxine groups (0·12 ± 0·03 and 0·15 ± 0·03 μg/h per liter, 126 ± 5 and 130 ± 5 ng/l respectively) (means ± s.e.m.). Despite stabilization of the circulating renin–angiotensin system, thyroid hormone induced cardiac hypertrophy (5·0 ± 0·5 vs 3·5 ± 0·1 mg/g) in conjunction with the increases in cardiac expression of renin mRNA, cardiac renin and cardiac angiotensin II (74 ± 2 vs 48 ± 2%, 6·5 ± 0·8 vs 3·8 ± 0·4 ng/h per g, 231 ± 30 vs 149 ± 2 pg/g respectively). These results indicate that the local renin–angiotensin system plays the primary role in the development of hyperthyroidism-induced cardiac hypertrophy. PMID:9854175

  14. Investigating the association of vitamin D with blood pressure and the renin-angiotensin-aldosterone system in hypertensive subjects: a cross-sectional prospective study.

    PubMed

    Cremer, Antoine; Tambosco, Chloé; Corcuff, Jean-Benoît; Boulestreau, Romain; Gaillard, Prune; Lainé, Marion; Papaioannou, Georgios; Gosse, Philippe

    2018-02-01

    The hypothesis that vitamin D (25(OH)D) insufficiency plays a role in occurring of various disease has led to a rise in requests of dosages and to an increase of health-care costs. 25(OH)D insufficiency is associated with increased risk of cardiovascular disease and hypertension in many studies. Animal studies demonstrated that 25(OH)D insufficiency activates renin angiotensin system but corresponding humans data are limited. The aim of the study was to document relationship between 25(OH)D, blood pressure, and renin angiotensin system in hypertensive subjects. In all, 248 hypertensive individuals, 46.8 years (±14), were hospitalized for an etiological assessment of hypertension in this cross-sectional study over two calendar years. 25(OH)D, plasma renin activity, and aldosterone were determined in stringent conditions and blood pressure was measure. Statistical analyses were carried out to analyze the association between 25(OH)D, blood pressure, and renin angiotensin system using linear and logistic regressions with adjustments on relevant variables. In all, 80% of the studied population had a 25(OH)D insufficiency. There were no significant association between 25(OH)D and levels of systolic or diastolic blood pressure, plasma renin activity, and aldosterone whatever the statiscal method used after adjustment. 25(OH)D is not associated with blood pressure and renin angiontensin component in hypertensive subjects. These results corroborate the interventional studies which are for a large majority negatives. A new definition of the 25(OH)D insufficiency in general population is necessary.

  15. The role of the renin-angiotensin system in the development of insulin resistance in skeletal muscle.

    PubMed

    Henriksen, Erik J; Prasannarong, Mujalin

    2013-09-25

    The canonical renin-angiotensin system (RAS) involves the initial action of renin to cleave angiotensinogen to angiotensin I (ANG I), which is then converted to ANG II by the angiotensin converting enzyme (ACE). ANG II plays a critical role in numerous physiological functions, and RAS overactivity underlies many conditions of cardiovascular dysregulation. In addition, ANG II, by acting on both endothelial and myocellular AT1 receptors, can induce insulin resistance by increasing cellular oxidative stress, leading to impaired insulin signaling and insulin-stimulated glucose transport activity. This insulin resistance associated with RAS overactivity, when coupled with progressive ß-cell dysfunction, eventually leads to the development of type 2 diabetes. Interventions that target RAS overactivity, including ACE inhibitors, ANG II receptor blockers, and, most recently, renin inhibitors, are effective both in reducing hypertension and in improving whole-body and skeletal muscle insulin action, due at least in part to enhanced Akt-dependent insulin signaling and insulin-dependent glucose transport activity. ANG-(1-7), which is produced from ANG II by the action of ACE2 and acts via Mas receptors, can counterbalance the deleterious actions of the ACE/ANG II/AT1 receptor axis on the insulin-dependent glucose transport system in skeletal muscle. This beneficial effect of the ACE2/ANG-(1-7)/Mas receptor axis appears to depend on the activation of Akt. Collectively, these findings underscore the importance of RAS overactivity in the multifactorial etiology of insulin resistance in skeletal muscle, and provide support for interventions that target the RAS to ameliorate both cardiovascular dysfunctions and insulin resistance in skeletal muscle tissue. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  16. Effect of propranolol on the splanchnic and peripheral renin angiotensin system in cirrhotic patients

    PubMed Central

    Vilas-Boas, Walkíria Wingester; Jr, Antônio Ribeiro-Oliveira; da Cunha Ribeiro, Renata; Vieira, Renata Lúcia Pereira; Almeida, Jerusa; Nadu, Ana Paula; Silva, Ana Cristina Simões e; Santos, Robson Augusto Souza

    2008-01-01

    AIM: To evaluate the effect of β-blockade on angiotensins in the splanchnic and peripheral circulation of cirrhotic patients and also to compare hemodynamic parameters during liver transplantation according to propranolol pre-treatment or not. METHODS: Patients were allocated into two groups: outpatients with advanced liver disease(LD) and during liver transplantation(LT). Both groups were subdivided according to treatment with propranolol or not. Plasma was collected through peripheral venipuncture to determine plasma renin activity(PRA), Angiotensin(Ang) I, Ang II, and Ang-(1-7) levels by radioimmunoassay in LD group. During liver transplantation, hemodynamic parameters were determined and blood samples were obtained from the portal vein to measure renin angiotensin system(RAS) components. RESULTS: PRA, Ang I, Ang II and Ang-(1-7) were significantly lower in the portal vein and periphery in all subgroups treated with propranolol as compared to non-treated. The relationships between Ang-(1-7) and Ang I levels and between Ang II and Ang I were significantly increased in LD group receiving propranolol. The ratio between Ang-(1-7) and Ang II remained unchanged in splanchnic and peripheral circulation in patients under β-blockade, whereas the relationship between Ang II and Ang I was significantly increased in splanchnic circulation of LT patients treated with propranolol. During liver transplantation, cardiac output and index as well systemic vascular resistance and index were reduced in propranolol-treated subgroup. CONCLUSION: In LD group, propranolol treatment reduced RAS mediators, but did not change the ratio between Ang-(1-7) and Ang II in splanchnic and peripheral circulation. Furthermore, the modification of hemodynamic parameters in propranolol treated patients was not associated with changes in the angiotensin ratio. PMID:19058308

  17. Impact of Renin-Angiotensin Aldosterone System Inhibition on Serum Potassium Levels among Peritoneal Dialysis Patients.

    PubMed

    Ribeiro, Silvia Carreira; Figueiredo, Ana Elizabeth; Barretti, Pasqual; Pecoits-Filho, Roberto; de Moraes, Thyago Proença

    2017-01-01

    The chronic use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blocker has been associated with hyperkalemia in patients with reduced renal function even after the initiation of hemodialysis. Whether such medications may cause a similar effect in peritoneal dialysis patients is not well established. So, the aim of our study was to analyze the impact of renin-angiotensin-aldosterone inhibitors on the serum levels of potassium in a national cohort of peritoneal dialysis patients. A prospective, observational, nationwide cohort study was conducted. We identified all incident patients on peritoneal dialysis that had angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) prescribed for at least 3 months and a similar period of time without these medications. Patients were divided into 4 groups: Groups I and III correspond to patients using, respectively, an ACEi or ARB and then got the drug suspended; Groups II and IV started peritoneal dialysis without the use of any renin-angiotensin aldosterone system inhibitor and then got, respectively, an ACEi or ARB introduced. Changes in potassium serum levels were compared using 2 statistical approaches: (1) the non-parametric Wilcoxon test for repeated measures and (2) a crossover analysis. Mean potassium serum levels at the first phase of the study for Groups I, II, III, and IV were, respectively, 4.46 ± 0.79, 4.33 ± 0.78, 4.41 ± 0.63, and 4.44 ± 0.56. Changes in mean potassium serum levels for Groups I, II, III, and IV were -0.10 ± 0.60, 0.02 ± 0.56, -0.06 ± 0.46, and 0.03 ± 0.50, respectively. The use of ACEi and ARB was not associated with a greater risk for hyperkalemia in stable peritoneal dialysis patients independently of residual renal function. © 2017 S. Karger AG, Basel.

  18. Race, obesity, and the renin-angiotensin-aldosterone system: treatment response in children with primary hypertension.

    PubMed

    South, Andrew M; Arguelles, Lester; Finer, Gal; Langman, Craig B

    2017-09-01

    Pediatric primary hypertension (HTN) is increasingly recognized, but the effect of patient characteristics such as obesity and race on treatment outcomes is not well described. The renin-angiotensin-aldosterone system (RAAS) may also contribute to HTN. We hypothesized patient parameters of these factors, including baseline RAAS, influence blood pressure (BP) response to pharmacological treatment in HTN. This was a retrospective cohort of 102 consecutive patients with HTN. Primary outcomes were changes per year in systolic and diastolic BP (SBP, DBP). Secondary outcome was change per year in left ventricular mass index (LVMI). We evaluated whether baseline plasma renin activity (PRA), aldosterone, renin-to-aldosterone ratio, overweight/obesity, race, initial drug choice, and multidrug therapy were associated with the outcomes using general linear regression models adjusted for confounding variables. Racially diverse (43% Hispanic, 28% black, 25% white) and predominantly overweight/obese (75%) patients were studied. Median length of follow-up was 14.5 months. Higher baseline aldosterone was associated with decreased SBP (-1.03 mmHg/year), DBP (-0.95 mmHg/year), and DBP z score (-0.07/year) during the study period. Higher baseline PRA was associated with decreased SBP z score (-0.04/year) and LVMI (-2.89 g/m 2.7 /year). Stratified analyses revealed the relationships between baseline aldosterone and PRA, and annual reductions in outcomes were strengthened in nonobese and white patients. Pretreatment aldosterone and PRA predicted short-term follow-up BP and LVMI, especially in nonobese and white patients. The RAAS profile could guide treatment of HTN and suggests consideration of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers as first-line treatment options.

  19. New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) II: Albumin Suppresses Angiotensin Converting Enzyme (ACE) Activity in Human

    PubMed Central

    Fagyas, Miklós; Úri, Katalin; Siket, Ivetta M.; Fülöp, Gábor Á.; Csató, Viktória; Daragó, Andrea; Boczán, Judit; Bányai, Emese; Szentkirályi, István Elek; Maros, Tamás Miklós; Szerafin, Tamás; Édes, István; Papp, Zoltán; Tóth, Attila

    2014-01-01

    About 8% of the adult population is taking angiotensin-converting enzyme (ACE) inhibitors to treat cardiovascular disease including hypertension, myocardial infarction and heart failure. These drugs decrease mortality by up to one-fifth in these patients. We and others have reported previously that endogenous inhibitory substances suppress serum ACE activity, in vivo, similarly to the ACE inhibitor drugs. Here we have made an effort to identify this endogenous ACE inhibitor substance. ACE was crosslinked with interacting proteins in human sera. The crosslinked products were immunoprecipitated and subjected to Western blot. One of the crosslinked products was recognized by both anti-ACE and anti-HSA (human serum albumin) antibodies. Direct ACE-HSA interaction was confirmed by binding assays using purified ACE and HSA. HSA inhibited human purified (circulating) and human recombinant ACE with potencies (IC50) of 5.7±0.7 and 9.5±1.1 mg/mL, respectively. Effects of HSA on the tissue bound native ACE were tested on human saphenous vein samples. Angiotensin I evoked vasoconstriction was inhibited by HSA in this vascular tissue (maximal force with HSA: 6.14±1.34 mN, without HSA: 13.54±2.63 mN), while HSA was without effects on angiotensin II mediated constrictions (maximal force with HSA: 18.73±2.17 mN, without HSA: 19.22±3.50 mN). The main finding of this study is that HSA was identified as a potent physiological inhibitor of the ACE. The enzymatic activity of ACE appears to be almost completely suppressed by HSA when it is present in its physiological concentration. These data suggest that angiotensin I conversion is limited by low physiological ACE activities, in vivo. PMID:24691203

  20. New Frontiers in the Intrarenal Renin-Angiotensin System: A Critical Review of Classical and New Paradigms

    PubMed Central

    Zhuo, Jia L.; Ferrao, Fernanda M.; Zheng, Yun; Li, Xiao C.

    2013-01-01

    The renin-angiotensin system (RAS) is well-recognized as one of the oldest and most important regulators of arterial blood pressure, cardiovascular, and renal function. New frontiers have recently emerged in the RAS research well beyond its classic paradigm as a potent vasoconstrictor, an aldosterone release stimulator, or a sodium-retaining hormone. First, two new members of the RAS have been uncovered, which include the renin/(Pro)renin receptor (PRR) and angiotensin-converting enzyme 2 (ACE2). Recent studies suggest that prorenin may act on the PRR independent of the classical ACE/ANG II/AT1 receptor axis, whereas ACE2 may degrade ANG II to generate ANG (1–7), which activates the Mas receptor. Second, there is increasing evidence that ANG II may function as an intracellular peptide to activate intracellular and/or nuclear receptors. Third, currently there is a debate on the relative contribution of systemic versus intrarenal RAS to the physiological regulation of blood pressure and the development of hypertension. The objectives of this article are to review and discuss the new insights and perspectives derived from recent studies using novel transgenic mice that either overexpress or are deficient of one key enzyme, ANG peptide, or receptor of the RAS. This information may help us better understand how ANG II acts, both independently or through interactions with other members of the system, to regulate the kidney function and blood pressure in health and disease. PMID:24273531

  1. Role of H2O2 in hypertension, renin-angiotensin system activation and renal medullary disfunction caused by angiotensin II

    PubMed Central

    Sousa, T; Oliveira, S; Afonso, J; Morato, M; Patinha, D; Fraga, S; Carvalho, F; Albino-Teixeira, A

    2012-01-01

    BACKGROUND AND PURPOSE Activation of the intrarenal renin-angiotensin system (RAS) and increased renal medullary hydrogen peroxide (H2O2) contribute to hypertension. We examined whether H2O2 mediated hypertension and intrarenal RAS activation induced by angiotensin II (Ang II). EXPERIMENTAL APPROACH Ang II (200 ng·kg−1·min−1) or saline were infused in Sprague Dawley rats from day 0 to day 14. Polyethylene glycol (PEG)-catalase (10 000 U·kg−1·day−1) was given to Ang II-treated rats, from day 7 to day 14. Systolic blood pressure was measured throughout the study. H2O2, angiotensin AT1 receptor and Nox4 expression and nuclear factor-κB (NF-κB) activation were evaluated in the kidney. Plasma and urinary H2O2 and angiotensinogen were also measured. KEY RESULTS Ang II increased H2O2, AT1 receptor and Nox4 expression and NF-κB activation in the renal medulla, but not in the cortex. Ang II raised plasma and urinary H2O2 levels, increased urinary angiotensinogen but reduced plasma angiotensinogen. PEG-catalase had a short-term antihypertensive effect and transiently suppressed urinary angiotensinogen. PEG-catalase decreased renal medullary expression of AT1 receptors and Nox4 in Ang II-infused rats. Renal medullary NF-κB activation was correlated with local H2O2 levels and urinary angiotensinogen excretion. Loss of antihypertensive efficacy was associated with an eightfold increase of plasma angiotensinogen. CONCLUSIONS AND IMPLICATIONS The renal medulla is a major target for Ang II-induced redox dysfunction. H2O2 appears to be the key mediator enhancing intrarenal RAS activation and decreasing systemic RAS activity. The specific control of renal medullary H2O2 levels may provide future grounds for the treatment of hypertension. PMID:22452317

  2. Maternal Dexamethasone Treatment Alters Tissue and Circulating Components of the Renin-Angiotensin System in the Pregnant Ewe and Fetus

    PubMed Central

    Jellyman, Juanita K.; De Blasio, Miles J.; Johnson, Emma; Giussani, Dino A.; Broughton Pipkin, Fiona; Fowden, Abigail L.

    2015-01-01

    Antenatal synthetic glucocorticoids promote fetal maturation in pregnant women at risk of preterm delivery and their mechanism of action may involve other endocrine systems. This study investigated the effect of maternal dexamethasone treatment, at clinically relevant doses, on components of the renin-angiotensin system (RAS) in the pregnant ewe and fetus. From 125 days of gestation (term, 145 ± 2 d), 10 ewes carrying single fetuses of mixed sex (3 female, 7 male) were injected twice im, at 10–11 pm, with dexamethasone (2 × 12 mg, n = 5) or saline (n = 5) at 24-hour intervals. At 10 hours after the second injection, maternal dexamethasone treatment increased angiotensin-converting enzyme (ACE) mRNA levels in the fetal lungs, kidneys, and heart and ACE concentration in the circulation and lungs, but not kidneys, of the fetuses. Fetal cardiac mRNA abundance of angiotensin II (AII) type 2 receptor decreased after maternal dexamethasone treatment. Between the two groups of fetuses, there were no significant differences in plasma angiotensinogen or renin concentrations; in transcript levels of renal renin, or AII type 1 or 2 receptors in the lungs and kidneys; or in pulmonary, renal or cardiac protein content of the AII receptors. In the pregnant ewes, dexamethasone administration increased pulmonary ACE and plasma angiotensinogen, and decreased plasma renin, concentrations. Some of the effects of dexamethasone treatment on the maternal and fetal RAS were associated with altered insulin and thyroid hormone activity. Changes in the local and circulating RAS induced by dexamethasone exposure in utero may contribute to the maturational and tissue-specific actions of antenatal glucocorticoid treatment. PMID:26039155

  3. The intricacies of the renin angiotensin system in metabolic regulation

    PubMed Central

    Bruce, Erin; de Kloet, Annette D.

    2017-01-01

    Over recent years, the renin-angiotensin-system (RAS), which is best-known as an endocrine system with established roles in hydromineral balance and blood pressure control, has emerged as a fundamental regulator of many additional physiological and pathophysiological processes. In this manuscript, we celebrate and honor Randall Sakai’s commitment to his trainees, as well as his contribution to science. Scientifically, Randall made many notable contributions to the recognition of the RAS’s roles in brain and behavior. His interests, in this regard, ranged from its traditionally-accepted roles in hydromineral balance, to its less-appreciated functions in stress responses and energy metabolism. Here we review the current understanding of the role of the RAS in the regulation of metabolism. In particular, the opposing actions of the RAS within adipose tissue vs. its actions within the brain are discussed. PMID:27887998

  4. Losartan, an Angiotensin type I receptor, restores erectile function by downregulation of cavernous renin-angiotensin system in streptozocin-induced diabetic rats.

    PubMed

    Yang, Rong; Yang, Bin; Wen, Yanting; Fang, Feng; Cui, Souxi; Lin, Guiting; Sun, Zeyu; Wang, Run; Dai, Yutian

    2009-03-01

    The high incidence of erectile dysfunction (ED) in diabetes highlights the need for good treatment strategies. Recent evidence indicates that blockade of the angiotensin type I receptor (AT1) may reverse ED from various diseases. To explore the role of cavernous renin-angiotensin system (RAS) in the pathogenesis of diabetic ED and the role of losartan in the treatment of diabetic ED. The AT1 blocker (ARB) losartan (30 mg/kg/d) was administered to rats with streptozocin (65 mg/kg)-induced diabetes. Erectile function, cavernous structure, and tissue gene and protein expression of RAS in the corpora cavernosa were studied. We sought to determine the changes of cavernous RAS in the condition of diabetes and after treatment with losartan. RAS components (angiotensinogen, [pro]renin receptor, angiotensin-converting enzyme [ACE], and AT1) were expressed in cavernosal tissue. In diabetic rats, RAS components were upregulated, resulting in the increased concentration of angiotensin II (Ang II) in the corpora. A positive feedback loop for Ang II formation in cavernosum was also identified, which could contribute to overactivity of cavernous RAS in diabetic rats. Administration of losartan blocked the effect of Ang II, downregulated the expression of AT1 and Ang II generated locally, and partially restored erectile function (losartan-treated group revealed an improved intracavernous pressure/mean systemic arterial pressure ratio as compared with the diabetic group (0.480 +/- 0.031 vs. 0.329 +/- 0.020, P < 0.01). However, losartan could not elevate the reduced smooth muscle/collagen ratio in diabetic rats. The cavernous RAS plays a role in modulating erectile function in corpora cavernosa and is involved in the pathogenesis of diabetic ED. ARB can restore diabetic ED through downregulating cavernous RAS.

  5. The Renin-Angiotensin-Aldosterone System in Greyhounds and Non-Greyhound Dogs.

    PubMed

    Martinez, J; Kellogg, C; Iazbik, M C; Couto, C G; Pressler, B M; Hoepf, T M; Radin, M J

    2017-07-01

    The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure, electrolyte homeostasis, and renal function. Blood pressure, serum sodium concentrations, and urinary albumin excretion are higher in Greyhounds than other purebred and mixed-breed dogs. Alterations in the RAAS in Greyhounds are associated with hemodynamic and clinicopathologic differences observed in the breed. Clinically healthy Greyhound and non-Greyhound dogs consecutively enrolled as blood donors (n = 20/group). Prospective study. Standard chemical analysis was performed on serum and urine. Serum angiotensin-converting enzyme (ACE) activity was determined by fluorometric assay. All other RAAS hormones were determined by radioimmunoassay. Symmetric dimethylarginine (SDMA) was measured by immunoassay. Measurements were compared to blood pressure and urine albumin concentration. Data are presented as mean ± SD or median, range. Serum creatinine (1.5 ± 0.2 vs 1.0 ± 0.1 mg/dL, P < .001), sodium (149, 147-152 vs 148, 146-150 mEq/L, P = .017), and SDMA (16.1 ± 2.9 vs 12.2 ± 1.8 μg/dL, P < .001) were significantly higher in Greyhounds versus non-Greyhounds, respectively. Plasma renin activity (0.69, 0.10-1.93 vs 0.65, 0.27-2.93 ng/mL/h, P = .60) and ACE activity (4.5, 2.1-8.5 vs 4.6, 2.1-11.4 activity/mL; P = .77) were similar between groups and did not correlate with higher systolic pressures and albuminuria in Greyhounds. Plasma aldosterone concentration was significantly lower in Greyhounds versus non-Greyhounds (11, 11-52 vs 15, 11-56 pg/mL, respectively, P = .002). Basal RAAS activation did not differ between healthy Greyhounds and non-Greyhounds. Lower aldosterone concentration in Greyhounds is an appropriate physiologic response to higher serum sodium concentration and blood pressure, suggesting that angiotensin II effects in the renal tubule predominate over those of aldosterone. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals

  6. Effect of chronic diuretic treatment on the plasma renin-angiotensin-aldosterone system in essential hypertension.

    PubMed Central

    Lijnen, P; Fagard, R; Staessen, J; Amery, A

    1981-01-01

    1 Chronic treatment with a constant dose of hydrochlorothiazide or tienilic acid increases plasma renin activity (PRA) acutely to reach a maximum within the first week. 2 During chronic diuretic therapy from 1 month to 1 year, PRA remained elevated at a rather constant level, though this was somewhat lower than the maximum level reached after 1 week. 3 A significant (P less than 0.01) correlation (r = 0.74) between changes in plasma angiotensin II and renin activity provoked by chronic treatment for 3 months with hydrochlorothiazide and tienilic acid was found. 4 The increase in plasma aldosterone during chronic treatment with hydrochlorothiazide and tienilic acid (1000 mg) is related (r = 0.68; P less than 0.01) to the rise in plasma angiotensin II. PMID:7028060

  7. Dual renin-angiotensin-aldosterone system blockade for diabetic kidney disease.

    PubMed

    Pichler, Raimund H; de Boer, Ian H

    2010-08-01

    Blockade of the renin-angiotensin-aldosterone system (RAAS) prevents the development and progression of diabetic kidney disease (DKD). It is controversial whether the simultaneous use of two RAAS inhibitors (ie, dual RAAS blockade) further improves renal outcomes. This review examines the scientific rationale and current clinical evidence addressing the use of dual RAAS blockade to prevent and treat DKD. It is concluded that dual RAAS blockade should not be routinely applied to patients with low or moderate risk of progressive kidney disease (normoalbuminuria or microalbuminuria with preserved glomerular filtration rate). For patients with high risk of progressive kidney disease (substantial albuminuria or impaired glomerular filtration rate), clinicians should carefully weigh the potential risks and benefits of dual RAAS blockade on an individual basis until ongoing clinical trials provide further insight.

  8. Capturing the dynamics of systemic Renin-Angiotensin-Aldosterone System (RAAS) peptides heightens the understanding of the effect of benazepril in dogs.

    PubMed

    Mochel, J P; Peyrou, M; Fink, M; Strehlau, G; Mohamed, R; Giraudel, J M; Ploeger, B; Danhof, M

    2013-04-01

    In dogs, activation of the Renin-Angiotensin-Aldosterone System (RAAS) is an important feature of congestive heart failure (CHF). Long-term increases in angiotensin II (AII) and aldosterone (ALD) lead to the progression of heart failure to its end stage. Angiotensin-converting enzyme inhibitors (ACEIs) are the foremost therapeutic option in the management of CHF. Recent literature has challenged the efficacy of ACEIs, based on modest reduction in urinary aldosterone (UALD) excretion despite marked inhibition of ACE activity. This study was designed to heighten the understanding of the effect of benazepril, a potent ACEI, on the RAAS, using a low-sodium diet as an experimental model of RAAS activation. Time course profiles of RAAS peptides and related areas under the curve (AUC) were used for comparison between benazepril and placebo groups. Results indicated substantial changes in the dynamics of these biomarkers. At presumed benazeprilat steady state, significant differences in AUC of plasma renin activity (+90%), angiotensin I (+43%), and AII (-53%) were found between benazepril and placebo-treated dogs. ALD decreased by 73% in plasma but only by 5% in urine. In conclusion, despite modest reduction in UALD excretion, benazepril markedly influences RAAS dynamics in dogs. © 2012 Blackwell Publishing Ltd.

  9. Changes in the renin-angiotensin-aldosterone system in response to dietary salt intake in normal and hypertensive pregnancy. A randomized trial.

    PubMed

    Nielsen, Lise H; Ovesen, Per; Hansen, Mie R; Brantlov, Steven; Jespersen, Bente; Bie, Peter; Jensen, Boye L

    2016-11-01

    It was hypothesized that primary renal sodium retention blunted the reactivity of the renin-angiotensin-aldosterone system to changes in salt intake in preeclampsia (PE). A randomized, cross-over, double-blinded, dietary intervention design was used to measure the effects of salt tablets or placebo during low-salt diet in PE patients (n = 7), healthy pregnant women (n = 15), and nonpregnant women (n = 13). High-salt intake decreased renin and angiotensin II concentrations significantly in healthy pregnant women (P < .03) and in nonpregnant women (P < .001), but not in PE (P = .58), while decreases in aldosterone and increases in brain natriuretic peptid (BNP) were similar in the groups. In PE patients, uterine and umbilical artery indices were not adversely changed during low-salt diet. Creatinine clearance was significantly lower in PE with no change by salt intake. PE patients displayed alterations of plasma renin and angiotensin II in response to changes in dietary salt intake compatible with a primary increase in renal sodium reabsorption in hypertensive pregnancies. Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

  10. Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration

    PubMed Central

    Labandeira-Garcia, Jose L.; Rodríguez-Perez, Ana I.; Garrido-Gil, Pablo; Rodriguez-Pallares, Jannette; Lanciego, Jose L.; Guerra, Maria J.

    2017-01-01

    Microglia can transform into proinflammatory/classically activated (M1) or anti-inflammatory/alternatively activated (M2) phenotypes following environmental signals related to physiological conditions or brain lesions. An adequate transition from the M1 (proinflammatory) to M2 (immunoregulatory) phenotype is necessary to counteract brain damage. Several factors involved in microglial polarization have already been identified. However, the effects of the brain renin-angiotensin system (RAS) on microglial polarization are less known. It is well known that there is a “classical” circulating RAS; however, a second RAS (local or tissue RAS) has been observed in many tissues, including brain. The locally formed angiotensin is involved in local pathological changes of these tissues and modulates immune cells, which are equipped with all the components of the RAS. There are also recent data showing that brain RAS plays a major role in microglial polarization. Level of microglial NADPH-oxidase (Nox) activation is a major regulator of the shift between M1/proinflammatory and M2/immunoregulatory microglial phenotypes so that Nox activation promotes the proinflammatory and inhibits the immunoregulatory phenotype. Angiotensin II (Ang II), via its type 1 receptor (AT1), is a major activator of the NADPH-oxidase complex, leading to pro-oxidative and pro-inflammatory effects. However, these effects are counteracted by a RAS opposite arm constituted by Angiotensin II/AT2 receptor signaling and Angiotensin 1–7/Mas receptor (MasR) signaling. In addition, activation of prorenin-renin receptors may contribute to activation of the proinflammatory phenotype. Aged brains showed upregulation of AT1 and downregulation of AT2 receptor expression, which may contribute to a pro-oxidative pro-inflammatory state and the increase in neuron vulnerability. Several recent studies have shown interactions between the brain RAS and different factors involved in microglial polarization, such as

  11. Inhibiting renin angiotensin system in rate limiting step by aliskiren as a new approach for preventing indomethacin induced gastric ulcers.

    PubMed

    Halici, Zekai; Polat, Beyzagul; Cadirci, Elif; Topcu, Atilla; Karakus, Emre; Kose, Duygu; Albayrak, Abdulmecit; Bayir, Yasin

    2016-10-25

    Previously blocking the renin angiotensin system (RAAS) has been effective in the prevention of gastric damage. Therefore, the aim of this study was to investigate the effects of aliskiren, and thus, direct renin blockage, in indomethacin-induced gastric damage model. Effects of aliskiren were evaluated in indomethacin-induced gastric damage model on Albino Wistar rats. Effects of famotidine has been investigated as standard antiulcer agent. Stereological analyses for ulcer area determination, biochemical analyses for oxidative status determination and molecular analyses for tissue cytokine and cyclooxygenase determination were performed on stomach tissues. In addition, to clarify antiulcer effect mechanism of aliskiren pylorus ligation-induced gastric acid secretion model was applied on rats. Aliskiren was able to inhibit indomethacin-induced ulcer formation. It also inhibited renin, and thus, decreased over-produced Angiotensin-II during ulcer formation. Aliskiren improved the oxidative status and cytokine profile of the stomach, which was most probably impaired by increased Angiotensin II concentration. Aliskiren also increased gastroprotective prostaglandin E2 concentration. Finally, aliskiren did not change the gastric acidity in pylorus ligation model. Aliskiren exerted its protective effects on stomach tissue by decreasing inflammatory cytokines and oxidative stress as a result of inhibiting the RAAS, at a rate-limiting step, as well as its end product, angiotensin II. Aliskiren also significantly increased protective factors such as PGE2, but not affect aggressive factors such as gastric acidity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. [Pathophysiological role of tissue renin-angiotensin-aldosterone system (RAAS) in human atherosclerosis].

    PubMed

    Fukui, Kensuke; Yamada, Hiroyuki; Matsubara, Hiroaki

    2012-09-01

    Renin-angiotensin-aldosterone system (RAAS) has been demonstrated to play an important role in the pathogenesis of atherosclerosis development both in animal experiments and in clinical studies. Numerous clinical studies have shown that blockade of RAAS exerts beneficial effects to restore the impaired endothelial function and to reduce the mortality and morbidity of cardiovascular diseases beyond their blood pressure lowering effect. However, the underlying mechanisms of stabilizing vulnerable plaque and inhibiting plaque rupture associated with acute coronary syndrome have not yet been fully elucidated. Here, we summarized the characteristics of tissue RAAS expressions in human atherosclerotic lesions and assessed their therapeutic relevance in the prevention of atherosclerotic cardiovascular diseases.

  13. Familial Analysis of Epistatic and Sex-Dependent Association of Genes of the Renin-Angiotensin-Aldosterone System and Blood Pressure.

    PubMed

    Scurrah, Katrina J; Lamantia, Angela; Ellis, Justine A; Harrap, Stephen B

    2017-06-01

    Renin-angiotensin-aldosterone system genes have been inconsistently associated with blood pressure, possibly because of unrecognized influences of sex-dependent genetic effects or gene-gene interactions (epistasis). We tested association of systolic blood pressure with single-nucleotide polymorphisms (SNPs) at renin ( REN ), angiotensinogen ( AGT ), angiotensin-converting enzyme ( ACE ), angiotensin II type 1 receptor ( AGTR1 ), and aldosterone synthase ( CYP11B2 ), including sex-SNP or SNP-SNP interactions. Eighty-eight tagSNPs were tested in 2872 white individuals in 809 pedigrees from the Victorian Family Heart Study using variance components models. Three SNPs (rs8075924 and rs4277404 at ACE and rs12721297 at AGTR1 ) were individually associated with lower systolic blood pressure with significant ( P <0.00076) effect sizes ≈1.7 to 2.5 mm Hg. Sex-specific associations were seen for 3 SNPs in men (rs2468523 and rs2478544 at AGT and rs11658531 at ACE ) and 1 SNP in women (rs12451328 at ACE ). SNP-SNP interaction was suggested ( P <0.005) for 14 SNP pairs, none of which had shown individual association with systolic blood pressure. Four SNP pairs were at the same gene (2 for REN , 1 for AGT , and 1 for AGTR1 ). The SNP rs3097 at CYP11B2 was represented in 5 separate pairs. SNPs at key renin-angiotensin-aldosterone system genes associate with systolic blood pressure individually in both sexes, individually in one sex only and only when combined with another SNP. Analyses that incorporate sex-dependent and epistatic effects could reconcile past inconsistencies and account for some of the missing heritability of blood pressure and are generally relevant to SNP association studies for any phenotype. © 2017 American Heart Association, Inc.

  14. CHBPR: ANGIOTENSIN II, INDEPENDENT OF PLASMA RENIN ACTIVITY, CONTRIBUTES TO THE HYPERTENSION OF AUTONOMIC FAILURE

    PubMed Central

    Arnold, Amy C.; Okamoto, Luis E.; Gamboa, Alfredo; Shibao, Cyndya; Raj, Satish R.; Robertson, David; Biaggioni, Italo

    2013-01-01

    At least half of primary autonomic failure patients exhibit supine hypertension, despite profound impairments in sympathetic activity. While the mechanisms underlying this hypertension are unknown, plasma renin activity is often undetectable suggesting renin-angiotensin pathways are not involved. However, because aldosterone levels are preserved, we tested the hypothesis that angiotensin II is intact and contributes to the hypertension of autonomic failure. Indeed, circulating angiotensin II was paradoxically increased in hypertensive autonomic failure patients (52±5 pg/ml, n=11) compared to matched healthy controls (27±4 pg/ml, n=10; p=0.002), despite similarly low renin activity (0.19±0.06 versus 0.34±0.13 ng/ml/hr, respectively; p=0.449). To determine the contribution of angiotensin II to supine hypertension in these patients, we administered the AT1 receptor blocker losartan (50 mg) at bedtime in a randomized, double-blind, placebo-controlled study (n=11). Losartan maximally reduced systolic blood pressure by 32±11 mmHg at 6 hours after administration (p<0.05), decreased nocturnal urinary sodium excretion (p=0.0461), and did not worsen morning orthostatic tolerance. In contrast, there was no effect of the captopril on supine blood pressure in a subset of these patients. These findings suggest that angiotensin II formation in autonomic failure is independent of plasma renin activity, and perhaps angiotensin converting enzyme. Furthermore, these studies suggest that elevations in angiotensin II contribute to the hypertension of autonomic failure, and provide rationale for the use of AT1 receptor blockers for treatment of these patients. PMID:23266540

  15. Epistatic Effects of Polymorphisms in Genes from the Renin-Angiotensin, Bradykinin, and Fibrinolytic Systems on Plasma t-PA and PAI-1 Levels

    PubMed Central

    Asselbergs, Folkert W.; Williams, Scott M.; Hebert, Patricia R.; Coffey, Christopher S.; Hillege, Hans L.; Navis, Gerjan; Vaughan, Douglas E.; van Gilst, Wiek H.; Moore, Jason H.

    2007-01-01

    Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thereby risk for arterial thrombosis. Activation of the renin-angiotensin system has been linked to the production of PAI-1 expression via the angiotensin II type 1 receptor (AT1R). In addition, bradykinin can induce the release of t-PA through a B2 receptor mechanism. In the present study, we aimed to investigate the epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin and fibrinolytic systems on plasma t-PA and PAI-1 levels in a large population-based sample (n=2,527). We demonstrated a strong significant interaction within genetic variations of the bradykinin B2 gene (p=0.002) and between ACE and bradykinin B2 (p=0.003) polymorphisms on t-PA levels in females. In males, polymorphisms in the bradykinin B2 and AT1R gene showed the most strong effect on t-PA levels (p=0.006). In both females as well as males, the bradykinin B2 gene interacted with AT1R gene on plasma PAI-1 levels (p=0.026 and p=0.039, respectively). In addition, the current study found a borderline significant interaction between PAI 4G5G and ACE I/D on plasma t-PA and PAI-1 levels. These results support the idea that the interplay between the renin-angiotensin, bradykinin, and fibrinolytic systems might play an important role in t-PA and PAI-1 biology. PMID:17207964

  16. Alteration at transcriptional level of cardiac renin-angiotensin system by letrozole treatment.

    PubMed

    Shekarforoush, Shahnaz; Koohpeyma, Farhad; Safari, Fatemeh

    2018-06-17

    The use of aromatase inhibitors (AIs) for breast cancer led to a marked change in ventricular function. Since accumulating evidence indicates that overactivation of the cardiac renin-angiotensin system (RAS) plays an important role in the development of cardiovascular diseases such as hypertrophy and remodelling, we aimed to investigate whether letrozole alters the transcription level of RAS related genes in the cardiac tissue. Twenty four rats were randomly divided into four groups (n = 6 per group): two groups were letrozole treated (1 and 2 mg/kg/day orally), one group was vehicle treated (DMSO) and one group was the control group without any treatment. 12 weeks after beginning treatment with letrozole, we examined the rate of transcription of renin, angiotensinogen, AngII type 1a and 1b (AT1a and AT1b) and type 2 receptors (AT2) in the rat heart using real-time polymerase chain reaction. The cardiac mRNA levels of several components of the RAS in the rats treated with letrozole were significantly increased including AT1a receptor (80%), renin (51%), and angiotensinogen (33%). Though not significant, AT2 receptor levels were observed to decrease with increasing doses of letrozole. Letrozole can induce significant changes in some RAS related genes. These alterations are important to understand the pathways and consequences beyond cardiac events induced by breast cancer treatments.

  17. Aldosterone response to angiotensin II during hypoxemia

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Colice, G.L.; Ramirez, G.

    1986-07-01

    Exercise stimulates the renin-angiotensin-aldosterone system (RAAS). However, increases in plasma aldosterone concentrations (PAC) are suppressed when exercise is performed at high altitude or under hypoxemic conditions. As the angiotensin-II response to high-altitude exercise is normal, it is speculated that an inhibitor, discharged during hypoxemia, acted to suppress angiotensin-II-mediated aldosterone release. A study was conducted to test this hypothesis, taking into account the measurement of the aldosterone response to exogenous angiotensin II during normoxemia and hypoxemia. It was found that the dose-response curve of PAC to angiotensin II was not significantly inhibited by the considered model of hypoxemia. The hypoxemia-mediated releasemore » of an angiotensin II inhibitor does, therefore, not explain the previous observations of PAC suppression during hypoxemic exercise. 28 references.« less

  18. [Renin-angiotensin-aldosterone system activity during head-up tilt testing in patients with vasovagal syncope].

    PubMed

    Gajek, Jacek; Zyśko, Dorota; Mazurek, Walentyna

    2005-08-01

    The stimulation of renin-angiotensin-aldosterone (RAA) system during tilt table test is caused by sympathetic nervous system activation by orthostatic stress and a serotonin release as well. In healthy individuals increase of plasma renin activity during test with maximal values on the peak of the test was described. The aim of the study was to assess the activation of RAAS in patients with neurally mediated syncope during the tilt table test by means of plasma renin activity and serum aldosterone levels. The study was carried out in 31 patients aged 39.4 +/- 15.0 years (18 women and 13 men) with neurally mediated syncope during tilt test. Plasma renin activity was assessed in the baseline conditions, immediately after the test and 10 minutes after the test using radioenzymatic assay. Aldosterone concentrations were measured radioimmunologically, twice: after 30 minutes supine rest and after the syncope. Plasma renin activity during supine rest was 2.2 +/- 2.4 ng/ml/h, rose after the syncope 2.5-fold to 5.2 +/- 4.5 ng/ml/h (p < 0.001 comparing to baseline) stayed on similar level approximately for the next 10 minutes--4.9 +/- 5.5 ng/ml/h (p = n.s.). In 11 patients (35%) 10 minutes after the test even further increase of PRA was observed. Serum aldosterone level increased significantly immediately after tilt test (90.0 +/- 72.9 vs 178.8 +/- 150.1 pg/ml, p < 0.01). Authors showed, that in patients with NMS plasma renin activity increases and this increase lasts for 10 minutes after the syncope and the concentration of aldosterone increases immediately after tilt test.

  19. High-fat diet amplifies renal renin angiotensin system expression, blood pressure elevation, and renal dysfunction caused by Ceacam1 null deletion.

    PubMed

    Li, Caixia; Culver, Silas A; Quadri, Syed; Ledford, Kelly L; Al-Share, Qusai Y; Ghadieh, Hilda E; Najjar, Sonia M; Siragy, Helmy M

    2015-11-01

    Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAMl), a substrate of the insulin receptor tyrosine kinase, regulates insulin action by promoting insulin clearance. Global null mutation of Ceacam1 gene (Cc1(-/-)) results in features of the metabolic syndrome, including insulin resistance, hyperinsulinemia, visceral adiposity, elevated blood pressure, and albuminuria. It also causes activation of the renal renin-angiotensin system (RAS). In the current study, we tested the hypothesis that high-fat diet enhances the expression of RAS components. Three-month-old wild-type (Cc1(+/+)) and Cc1(-/-) mice were fed either a regular or a high-fat diet for 8 wk. At baseline under regular feeding conditions, Cc1(-/-) mice exhibited higher blood pressure, urine albumin-to-creatinine ratio (UACR), and renal expression of angiotensinogen, renin/prorenin, angiotensin-converting enzyme, (pro)renin receptor, angiotensin subtype AT1 receptor, angiotensin II, and elevated PI3K phosphorylation, as detected by p85α (Tyr(508)) immunostaining, inflammatory response, and the expression of collagen I and collagen III. In Cc1(+/+) mice, high-fat diet increased blood pressure, UACR, the expression of angiotensin-converting enzyme and angiotensin II, PI3K phosphorylation, inflammatory response, and the expression of collagen I and collagen III. In Cc1(-/-) mice, high-fat intake further amplified these parameters. Immunohistochemical staining showed increased p-PI3K p85α (Tyr(508)) expression in renal glomeruli, proximal, distal, and collecting tubules of Cc1(-/-) mice fed a high-fat diet. Together, this demonstrates that high-fat diet amplifies the permissive effect of Ceacam1 deletion on renal expression of all RAS components, PI3K phosphorylation, inflammation, and fibrosis. Copyright © 2015 the American Physiological Society.

  20. Reno-Cerebral Reflex Activates the Renin-Angiotensin System, Promoting Oxidative Stress and Renal Damage After Ischemia-Reperfusion Injury.

    PubMed

    Cao, Wei; Li, Aiqing; Li, Jiawen; Wu, Chunyi; Cui, Shuang; Zhou, Zhanmei; Liu, Youhua; Wilcox, Christopher S; Hou, Fan Fan

    2017-09-01

    A kidney-brain interaction has been described in acute kidney injury, but the mechanisms are uncertain. Since we recently described a reno-cerebral reflex, we tested the hypothesis that renal ischemia-reperfusion injury (IRI) activates a sympathetic reflex that interlinks the renal and cerebral renin-angiotensin axis to promote oxidative stress and progression of the injury. Bilateral ischemia-reperfusion activated the intrarenal and cerebral, but not the circulating, renin-angiotensin system (RAS), increased sympathetic activity in the kidney and the cerebral sympathetic regulatory regions, and induced brain inflammation and kidney injury. Selective renal afferent denervation with capsaicin or renal denervation significantly attenuated IRI-induced activation of central RAS and brain inflammation. Central blockade of RAS or oxidative stress by intracerebroventricular (ICV) losartan or tempol reduced the renal ischemic injury score by 65% or 58%, respectively, and selective renal afferent denervation or reduction of sympathetic tone by ICV clonidine decreased the score by 42% or 52%, respectively (all p < 0.05). Ischemia-reperfusion-induced renal damage and dysfunction persisted after controlling blood pressure with hydralazine. This study uncovered a novel reflex pathway between ischemic kidney and the brain that sustains renal oxidative stress and local RAS activation to promote ongoing renal damage. These data suggest that the renal and cerebral renin-angiotensin axes are interlinked by a reno-cerebral sympathetic reflex that is activated by ischemia-reperfusion, which contributes to ischemia-reperfusion-induced brain inflammation and worsening of the acute renal injury. Antioxid. Redox Signal. 27, 415-432.

  1. Estradiol, acting through ERα, induces endothelial non-classic renin-angiotensin system increasing angiotensin 1-7 production.

    PubMed

    Mompeón, Ana; Lázaro-Franco, Macarena; Bueno-Betí, Carlos; Pérez-Cremades, Daniel; Vidal-Gómez, Xavier; Monsalve, Elena; Gironacci, Mariela M; Hermenegildo, Carlos; Novella, Susana

    2016-02-15

    Intracellular renin-angiotensin system (RAS) can operate independently of the circulating RAS. Estrogens provide protective effects by modulating the RAS. Our aim was to investigate the effect of estradiol (E2) on angiotensin converting enzymes (ACE) 1 and ACE2 expression and activities in human endothelial cells (HUVEC), and the role of estrogen receptors (ER). The results confirmed the presence of active intracellular RAS in HUVEC. Physiological concentrations of E2 induced a concentration-dependent increase of ACE1 and ACE2 mRNA expression and ACE1, but not ACE2, protein levels. ACE1 and ACE2 enzymatic activities were also induced with E2. These effects were mediated through ERα activation, since ER antagonists ICI 182780 and MPP completely abolished the effect of E2. Moreover, the ERα agonist PPT mirrored the E2 effects on ACE1 and ACE2 protein expression and activity. Exposure of endothelial cells to E2 significantly increased Ang-(1-7) production. In conclusion, E2 increases Ang-(1-7) production, through ERα, involving increased ACE1 and ACE2 mRNA expression and activity and ACE1 protein levels. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. Association between polymorphisms in renin-angiotensin system genes and primary ovarian insufficiency in Korean women.

    PubMed

    Jung, Yong Wook; Jeon, Young Joo; Park, Hye Mi; Lee, Bo Eun; Rah, Hyungchul; Lee, Woo Sik; Yoon, Tae Ki; Kim, Nam Keun

    2013-05-01

    The purpose of this study was to evaluate the relationship between angiotensin-converting enzyme (ACE; insertion/deletion), angiotensinogen (AGT M235T), and angiotensin II type 1 receptor (AT1R 1166A>C) and the prevalence of primary ovarian insufficiency (POI) in Korean women. A total of 133 women with POI and 238 controls were genotyped for polymorphic sites in each gene using polymerase chain reaction-restriction fragment length polymorphism analysis. ACE ID and ID + II variants occurred more frequently in women with POI than in controls (odds ratio [OR], 1.830; 95% CI, 1.040-3.221; P = 0.040; and OR, 1.797; 95% CI, 1.055-3.060; P = 0.031, respectively). The AT1R 1166AC genotype occurred more frequently in participants with POI than in controls (OR, 3.171; 95% CI, 1.562-6.436; P = 0.002). Comparing the combined genotype frequencies of ACE/AT1R revealed that the frequencies of ID/AA, ID/AC, and II/AC were higher in participants than in controls (OR, 1.916; 95% CI, 1.053-3.485; P = 0.043; OR, 3.544; 95% CI, 1.207-10.407; P = 0.036; and OR, 7.875; 95% CI, 2.224-27.881; P = 0.001, respectively). The TT/AC genotype for combined genotyping of AGT/AT1R was more frequently observed in the POI group than in the control group (OR, 3.472; 95% CI, 1.450-8.313; P = 0.006). In multifactor dimensionality reduction-based haplotype analysis, the I-T-C genotype of ACE/AGT/AT1R was a possible predisposing factor for POI (OR, 4.678; 95% CI, 1.721-12.717; P = 0.002). This study demonstrates that polymorphisms in the renin-angiotensin system are related to the prevalence of POI. Thus, these renin-angiotensin system genes may serve as a novel marker for predicting the development of POI.

  3. Dual renin-angiotensin-aldosterone blockade: promises and pitfalls.

    PubMed

    Chrysant, Steven G; Chrysant, George S

    2015-01-01

    Single renin-angiotensin-aldosterone system (RAAS) blockade has been shown to be effective and safe for the treatment of hypertension, coronary heart disease (CHD), heart failure (HF), diabetes, and chronic kidney disease (CKD) with proteinuria. Due to the action of RAAS blockers at various levels of the RAAS cascade, it was hypothesized that dual RAAS blockade would result in more complete inhibition of angiotensin II (Ang II) production and be more effective in blocking its detrimental cardiovascular remodeling effects. Unfortunately, several clinical trials in patients with hypertension, CHD, HF, and CKD with proteinuria have demonstrated no superiority of dual versus single RAAS blockade, but a higher incidence of adverse events. Based on these findings, dual RAAS blockade is no longer recommended for the routine treatment of various cardiovascular diseases, except diabetic nephropathy with proteinuria and HF with reduced ejection fraction. All the new information gathered from studies within the last 3 years will be presented in this review.

  4. Plasma soluble (pro)renin receptor is independent of plasma renin, prorenin, and aldosterone concentrations but is affected by ethnicity.

    PubMed

    Nguyen, Geneviève; Blanchard, Anne; Curis, Emmanuel; Bergerot, Damien; Chambon, Yann; Hirose, Takuo; Caumont-Prim, Aurore; Tabard, Sylvie Brailly; Baron, Stéphanie; Frank, Michael; Totsune, Kazuhito; Azizi, Michel

    2014-02-01

    A soluble (pro)renin receptor (sPRR) circulates in plasma and is able to bind renin and prorenin. It is not known whether plasma sPRR concentrations vary with the activity of the renin-angiotensin system. We measured plasma sPRR, renin, prorenin, and aldosterone concentrations in 121 white and 9 black healthy subjects, 40 patients with diabetes mellitus, 41 hypertensive patients with or without renin-angiotensin system blockers, 9 patients with primary aldosteronism, and 10 patients with Gitelman syndrome. Median physiological plasma sPRR concentration was 23.5 ng/mL (interquartile range, 20.9-26.5) under usual uncontrolled sodium diet. sPRR concentration in healthy subjects, unlike renin and prorenin, did not display circadian variation or dependence on age, sex, posture, or hormonal status. sPRR concentrations were ≈25% lower in black than in white subjects, whereas renin concentrations were ≈40% lower. Patients with diabetes mellitus (average renin-high prorenin levels) and with hypertension only (average renin-average prorenin levels) had sPRR concentrations similar to healthy subjects. Renin-angiotensin system blockade was associated with increase of sPRR concentration by ≈12%. sPRR in patients with primary aldosteronism (low renin-low prorenin) and Gitelman syndrome (high renin-high prorenin) were similar and ≈10% higher than in healthy subjects. There was no correlation between sPRR and renin or prorenin. In conclusion, our results show that plasma sPRR concentrations are dependent on ethnicity and independent of renin, prorenin, and aldosterone concentrations in healthy subjects and in patients with contrasted degrees of renin-angiotensin system activity.

  5. Renin-Angiotensin System Gene Variants and Type 2 Diabetes Mellitus: Influence of Angiotensinogen

    PubMed Central

    Joyce-Tan, Siew Mei; Zain, Shamsul Mohd; Abdul Sattar, Munavvar Zubaid; Abdullah, Nor Azizan

    2016-01-01

    Genome-wide association studies (GWAS) have been successfully used to call for variants associated with diseases including type 2 diabetes mellitus (T2DM). However, some variants are not included in the GWAS to avoid penalty in multiple hypothetic testing. Thus, candidate gene approach is still useful even at GWAS era. This study attempted to assess whether genetic variations in the renin-angiotensin system (RAS) and their gene interactions are associated with T2DM risk. We genotyped 290 T2DM patients and 267 controls using three genes of the RAS, namely, angiotensin converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AGTR1). There were significant differences in allele frequencies between cases and controls for AGT variants (P = 0.05) but not for ACE and AGTR1. Haplotype TCG of the AGT was associated with increased risk of T2DM (OR 1.92, 95% CI 1.15–3.20, permuted P = 0.012); however, no evidence of significant gene-gene interactions was seen. Nonetheless, our analysis revealed that the associations of the AGT variants with T2DM were independently associated. Thus, this study suggests that genetic variants of the RAS can modestly influence the T2DM risk. PMID:26682227

  6. Renin-Angiotensin Inhibitors Decrease Recurrence after Transurethral Resection of Bladder Tumor in Patients with Nonmuscle Invasive Bladder Cancer.

    PubMed

    Blute, Michael L; Rushmer, Timothy J; Shi, Fangfang; Fuller, Benjamin J; Abel, E Jason; Jarrard, David F; Downs, Tracy M

    2015-11-01

    Prior reports suggest that renin-angiotensin system inhibition may decrease nonmuscle invasive bladder cancer recurrence. We evaluated whether angiotensin converting enzyme inhibitor or angiotensin receptor blocker treatment at initial surgery was associated with decreased recurrence or progression in patients with nonmuscle invasive bladder cancer. Using an institutional bladder cancer database we identified 340 patients with data available on initial transurethral resection of bladder tumor. Progression was defined as an increase to stage T2. Cox proportional hazards models were used to evaluate associations with recurrence-free and progression-free survival. Median patient age was 69.6 years. During a median followup of 3 years (IQR 1.3-6.1) 200 patients (59%) had recurrence and 14 (4.1%) had stage progression. Of those patients 143 were receiving angiotensin converting enzyme inhibitor/angiotensin receptor blockers at the time of the first transurethral resection. On univariate analysis factors associated with improved recurrence-free survival included carcinoma in situ (p = 0.040), bacillus Calmette-Guérin therapy (p = 0.003) and angiotensin converting enzyme inhibitor/angiotensin receptor blocker therapy (p = 0.009). Multivariate analysis demonstrated that patients treated with bacillus Calmette-Guérin therapy (HR 0.68, 95% CI 0.47-0.87, p = 0.002) or angiotensin converting enzyme inhibitor/angiotensin receptor blocker therapy (HR 0.61, 95% CI 0.45-0.84, p = 0.005) were less likely to experience tumor recurrence. The 5-year recurrence-free survival rate was 45.6% for patients treated with angiotensin converting enzyme inhibitor/angiotensin receptor blockers and 28.1% in those not treated with angiotensin converting enzyme inhibitor/angiotensin receptor blockers (p = 0.009). Subgroup analysis was performed to evaluate nonmuscle invasive bladder cancer pathology (Ta, T1 and carcinoma in situ) in 85 patients on bacillus Calmette-Guérin therapy alone and in

  7. 2C.07: INVOLVEMENT OF THE RENIN-ANGIOTENSIN SYSTEM IN A PREMATURE AGING MOUSE MODEL.

    PubMed

    Van Thiel, B S; Ridwan, Y; Garrelds, I M; Vermeij, M; Groningen, M C Clahsen-Van; Danser, A H J; Essers, J; Van Der Pluijm, I

    2015-06-01

    Changes in the renin-angiotensin system (RAS), known for its critical role in the regulation of blood pressure and sodium homeostasis, may contribute to aging and age-related diseases. Here we characterized the RAS and kidney pathology in mice with genomic instability due to a defective nucleotide excision repair gene (Ercc1d/- mice). These mice display premature features of aging, including vascular dysfunction. Studies were performed in male and female Ercc1d/- mice and their wild type controls (Ercc1+/+) at the age of 12 or 18 weeks before and after treatment with losartan. The renin-activatable near-infrared fluorescent probe ReninSense 680™ was applied in vivo to allow non-invasive imaging of renin activity. Plasma renin concentrations (PRC) were additionally measured ex vivo by quantifying Ang I generation in the presence of excess angiotensinogen. Kidneys were harvested and examined for markers of aging, and albumin was determined in urine. Kidneys of 12-week old Ercc1d/- mice showed signs of aging, including tubular anisokaryosis, cell-senescence and increased apoptosis. This was even more pronounced at the age of 18 weeks. Yet, urinary albumin was normal at 12 weeks. The ReninSense 680™ probe showed increased intrarenal renin activity in Ercc1d/- mice versus Ercc1+/+ mice, both at 12 and 18 weeks of age, while PRC in these mice tended to be lower compared to Ercc1+/+ mice. Renin was higher in male than female mice, both in the kidney and in plasma, and losartan increased kidney and plasma renin in both Ercc1d/- and Ercc1+/+ mice. Rapidly aging Ercc1d/- mice display an activated intrarenal RAS, as evidenced by the increased fluorescence detected with the ReninSense 680™ probe. This increased RAS activity may contribute to the disturbed kidney pathology in these mice. The increased intrarenal activity detected with the ReninSense 680™ probe in male vs. female mice, as well as after losartan treatment, are in full agreement with the literature, and

  8. A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity

    PubMed Central

    Hilzendeger, Aline M.; Morgan, Donald A.; Brooks, Leonard; Dellsperger, David; Liu, Xuebo; Grobe, Justin L.; Rahmouni, Kamal; Sigmund, Curt D.

    2012-01-01

    The sympathetic nervous system, leptin, and renin-angiotensin system (RAS) have been implicated in obesity-associated hypertension. There is increasing evidence for the presence of both leptin and angiotensin II receptors in several key brain cardiovascular and metabolic control regions. We tested the hypothesis that the brain RAS plays a facilitatory role in the sympathetic nerve responses to leptin. In rats, intracerebroventricular (ICV) administration of losartan (5 μg) selectively inhibited increases in renal and brown adipose tissue (BAT) sympathetic nerve activity (SNA) produced by leptin (10 μg ICV) but did not reduce the SNA responses to corticotrophin-releasing factor (CRF) or the melanocortin receptor agonist MTII. In mice with deletion of angiotensin II type-1a receptors (AT1aR−/−), increases in renal and BAT SNA induced by leptin (2 μg ICV) were impaired whereas SNA responses to MTII were preserved. Decreases in food intake and body weight with ICV leptin did not differ in AT1aR−/− vs. AT1aR+/+ mice. ICV leptin in rats increased AT1aR and angiotensin-converting enzyme (ACE) mRNA in the subfornical organ and AT1aR mRNA in the arcuate nucleus, suggesting leptin-induced upregulation of the brain RAS in specific brain regions. To evaluate the role of de novo production of brain angiotensin II in SNA responses to leptin, we treated rats with captopril (12.5 μg ICV). Captopril attenuated leptin effects on renal and BAT SNA. In conclusion, these studies provide evidence that the brain RAS selectively facilitates renal and BAT sympathetic nerve responses to leptin while sparing effects on food intake. PMID:22610169

  9. A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity.

    PubMed

    Hilzendeger, Aline M; Morgan, Donald A; Brooks, Leonard; Dellsperger, David; Liu, Xuebo; Grobe, Justin L; Rahmouni, Kamal; Sigmund, Curt D; Mark, Allyn L

    2012-07-15

    The sympathetic nervous system, leptin, and renin-angiotensin system (RAS) have been implicated in obesity-associated hypertension. There is increasing evidence for the presence of both leptin and angiotensin II receptors in several key brain cardiovascular and metabolic control regions. We tested the hypothesis that the brain RAS plays a facilitatory role in the sympathetic nerve responses to leptin. In rats, intracerebroventricular (ICV) administration of losartan (5 μg) selectively inhibited increases in renal and brown adipose tissue (BAT) sympathetic nerve activity (SNA) produced by leptin (10 μg ICV) but did not reduce the SNA responses to corticotrophin-releasing factor (CRF) or the melanocortin receptor agonist MTII. In mice with deletion of angiotensin II type-1a receptors (AT(1a)R(-/-)), increases in renal and BAT SNA induced by leptin (2 μg ICV) were impaired whereas SNA responses to MTII were preserved. Decreases in food intake and body weight with ICV leptin did not differ in AT(1a)R(-/-) vs. AT(1a)R(+/+) mice. ICV leptin in rats increased AT(1a)R and angiotensin-converting enzyme (ACE) mRNA in the subfornical organ and AT(1a)R mRNA in the arcuate nucleus, suggesting leptin-induced upregulation of the brain RAS in specific brain regions. To evaluate the role of de novo production of brain angiotensin II in SNA responses to leptin, we treated rats with captopril (12.5 μg ICV). Captopril attenuated leptin effects on renal and BAT SNA. In conclusion, these studies provide evidence that the brain RAS selectively facilitates renal and BAT sympathetic nerve responses to leptin while sparing effects on food intake.

  10. Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases.

    PubMed

    Tan, Wan Shun Daniel; Liao, Wupeng; Zhou, Shuo; Mei, Dan; Wong, Wai-Shiu Fred

    2017-12-27

    The renin-angiotensin system (RAS) plays a major role in regulating electrolyte balance and blood pressure. RAS has also been implicated in the regulation of inflammation, proliferation and fibrosis in pulmonary diseases such as asthma, acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). Current therapeutics suffer from some drawbacks like steroid resistance, limited efficacies and side effects. Novel intervention is definitely needed to offer optimal therapeutic strategy and clinical outcome. This review compiles and analyses recent investigations targeting RAS for the treatment of inflammatory lung diseases. Inhibition of the upstream angiotensin (Ang) I/Ang II/angiotensin receptor type 1 (AT 1 R) pathway and activation of the downstream angiotensin-converting enzyme 2 (ACE2)/Ang (1-7)/Mas receptor pathway are two feasible strategies demonstrating efficacies in various pulmonary disease models. More recent studies favor the development of targeting the downstream ACE2/Ang (1-7)/Mas receptor pathway, in which diminazene aceturate, an ACE2 activator, GSK2586881, a recombinant ACE2, and AV0991, a Mas receptor agonist, showed much potential for further development. As the pathogenesis of pulmonary diseases is so complex that RAS modulation may be used alone or in combination with existing drugs like corticosteroids, pirfenidone/nintedanib or endothelin receptor antagonists for different pulmonary diseases. Personalized medicine through genetic screening and phenotyping for angiotensinogen or ACE would aid treatment especially for non-responsive patients. This review serves to provide an update on the latest development in the field of RAS targeting for pulmonary diseases, and offer some insights into future direction. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Effects of olmesartan on the renin-angiotensin-aldosterone system for patients with essential hypertension after cardiac surgery--investigation using a candesartan change-over study.

    PubMed

    Sezai, Akira; Soma, Masayoshi; Hata, Mitsumasa; Yoshitake, Isamu; Unosawa, Satoshi; Wakui, Shinji; Shiono, Motomi

    2011-01-01

    Various angiotensin II receptor blockers are widely used for the treatment of hypertension in recent years. The results of large-scale clinical studies have shown that they have various efficacies: not only hypotensive effects but also organ protective effects. In this study, the effects of a change-over from candesartan to olmesartan on renin-angiotensin-aldsterone system, cardiomegaly and peripheral circulation were studied. Participants enrolled in this trial were outpatients with essential hypertension after cardiac surgery who had received candesartan for more than one year. Fifty-six patients switched from candesartan to olmesartan. The primary endpoints were 1) renin activity, angiotensin II, aldosterone, and 2) left ventricular mass index (LVMI). It was clear that angiotensin II and aldosterone are decreased by the potent hypotensive effects of olmesartan in a change-over from candesartan to olmesartan. Since LVMI and BNP were decreased, inhibitory effects on myocardial hypertrophy were also confirmed. In the present study, left ventricular hypertrophy and on arterial compliance were inhibited by a decrease in angiotensin II and aldosterone due to the change-over to olmesartan. In the future, protective effects on organs will be clarified by long-term observations.

  12. Long-term effects of telmisartan on blood pressure, the renin-angiotensin-aldosterone system, and lipids in hypertensive patients.

    PubMed

    Aoki, Akiko; Ogawa, Tetsuya; Sumino, Hiroyuki; Kumakura, Hisao; Takayama, Yoshiaki; Ichikawa, Shuichi; Nitta, Kosaku

    2010-05-01

    We prospectively evaluated long-term (12 months) effects of telmisartan on blood pressure (BP), circulating renin-angiotensin-aldosterone levels, and lipids in hypertensive patients. There were 13 men and 11 women, 59 +/- 8.7 years of age (mean +/- SEM), with untreated essential hypertension. The 20-60 mg doses of telmisartan were administered once daily in the morning until BP130/85 was obtained. Blood pressure and plasma renin activity, plasma angiotensin (Ang) I and Ang II, serum angiotensin-converting enzyme (ACE) activity, plasma aldosterone concentration, plasma human atrial natriuretic peptide (hANP) concentration, and serum lipids were obtained 6 and 12 months after starting telmisartan administration. Systolic and diastolic BP were significantly (P < 0.001, P < 0.001) decreased from 162 +/- 3.3 and 97.7 +/- 2.1 mmHg to 128 +/- 3.8 and 79.6 +/- 2.0 mmHg after 12 months of treatment, respectively. Plasma Ang I and Ang II were unchanged at 12 months. Plasma renin activity and serum ACE activity were significantly (P < 0.001, P < 0.05) increased and plasma aldosterone concentration was unchanged during the study period. Total cholesterol levels were unchanged, but serum triglycerides levels were significantly decreased at 12 months (P < 0.01). Plasma hANP showed no significant alteration throughout the 12-month period. In hypertensive patients, telmisartan is a beneficial antihypertensive drug that also lowers serum triglycerides.

  13. Targeting the Vasoprotective Axis of the Renin-Angiotensin System: A Novel Strategic Approach to Pulmonary Hypertensive Therapy

    PubMed Central

    Bradford, Chastity N.; Ely, Debra R.

    2010-01-01

    A decade has passed since the discovery of angiotensin-converting enzyme 2 (ACE2), a component of the ACE2–angiotensin (Ang)-(1-7)–Mas counterregulatory axis of the renin angiotensin system (RAS). ACE2 is considered an endogenous regulator of the vasoconstrictive, proliferative, fibrotic, and proinflammatory effects of the ACE–Ang II–angiotensin II type 1 receptor (AT1R) axis. Both animal and clinical studies have emerged to define a role for ACE2 in pulmonary arterial hypertension (PAH). There is scientific evidence supporting the concept that ACE2 maintains the RAS balance and plays a protective role in PAH. The activation of pulmonary ACE2 could influence the pathogenesis of PAH and serve as a novel therapeutic target in PAH. Current therapeutic strategies and interventions have limited success, and PAH remains a fatal disease. Thus, more research that establishes the novel therapeutic potential and defines the mechanism of the ACE2–Ang-(1-7)–Mas counterregulatory axis in PAH is needed. PMID:20556668

  14. The physiology of a local renin-angiotensin system in the pancreas.

    PubMed

    Leung, Po Sing

    2007-04-01

    The systemic renin-angiotensin system (RAS) plays an important role in regulating blood pressure, electrolyte and fluid homeostasis. However, local RASs also exist in diverse tissues and organs, where they play a multitude of autocrine, paracrine and intracrine physiological roles. The existence of a local RAS is now recognized in pancreatic acinar, islet, duct, endothelial and stellate cells, the expression of which is modulated in response to physiological and pathophysiological stimuli such as hypoxia, pancreatitis, islet transplantation, hyperglycaemia, and diabetes mellitus. This pancreatic RAS has been proposed to have important endocrine and exocrine roles in the pancreas, regulating local blood flow, duct cell sodium bicarbonate secretion, acinar cell digestive enzyme secretion, islet beta-cell (pro)insulin biosynthesis, and thus, glucose-stimulated insulin release, delta-cell somatostatin secretion, and pancreatic cell proliferation and differentiation. It may further mediate oxidative stress-induced cell inflammation, apoptosis and fibrosis. Further exploration of this system would probably offer new insights into the pathogenesis of pancreatitis, diabetes, cystic fibrosis and pancreatic cancer formation. New therapeutic targets and strategies might thus be suggested.

  15. New evidence on the importance of the renin-angiotensin system in the treatment of higher-risk patients with hypertension.

    PubMed

    Sleight, Peter; Yusuf, Salim

    2003-09-01

    We reviewed the drug treatment of hypertension in the light of recent trials. beta-Blockers and diuretics clearly reduce mortality, strokes, and coronary heart disease (CHD) in hypertension. Recent trials assessed whether newer agents that block the renin-angiotensin-aldosterone system, or calcium blockers, offer any additional advantage, or have benefits in high-risk individuals with conventionally 'normal' blood pressure. The recent ALLHAT study claimed no differences in CHD or mortality when chlorthalidone, amlodipine, and lisinopril were compared. However, the decrease in blood pressure was not the same with the three agents, and a substantial proportion of patients enrolled did not have clinical disease. In contrast, the LIFE study (comparing losartan and a beta-blocker) and the ANBP-2 study [comparing angiotensin-converting enzyme (ACE) inhibition and a diuretic] reduced blood pressure similarly, yet demonstrated benefits in favour of angiotensin II type 1 receptor blockers (ARBs) and ACE inhibitors. Other trials indicated similar advantages of ACE inhibitors or ARBs in patients with diabetic nephropathy. Among high-risk patients with initial blood pressure in the 'normal' range, ACE inhibitors significantly reduce clinical events (mortality, strokes, and myocardial infarction), despite modest decreases in blood pressure, suggesting that additional mechanisms are responsible. Recent results of the Prospective Studies Collaboration show lower risk, even in the normal blood pressure range; high-risk patients will benefit further from ACE inhibitors and ARBs (and beta-blockers after myocardial infarction). Data for other blood pressure decreasing agents are unavailable in such populations. We conclude that blood pressure decreasing per se is of clinical benefit, but drugs that block the renin-angiotensin system offer additional advantages. Drug choice is best determined by the patient's clinical condition.

  16. Renin-angiotensin system phenotyping as a guidance toward personalized medicine for ACE inhibitors: can the response to ACE inhibition be predicted on the basis of plasma renin or ACE?

    PubMed

    Schilders, Joyce E M; Wu, Haiyan; Boomsma, Frans; van den Meiracker, Anton H; Danser, A H Jan

    2014-08-01

    Not all hypertensive patients respond well to ACE inhibition. Here we determined whether renin-angiotensin system (RAS) phenotyping, i.e., the measurement of renin or ACE, can predict the individual response to RAS blockade, either chronically (enalapril vs. enalapril + candesartan) or acutely (enalapril ± hydrochlorothiazide, HCT). Chronic enalapril + candesartan induced larger renin rises, but did not lower blood pressure (BP) more than enalapril. Similar observations were made for enalapril + HCT vs. enalapril when given acutely. Baseline renin predicted the peak changes in BP chronically, but not acutely. Baseline ACE levels had no predictive value. Yet, after acute drug intake, the degree of ACE inhibition, like Δrenin, did correlate with ΔBP. Only the relationship with Δrenin remained significant after chronic RAS blockade. Thus, a high degree of ACE inhibition and a steep renin rise associate with larger acute responses to enalapril. However, variation was large, ranging >50 mm Hg for a given degree of ACE inhibition or Δrenin. The same was true for the relationships between Δrenin and ΔBP, and between baseline renin and the maximum reduction in BP in the chronic study. Our data do not support that RAS phenotyping will help to predict the individual BP response to RAS blockade. Notably, these conclusions were reached in a carefully characterized, homogenous population, and when taking into account the known fluctuations in renin that relate to gender, age, ethnicity, salt intake and diuretic treatment, it seems unlikely that a cut-off renin level can be defined that has predictive value.

  17. The renin-angiotensin system: a target of and contributor to dyslipidemias, altered glucose homeostasis, and hypertension of the metabolic syndrome

    PubMed Central

    Putnam, Kelly; Shoemaker, Robin; Yiannikouris, Frederique

    2012-01-01

    The renin-angiotensin system (RAS) is an important therapeutic target in the treatment of hypertension. Obesity has emerged as a primary contributor to essential hypertension in the United States and clusters with other metabolic disorders (hyperglycemia, hypertension, high triglycerides, low HDL cholesterol) defined within the metabolic syndrome. In addition to hypertension, RAS blockade may also serve as an effective treatment strategy to control impaired glucose and insulin tolerance and dyslipidemias in patients with the metabolic syndrome. Hyperglycemia, insulin resistance, and/or specific cholesterol metabolites have been demonstrated to activate components required for the synthesis [angiotensinogen, renin, angiotensin-converting enzyme (ACE)], degradation (ACE2), or responsiveness (angiotensin II type 1 receptors, Mas receptors) to angiotensin peptides in cell types (e.g., pancreatic islet cells, adipocytes, macrophages) that mediate specific disorders of the metabolic syndrome. An activated local RAS in these cell types may contribute to dysregulated function by promoting oxidative stress, apoptosis, and inflammation. This review will discuss data demonstrating the regulation of components of the RAS by cholesterol and its metabolites, glucose, and/or insulin in cell types implicated in disorders of the metabolic syndrome. In addition, we discuss data supporting a role for an activated local RAS in dyslipidemias and glucose intolerance/insulin resistance and the development of hypertension in the metabolic syndrome. Identification of an activated RAS as a common thread contributing to several disorders of the metabolic syndrome makes the use of angiotensin receptor blockers and ACE inhibitors an intriguing and novel option for multisymptom treatment. PMID:22227126

  18. Functional and molecular evidence for expression of the renin angiotensin system and ADAM17-mediated ACE2 shedding in COS7 cells

    PubMed Central

    Grobe, Nadja; Di Fulvio, Mauricio; Kashkari, Nada; Chodavarapu, Harshita; Somineni, Hari K.; Singh, Richa

    2015-01-01

    The renin angiotensin system (RAS) plays a vital role in the regulation of the cardiovascular and renal functions. COS7 is a robust and easily transfectable cell line derived from the kidney of the African green monkey, Cercopithecus aethiops. The aims of this study were to 1) demonstrate the presence of an endogenous and functional RAS in COS7, and 2) investigate the role of a disintegrin and metalloproteinase-17 (ADAM17) in the ectodomain shedding of angiotensin converting enzyme-2 (ACE2). Reverse transcription coupled to gene-specific polymerase chain reaction demonstrated expression of ACE, ACE2, angiotensin II type 1 receptor (AT1R), and renin at the transcript levels in total RNA cell extracts. Western blot and immunohistochemistry identified ACE (60 kDa), ACE2 (75 kDa), AT1R (43 kDa), renin (41 kDa), and ADAM17 (130 kDa) in COS7. At the functional level, a sensitive and selective mass spectrometric approach detected endogenous renin, ACE, and ACE2 activities. ANG-(1–7) formation (m/z 899) from the natural substrate ANG II (m/z 1,046) was detected in lysates and media. COS7 cells stably expressing shRNA constructs directed against endogenous ADAM17 showed reduced ACE2 shedding into the media. This is the first study demonstrating endogenous expression of the RAS and ADAM17 in the widely used COS7 cell line and its utility to study ectodomain shedding of ACE2 mediated by ADAM17 in vitro. The transfectable nature of this cell line makes it an attractive cell model for studying the molecular, functional, and pharmacological properties of the renal RAS. PMID:25740155

  19. Activation of the Endogenous Renin-Angiotensin-Aldosterone System or Aldosterone Administration Increases Urinary Exosomal Sodium Channel Excretion.

    PubMed

    Qi, Ying; Wang, Xiaojing; Rose, Kristie L; MacDonald, W Hayes; Zhang, Bing; Schey, Kevin L; Luther, James M

    2016-02-01

    Urinary exosomes secreted by multiple cell types in the kidney may participate in intercellular signaling and provide an enriched source of kidney-specific proteins for biomarker discovery. Factors that alter the exosomal protein content remain unknown. To determine whether endogenous and exogenous hormones modify urinary exosomal protein content, we analyzed samples from 14 mildly hypertensive patients in a crossover study during a high-sodium (HS, 160 mmol/d) diet and low-sodium (LS, 20 mmol/d) diet to activate the endogenous renin-angiotensin-aldosterone system. We further analyzed selected exosomal protein content in a separate cohort of healthy persons receiving intravenous aldosterone (0.7 μg/kg per hour for 10 hours) versus vehicle infusion. The LS diet increased plasma renin activity and aldosterone concentration, whereas aldosterone infusion increased only aldosterone concentration. Protein analysis of paired urine exosome samples by liquid chromatography-tandem mass spectrometry-based multidimensional protein identification technology detected 2775 unique proteins, of which 316 exhibited significantly altered abundance during LS diet. Sodium chloride cotransporter (NCC) and α- and γ-epithelial sodium channel (ENaC) subunits from the discovery set were verified using targeted multiple reaction monitoring mass spectrometry quantified with isotope-labeled peptide standards. Dietary sodium restriction or acute aldosterone infusion similarly increased urine exosomal γENaC[112-122] peptide concentrations nearly 20-fold, which correlated with plasma aldosterone concentration and urinary Na/K ratio. Urine exosomal NCC and αENaC concentrations were relatively unchanged during these interventions. We conclude that urinary exosome content is altered by renin-angiotensin-aldosterone system activation. Urinary measurement of exosomal γENaC[112-122] concentration may provide a useful biomarker of ENaC activation in future clinical studies. Copyright © 2016 by

  20. Activation of the Endogenous Renin-Angiotensin-Aldosterone System or Aldosterone Administration Increases Urinary Exosomal Sodium Channel Excretion

    PubMed Central

    Qi, Ying; Wang, Xiaojing; Rose, Kristie L.; MacDonald, W. Hayes; Zhang, Bing; Schey, Kevin L.

    2016-01-01

    Urinary exosomes secreted by multiple cell types in the kidney may participate in intercellular signaling and provide an enriched source of kidney-specific proteins for biomarker discovery. Factors that alter the exosomal protein content remain unknown. To determine whether endogenous and exogenous hormones modify urinary exosomal protein content, we analyzed samples from 14 mildly hypertensive patients in a crossover study during a high-sodium (HS, 160 mmol/d) diet and low-sodium (LS, 20 mmol/d) diet to activate the endogenous renin-angiotensin-aldosterone system. We further analyzed selected exosomal protein content in a separate cohort of healthy persons receiving intravenous aldosterone (0.7 μg/kg per hour for 10 hours) versus vehicle infusion. The LS diet increased plasma renin activity and aldosterone concentration, whereas aldosterone infusion increased only aldosterone concentration. Protein analysis of paired urine exosome samples by liquid chromatography-tandem mass spectrometry–based multidimensional protein identification technology detected 2775 unique proteins, of which 316 exhibited significantly altered abundance during LS diet. Sodium chloride cotransporter (NCC) and α- and γ-epithelial sodium channel (ENaC) subunits from the discovery set were verified using targeted multiple reaction monitoring mass spectrometry quantified with isotope-labeled peptide standards. Dietary sodium restriction or acute aldosterone infusion similarly increased urine exosomal γENaC[112–122] peptide concentrations nearly 20-fold, which correlated with plasma aldosterone concentration and urinary Na/K ratio. Urine exosomal NCC and αENaC concentrations were relatively unchanged during these interventions. We conclude that urinary exosome content is altered by renin-angiotensin-aldosterone system activation. Urinary measurement of exosomal γENaC[112–122] concentration may provide a useful biomarker of ENaC activation in future clinical studies. PMID:26113616

  1. Renin-Angiotensin-Aldosterone System Blockade in Diabetic Nephropathy. Present Evidences

    PubMed Central

    Lozano-Maneiro, Luz; Puente-García, Adriana

    2015-01-01

    Diabetic Kidney Disease (DKD) is the leading cause of chronic kidney disease in developed countries and its prevalence has increased dramatically in the past few decades. These patients are at an increased risk for premature death, cardiovascular disease, and other severe illnesses that result in frequent hospitalizations and increased health-care utilization. Although much progress has been made in slowing the progression of diabetic nephropathy, renal dysfunction and the development of end-stage renal disease remain major concerns in diabetes. Dysregulation of the renin-angiotensin-aldosterone system (RAAS) results in progressive renal damage. RAAS blockade is the cornerstone of treatment of DKD, with proven efficacy in many arenas. The theoretically-attractive option of combining these medications that target different points in the pathway, potentially offering a more complete RAAS blockade, has also been tested in clinical trials, but long-term outcomes were disappointing. This review examines the “state of play” for RAAS blockade in DKD, dual blockade of various combinations, and a perspective on its benefits and potential risks. PMID:26569322

  2. Maternal high-sodium intake alters the responsiveness of the renin-angiotensin system in adult offspring.

    PubMed

    Ramos, Débora R; Costa, Nauilo L; Jang, Karen L L; Oliveira, Ivone B; da Silva, Alexandre A; Heimann, Joel C; Furukawa, Luzia N S

    2012-05-22

    The goal of the current study was to evaluate the impact of maternal sodium intake during gestation on the systemic and renal renin-angiotensin-aldosterone-system (RAAS) of the adult offspring. Female Wistar rats were fed high- (HSD-8.0% NaCl) or normal-sodium diets (NSD-1.3% NaCl) from 8 weeks of age until the delivery of their first litter. After birth, the offspring received NSD. Tail-cuff blood pressure (TcBP) was measured in the offspring between 6 and 12 weeks of age. At 12 weeks of age, the offspring were subjected to either one week of HSD or low sodium diet (LSD-0.16% NaCl) feeding to evaluate RAAS responsiveness or to acute saline overload to examine sodium excretory function. Plasma (PRA) and renal renin content (RRC), serum aldosterone (ALDO) levels, and renal cortical and medullary renin mRNA expression levels were evaluated at the end of the study. TcBP was higher among dams fed HSD, but no TcBP differences were observed among the offspring. Male offspring, however, exhibited increased TcBP after one week of HSD feeding, and this effect was independent of maternal diet. Increased RAAS responsiveness to the HSD and LSD was also observed in male offspring. The baseline levels of PRA, ALDO, and cortical and medullary renin gene expression were lower but the RRC levels were higher among HSD-fed male offspring (HSDoff). Conversely, female HSDoff showed reduced sodium excretion 4 h after saline overload compared with female NSDoff. High maternal sodium intake is associated with gender-specific changes in RAAS responsiveness among adult offspring. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. Changeover Trial of Azilsartan and Olmesartan Comparing Effects on the Renin-Angiotensin-Aldosterone System in Patients with Essential Hypertension after Cardiac Surgery (CHAOS Study)

    PubMed Central

    Osaka, Shunji; Yaoita, Hiroko; Arimoto, Munehito; Hata, Hiroaki; Shiono, Motomi; Sakino, Hisakuni

    2016-01-01

    Background: Angiotensin II receptor blockers (ARBs) have been widely used to treat hypertension and large-scale clinical studies have shown various benefits. In this study, we compared olmesartan with azilsartan, the newest ARB. Methods: The subjects were outpatients who were clinically stable after cardiac surgery. Sixty patients were randomized to receive either azilsartan or olmesartan for 1 year and were switched to the other drug for the following 1 year. The primary endpoints were the levels of plasma renin activity, angiotensin II, and aldosterone. Results: Home blood pressure exceeded 140/90 mmHg and additional antihypertensive medication was administered to 12 patients (20 episodes) in the azilsartan group versus 4 patients (4 episodes) in the olmesartan group, with the number being significantly higher in the azilsartan group. After 1 year of treatment, both angiotensin II and aldosterone levels were significantly lower in the olmesartan group than the azilsartan group. Left ventricular mass index was also significantly lower in the olmesartan group than the azilsartan group. Conclusion: This study showed that olmesartan reduces angiotensin II and aldosterone levels more effectively than azilsartan. Accordingly, it may be effective in patients with increased renin-angiotensin-aldosterone system activity after cardiac surgery or patients with severe cardiac hypertrophy. PMID:27086671

  4. Changeover Trial of Azilsartan and Olmesartan Comparing Effects on the Renin-Angiotensin-Aldosterone System in Patients with Essential Hypertension after Cardiac Surgery (CHAOS Study).

    PubMed

    Sezai, Akira; Osaka, Shunji; Yaoita, Hiroko; Arimoto, Munehito; Hata, Hiroaki; Shiono, Motomi; Sakino, Hisakuni

    2016-06-20

    Angiotensin II receptor blockers (ARBs) have been widely used to treat hypertension and large-scale clinical studies have shown various benefits. In this study, we compared olmesartan with azilsartan, the newest ARB. The subjects were outpatients who were clinically stable after cardiac surgery. Sixty patients were randomized to receive either azilsartan or olmesartan for 1 year and were switched to the other drug for the following 1 year. The primary endpoints were the levels of plasma renin activity, angiotensin II, and aldosterone. Home blood pressure exceeded 140/90 mmHg and additional antihypertensive medication was administered to 12 patients (20 episodes) in the azilsartan group versus 4 patients (4 episodes) in the olmesartan group, with the number being significantly higher in the azilsartan group. After 1 year of treatment, both angiotensin II and aldosterone levels were significantly lower in the olmesartan group than the azilsartan group. Left ventricular mass index was also significantly lower in the olmesartan group than the azilsartan group. This study showed that olmesartan reduces angiotensin II and aldosterone levels more effectively than azilsartan. Accordingly, it may be effective in patients with increased renin-angiotensin-aldosterone system activity after cardiac surgery or patients with severe cardiac hypertrophy.

  5. Low LBNP Tolerance in Men is Associated With Attenuated Activation of Renin-Angiotensin System

    NASA Technical Reports Server (NTRS)

    Greenleaf, John E.; Petersen, T. W.; Gabrielsen, A.; Pump, B.; Bie, P.; Christensen, N.-J.; Warberg, J.; Videbaeck, R.; Simonson, S. R.; Norsk, P.; hide

    1999-01-01

    Vasoactive hormone concentrations (epinephrine (pE), norepinephrine (pNE), angiotensin II (pATII), vasopressin (pVP), endothelin 1 (pET1)] and plasma renin activity (pRA) were measured during lower body negative pressure (LBNP) to test the hypothesis that responsiveness of the reninangiotensin system is related to LBNP tolerance. Healthy men (2,822 cal per day, 2 mmol per kilogram per day Na (+)) were exposed to 30 min of progressive LBNP to -50mmHg. LBNP was uneventful for 7 men (2512 yr, HiTol group), but 8 men (26 plus or minus 3 yr) reached pre-syncope after 11 plus or minus 1 min (P less than 0.001, LoTol group). Mean arterial pressure was unchanged. Central venous pressure and left atrial diameter decreased in both groups (5-6 mmHg by 30%, P less than 0.05). Control [hormone] were similar but, pRA differed between groups (LoTol 0.6 plus or minus 0.1, HiTol 1.2 plus or minus 0.1 ng Ang1 per milliliter per hour, per hour, P less than 0.05). LBNP increased (P less than 0.05) pRA and pATII more in HiTol (9.9 plus or minus 2.2 ng Ang1 per milliliter per hour and 58 plus or minus 12 pg per milliliter) than LoTol (4.3 plus or minus 0.9 ng Angl per milliliter per hour and 28 plus or minus 6 pg per milliliter). In contrast, pVP was higher (P less than 0.05) in LoTol than in HiTol. The response of the renin-angiotensin system seems linked to the occurrence of pre-syncope, and measurement of resting pRA may be predictive.

  6. The Renin Angiotensin Aldosterone System in Obesity and Hypertension: Roles in the Cardiorenal Metabolic Syndrome.

    PubMed

    Cabandugama, Peminda K; Gardner, Michael J; Sowers, James R

    2017-01-01

    In the United States, more than 50 million people have blood pressure at or above 120/80 mm Hg. All components of cardiorenal metabolic syndrome (CRS) are linked to metabolic abnormalities and obesity. A major driver for CRS is obesity. Current estimates show that many of those with hypertension and CRS show some degree of systemic and cardiovascular insulin resistance. Several pathophysiologic factors participate in the link between hypertension and CRS. This article updates recent literature with a focus on the function of insulin resistance, obesity, and renin angiotensin aldosterone system-mediated oxidative stress on endothelial dysfunction and the pathogenesis of hypertension. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. No evidence for a local renin-angiotensin system in liver mitochondria

    PubMed Central

    Astin, Ronan; Bentham, Robert; Djafarzadeh, Siamak; Horscroft, James A.; Kuc, Rhoda E.; Leung, Po Sing; Skipworth, James R. A.; Vicencio, Jose M.; Davenport, Anthony P.; Murray, Andrew J.; Takala, Jukka; Jakob, Stephan M.; Montgomery, Hugh; Szabadkai, Gyorgy

    2013-01-01

    The circulating, endocrine renin-angiotensin system (RAS) is important to circulatory homeostasis, while ubiquitous tissue and cellular RAS play diverse roles, including metabolic regulation. Indeed, inhibition of RAS is associated with improved cellular oxidative capacity. Recently it has been suggested that an intra-mitochondrial RAS directly impacts on metabolism. Here we sought to rigorously explore this hypothesis. Radiolabelled ligand-binding and unbiased proteomic approaches were applied to purified mitochondrial sub-fractions from rat liver, and the impact of AngII on mitochondrial function assessed. Whilst high-affinity AngII binding sites were found in the mitochondria-associated membrane (MAM) fraction, no RAS components could be detected in purified mitochondria. Moreover, AngII had no effect on the function of isolated mitochondria at physiologically relevant concentrations. We thus found no evidence of endogenous mitochondrial AngII production, and conclude that the effects of AngII on cellular energy metabolism are not mediated through its direct binding to mitochondrial targets. PMID:23959064

  8. A Brief Introduction into the Renin-Angiotensin-Aldosterone System: New and Old Techniques.

    PubMed

    Thatcher, Sean E

    2017-01-01

    The renin-angiotensin-aldosterone system (RAAS) is a complex system of enzymes, receptors, and peptides that help to control blood pressure and fluid homeostasis. Techniques in studying the RAAS can be difficult due to such factors as peptide/enzyme stability and receptor localization. This paper gives a brief account of the different components of the RAAS and current methods in measuring each component. There is also a discussion of different methods in measuring stem and immune cells by flow cytometry, hypertension, atherosclerosis, oxidative stress, energy balance, and other RAAS-activated phenotypes. While studies on the RAAS have been performed for over 100 years, new techniques have allowed scientists to come up with new insights into this system. These techniques are detailed in this Methods in Molecular Biology Series and give students new to studying the RAAS the proper controls and technical details needed to perform each procedure.

  9. A Detailed Physiologically Based Model to Simulate the Pharmacokinetics and Hormonal Pharmacodynamics of Enalapril on the Circulating Endocrine Renin-Angiotensin-Aldosterone System

    PubMed Central

    Claassen, Karina; Willmann, Stefan; Eissing, Thomas; Preusser, Tobias; Block, Michael

    2013-01-01

    The renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathogenesis of cardiovascular disorders including hypertension and is one of the most important targets for drugs. A whole body physiologically based pharmacokinetic (wb PBPK) model integrating this hormone circulation system and its inhibition can be used to explore the influence of drugs that interfere with this system, and thus to improve the understanding of interactions between drugs and the target system. In this study, we describe the development of a mechanistic RAAS model and exemplify drug action by a simulation of enalapril administration. Enalapril and its metabolite enalaprilat are potent inhibitors of the angiotensin-converting-enzyme (ACE). To this end, a coupled dynamic parent-metabolite PBPK model was developed and linked with the RAAS model that consists of seven coupled PBPK models for aldosterone, ACE, angiotensin 1, angiotensin 2, angiotensin 2 receptor type 1, renin, and prorenin. The results indicate that the model represents the interactions in the RAAS in response to the pharmacokinetics (PK) and pharmacodynamics (PD) of enalapril and enalaprilat in an accurate manner. The full set of RAAS-hormone profiles and interactions are consistently described at pre- and post-administration steady state as well as during their dynamic transition and show a good agreement with literature data. The model allows a simultaneous representation of the parent-metabolite conversion to the active form as well as the effect of the drug on the hormone levels, offering a detailed mechanistic insight into the hormone cascade and its inhibition. This model constitutes a first major step to establish a PBPK-PD-model including the PK and the mode of action (MoA) of a drug acting on a dynamic RAAS that can be further used to link to clinical endpoints such as blood pressure. PMID:23404365

  10. High potassium promotes mutual interaction between (pro)renin receptor and the local renin-angiotensin-aldosterone system in rat inner medullary collecting duct cells.

    PubMed

    Xu, Chuanming; Fang, Hui; Zhou, Li; Lu, Aihua; Yang, Tianxin

    2016-10-01

    (Pro)renin receptor (PRR) is predominantly expressed in the collecting duct (CD) with unclear functional implication. It is not known whether CD PRR is regulated by high potassium (HK). Here, we aimed to investigate the effect of HK on PRR expression and its role in regulation of aldosterone synthesis and release in the CD. In primary rat inner medullary CD cells, HK augmented PRR expression and soluble PPR (sPRR) release in a time- and dose-dependent manner, which was attenuated by PRR small interfering RNA (siRNA), eplerenone, and losartan. HK upregulated aldosterone release in parallel with an increase of CYP11B2 (cytochrome P-450, family 11, subfamily B, polypeptide 2) protein expression and upregulation of medium renin activity, both of which were attenuated by a PRR antagonist PRO20, PRR siRNA, eplerenone, and losartan. Similarly, prorenin upregulated aldosterone release and CYP11B2 expression, both of which were attenuated by PRR siRNA. Interestingly, a recombinant sPRR (sPRR-His) also stimulated aldosterone release and CYP11B2 expression. Taken together, we conclude that HK enhances a local renin-angiotensin-aldosterone system (RAAS), leading to increased PRR expression, which in turn amplifies the response of the RAAS, ultimately contributing to heightened aldosterone release.

  11. High potassium promotes mutual interaction between (pro)renin receptor and the local renin-angiotensin-aldosterone system in rat inner medullary collecting duct cells

    PubMed Central

    Xu, Chuanming; Fang, Hui; Zhou, Li; Lu, Aihua

    2016-01-01

    (Pro)renin receptor (PRR) is predominantly expressed in the collecting duct (CD) with unclear functional implication. It is not known whether CD PRR is regulated by high potassium (HK). Here, we aimed to investigate the effect of HK on PRR expression and its role in regulation of aldosterone synthesis and release in the CD. In primary rat inner medullary CD cells, HK augmented PRR expression and soluble PPR (sPRR) release in a time- and dose-dependent manner, which was attenuated by PRR small interfering RNA (siRNA), eplerenone, and losartan. HK upregulated aldosterone release in parallel with an increase of CYP11B2 (cytochrome P-450, family 11, subfamily B, polypeptide 2) protein expression and upregulation of medium renin activity, both of which were attenuated by a PRR antagonist PRO20, PRR siRNA, eplerenone, and losartan. Similarly, prorenin upregulated aldosterone release and CYP11B2 expression, both of which were attenuated by PRR siRNA. Interestingly, a recombinant sPRR (sPRR-His) also stimulated aldosterone release and CYP11B2 expression. Taken together, we conclude that HK enhances a local renin-angiotensin-aldosterone system (RAAS), leading to increased PRR expression, which in turn amplifies the response of the RAAS, ultimately contributing to heightened aldosterone release. PMID:27534754

  12. Atrial fibrillation and arterial hypertension: A common duet with dangerous consequences where the renin angiotensin-aldosterone system plays an important role.

    PubMed

    Seccia, Teresa Maria; Caroccia, Brasilina; Muiesan, Maria Lorenza; Rossi, Gian Paolo

    2016-03-01

    Atrial fibrillation (AF) represents the most common sustained cardiac arrhythmia, as it affects 1%-2% of the general population and up to 15% of people over 80 years. High blood pressure, due to its high prevalence in the general population, is by far the most common condition associated with AF, although a variety of diseases, including valvular, coronary heart and metabolic diseases, are held to create the substrate favouring AF. Due to the concomitance of these conditions, it is quite challenging to dissect the precise role of high blood pressure in triggering/causing AF. Hence, even though the intimate association between high blood pressure and AF has been known for decades, the underlying mechanisms remain partially unknown. Accumulating evidences point to a major role of the renin-angiotensin-aldosterone system in inducing cardiac inflammation and fibrosis, and therefore electric and structural atrial and ventricular remodelling, with changes in ions and cell junctions leading to AF development. These evidences are herein reviewed with a particular emphasis to the role of the renin-angiotensin-system aldosterone system. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. Addressing the theoretical and clinical advantages of combination therapy with inhibitors of the renin-angiotensin-aldosterone system: antihypertensive effects and benefits beyond BP control.

    PubMed

    Ferrario, Carlos M

    2010-02-27

    This article reviews the importance of the renin-angiotensin-aldosterone system (RAAS) in the cardiometabolic continuum; presents the pros and cons of dual RAAS blockade with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs); and examines the theoretical and practical benefits supporting the use of direct renin inhibitors (DRIs) in combination with ACEIs or ARBs. The author reviewed the literature for key publications related to the biochemical physiology of the RAAS and the pharmacodynamic effects of ACEIs, ARBs, and DRIs, with a particular focus on dual RAAS blockade with these drug classes. Although ACEI/ARB combination therapy produces modest improvement in BP, it has not resulted in the major improvements predicted given the importance of the RAAS across the cardiorenal disease continuum. This may reflect the fact that RAAS blockade with ACEIs and/or ARBs leads to exacerbated renin release through loss of negative-feedback inhibition, as well as ACE/aldosterone escape through RAAS and non-RAAS-mediated mechanisms. Plasma renin activity (PRA) is an independent predictor of morbidity and mortality, even for patients receiving ACEIs and ARBs. When used alone or in combination with ACEIs and ARBs, the DRI aliskiren effectively reduces PRA. Reductions in BP are greater with these combinations, relative to the individual components alone. It is possible that aliskiren plus either an ACEI or ARB may provide greater RAAS blockade than monotherapy with ACEIs or ARBs, and lead to additive improvement in BP and clinically important outcomes. Copyright 2009 Elsevier Inc. All rights reserved.

  14. The therapeutic potential of renin angiotensin aldosterone system (RAAS) in chronic pain: from preclinical studies to clinical trials.

    PubMed

    Bessaguet, Flavien; Magy, Laurent; Desmoulière, Alexis; Demiot, Claire

    2016-01-01

    The prevalence rate of chronic pain is 15% to 25% in adults while the therapeutic arsenal is still insufficient, especially in relieving neuropathic pain. Peripheral pain transmission is conducted by the small Aδ and C sensory nerve fibres. They express elements from the renin-angiotensin-aldosterone system (RAAS), a well-known blood pressure regulator. Recently, studies have demonstrated the role of angiotensin II, its derivatives and aldosterone in the modulation of pain perception, by interacting with receptors expressed by sensory nerve fibres or through the central nervous system. Here, we assess the effects of RAAS modulators in the conduction of pain with molecular, preclinical and clinical approaches, in normal or pathological conditions. Currently, some clinical studies have been carried out on the pain-relieving effect of RAAS modulators and suggest their potential in the management of chronic, inflammatory or neuropathic pain.

  15. Urinary angiotensinogen as a potential biomarker of intrarenal renin-angiotensin system activity in Chinese chronic kidney disease patients.

    PubMed

    Xu, Z; Xu, B; Xu, C

    2015-06-01

    Urinary angiotensinogen (AGT) mainly derives from the AGT produced in proximal tubular cells. Evidence exists that supports the correlation between urinary AGT and circulating AGT. To investigate the role of urinary AGT as a potential biomarker of intrarenal renin-angiotensin system activity in Chinese chronic kidney disease (CKD) patients. ELISA-based method used to quantify urinary AGT. Analyzed the relationship between urinary AGT and intrarenal angiotensin II (Ang II) activity in 128 CKD patients. ELISA was applied to measure the urinary and plasma renin activity, AGT, Ang II and aldosterone. Furthermore expression levels of intrarenal renin, AGT, Ang II and Ang II receptor were examined by immunohistochemistry staining (IHCS) in 72 CKD patients undergoing renal biopsy. The logarithmic transformation Log(urinary AGT/UCre) levels showed a normal distribution. Therefore, Log(urinary AGT/UCre) levels were used for the analyses. Average urinary AGT was 2.02 ± 0.55 ng/(mg Cr). Hypertension, urinary protein, urinary Ang II and urinary type IV collagen (Col IV) positively correlated with urinary AGT. Estimated glomerular filtration rate (eGFR), urinary sodium and serum AGT negatively correlated with urinary AGT. Multiple regression analysis indicated that low serum AGT, high urinary protein, urinary Ang II and urinary Col IV correlated significantly with high urinary AGT. We observed positive correlation between urinary AGT and positive IHCS area of AGT, Ang II and Ang II type 1 receptor in renal tissue. These data suggest that urinary AGT might be a potential biomarker of intrarenal Ang II activity in CKD patients.

  16. Ovariectomy modify local renin-angiotensin-aldosterone system gene expressions in the heart of ApoE (-/-) mice.

    PubMed

    Borges, Celina Carvalho; Penna-de-Carvalho, Aline; Medeiros Junior, Jorge L; Aguila, Marcia Barbosa; Mandarim-de-Lacerda, Carlos A

    2017-12-15

    The evaluation of the local Renin-Angiotensin-Aldosterone system (RAAS) gene expressions in the heart of ovariectomized (OVX) apolipoprotein E deficient mice (ApoE). Four-months old C57BL/6 female mice (wild-type, wt, n=20), and ApoE female mice (n=20), were submitted to OVX or a surgical procedure without ovary removal (SHAM) and formed four groups (n=10/group): SHAM/wt, SHAM/ApoE, OVX/wt, and OVX/ApoE. OVX led to greater body mass, plasma triglycerides (TG) and total cholesterol, and resulted in insulin resistance and altered RAAS gene expressions in the heart tissue. The gene expression of angiotensin-converting enzyme (ACE)-2 was lower in OVX/wt than in SHAM/wt (P=0.0004), Mas receptor (MASr) was lower in OVX/wt compared to SHAM/wt (P<0.0001). Also, angiotensin II receptor type 1 (AT1r) was higher in OVX/wt than in SHAM/wt (P=0.0229), and AT2r was lower in OVX/wt than in SHAM/wt (P=0.0121). OVX and ApoE deficiency showed interaction potentializing the insulin resistance, increasing TG levels and altering ACE and MASr gene expressions. ACE gene expression was higher in OVX/ApoE than in OVX/wt (P<0.0001), and MASr gene expression was lower in OVX/ApoE than in OVX/wt (P<0.0001). The impact of OVX on local RAAS cascade in the heart of ApoE deficient animals, besides the metabolic changes culminating with insulin resistance, involves an upregulation of renin, ACE, and AT1r gene expressions. The findings may contribute to clarify the mechanisms of development of postmenopausal hypertension and the link between RAAS and apolipoprotein E. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Renin angiotensin system blockers-associated angioedema in the Thai population: analysis from Thai National Pharmacovigilance Database.

    PubMed

    Win, Thet Su Zin; Chaiyakunapruk, Nathorn; Suwankesawong, Wimon; Dilokthornsakul, Piyameth; Nathisuwan, Surakit

    2015-09-01

    Renin-angiotensin-aldosterone system (RAS) blockers are commonly used for cardiovascular diseases. Currently, little information exists for the Asian population on angioedema, a rare yet serious adverse event. This study aimed to describe characteristics of RAS blockers-associated angioedema (RASBA) in Thai patients. A retrospective study using the national pharmacovigilance database of Thailand was undertaken. Cases indicating the presence of angioedema with RAS blockers uses from 1984-2011 were identified. Patient demographics, co-morbidities, concomitant drugs, information for the RAS blockers and angioedema were obtained as well as causality assessment and quality of reports. A total of 895 cases were identified. Mean age was 59.9+12.8 years and 66.5% being female. Most angioedema events (48.6%) occurred during the first week of treatment. Angiotensin converting enzyme inhibitors (87.7%) were the most commonly implicated agents followed by angiotensin receptor blockers (10.5%), aldosterone antagonist (2.1%) and direct renin inhibitor (0.2%). Out of the 895 cases incorporated in this study, 165 (18.4%) were classified as serious events and resulted in hospitalization. The overall case fatality rate was 0.4%. Respiratory disturbance occurred in 46 cases (5.1%). Patients with respiratory complications tended to be younger (53.4+13.9 vs 60.3+12.7 years old; p=0.002) and with higher frequency of allergy history (26.1% vs 14.7%; p=0.032) compared to those without respiratory complications. Based on multivariate logistic regression, the adjusted OR for history of allergy was 2.23 (95%CI: 1.04 - 4.78, p = 0.041). RASBA in Thai population occurred mostly in elderly female patients and often led to hospitalization. Since large number of patients is regularly exposed to RAS-blockers, a nationwide attempt to raise awareness of clinicians when prescribing RAS-blockers is prudent.

  18. Sildenafil Protects against Myocardial Ischemia-Reperfusion Injury Following Cardiac Arrest in a Porcine Model: Possible Role of the Renin-Angiotensin System

    PubMed Central

    Wang, Guoxing; Zhang, Qian; Yuan, Wei; Wu, Junyuan; Li, Chunsheng

    2015-01-01

    Sildenafil, a phosphodiesterase-5 inhibitor sold as Viagra, is a cardioprotector against myocardial ischemia/reperfusion (I/R) injury. Our study explored whether sildenafil protects against I/R-induced damage in a porcine cardiac arrest and resuscitation (CAR) model via modulating the renin-angiotensin system. Male pigs were randomly divided to three groups: Sham group, Saline group, and sildenafil (0.5 mg/kg) group. Thirty min after drug infusion, ventricular fibrillation (8 min) and cardiopulmonary resuscitation (up to 30 min) was conducted in these animals. We found that sildenafil ameliorated the reduced cardiac function and improved the 24-h survival rate in this model. Sildenafil partly attenuated the increases of plasma angiotensin II (Ang II) and Ang (1–7) levels after CAR. Sildenafil also decreased apoptosis and Ang II expression in myocardium. The increases of expression of angiotensin-converting-enzyme (ACE), ACE2, Ang II type 1 receptor (AT1R), and the Ang (1–7) receptor Mas in myocardial tissue were enhanced after CAR. Sildenafil suppressed AT1R up-regulation, but had no effect on ACE, ACE2, and Mas expression. Sildenafilfurther boosted the upregulation of endothelial nitric oxide synthase (eNOS), cyclic guanosine monophosphate (cGMP) and inducible nitric oxide synthase(iNOS). Collectively, our results suggest that cardioprotection of sildenafil in CAR model is accompanied by an inhibition of Ang II-AT1R axis activation. PMID:26569234

  19. Natriuretic peptides buffer renin-dependent hypertension.

    PubMed

    Demerath, Theo; Staffel, Janina; Schreiber, Andrea; Valletta, Daniela; Schweda, Frank

    2014-06-15

    The renin-angiotensin-aldosterone system and cardiac natriuretic peptides [atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP)] are opposing control mechanisms for arterial blood pressure. Accordingly, an inverse relationship between plasma renin concentration (PRC) and ANP exists in most circumstances. However, PRC and ANP levels are both elevated in renovascular hypertension. Because ANP can directly suppress renin release, we used ANP knockout (ANP(-/-)) mice to investigate whether high ANP levels attenuate the increase in PRC in response to renal hypoperfusion, thus buffering renovascular hypertension. ANP(-/-) mice were hypertensive and had reduced PRC compared with that in wild-type ANP(+/+) mice under control conditions. Unilateral renal artery stenosis (2-kidney, 1-clip) for 1 wk induced similar increases in blood pressure and PRC in both genotypes. Unexpectedly, plasma BNP concentrations in ANP(-/-) mice significantly increased in response to two-kidney, one-clip treatment, potentially compensating for the lack of ANP. In fact, in mice lacking guanylyl cyclase A (GC-A(-/-) mice), which is the common receptor for both ANP and BNP, renovascular hypertension was markedly augmented compared with that in wild-type GC-A(+/+) mice. However, the higher blood pressure in GC-A(-/-) mice was not caused by disinhibition of the renin system because PRC and renal renin synthesis were significantly lower in GC-A(-/-) mice than in GC-A(+/+) mice. Thus, natriuretic peptides buffer renal vascular hypertension via renin-independent effects, such as vasorelaxation. The latter possibility is supported by experiments in isolated perfused mouse kidneys, in which physiological concentrations of ANP and BNP elicited renal vasodilatation and attenuated renal vasoconstriction in response to angiotensin II. Copyright © 2014 the American Physiological Society.

  20. Tagging SNPs in REN, AGTR1 and AGTR2 genes and response of renin activity, angiotensin II and aldosterone concentrations to antihypertensive treatment in Kazakans.

    PubMed

    Yan, Weili; Zhang, Yuanming; Shan, Zimei; Wang, Qian; Huang, Yongdi; Wang, Chenchen; Yan, Kai

    2011-12-01

    Polymorphisms of REN, AGTR1 and AGTR2 may be associated with responses of renin-angiotensin-aldosterone system (RAAS) activity phenotypes to angiotensin-converting enzyme inhibitor (ACEI) antihypertensive treatment. A total of 400 first diagnosed Kazak hypertensives were randomly allocated to two groups and received a 3-week course of either captopril and atenolol as monotherapy under double blinding. Genotype-phenotype association analyses were performed by covariance analyses between baseline level and responses of blood pressure, renin, angiotensin II and aldosterone concentrations with tagging single nucleotide polymorphisms (SNPs) in REN, AGTR1 and AGTR2 genes. A false discovery rate method was used to adjust multiple testing. After adjustment for multiple testing, we found that the G allele of rs6676670 (T/G) in intron 1 of REN was significantly associated with higher baseline aldosterone concentrations (p < 0.0001, explained variance (EV) = 2.3%). Significant associations after adjustments were also found between the A allele of rs2887284, with higher baseline renin activity (p = 0.022, EV = 1.0%), higher responses of renin (p = 0.018 EV = 5.4%), and higher responses of angiotensin II (p = 0.0255, EV = 3.13%) to the treatment of ACEI. The carriers of the A allele of rs2887284 appeared to be more sensitive to the ACEI treatment. rs2887284 in intron 9 of REN is associated with the response of renin and angiotensin II levels to ACEI treatment.

  1. Upregulation of circulating components of the alternative renin-angiotensin system in inflammatory bowel disease: A pilot study.

    PubMed

    Garg, Mayur; Burrell, Louise M; Velkoska, Elena; Griggs, Karen; Angus, Peter W; Gibson, Peter R; Lubel, John S

    2015-09-01

    The relationship between intestinal inflammation and circulating components of the renin-angiotensin system (RAS) is poorly understood. Demographic and clinical data were obtained from healthy controls and patients with inflammatory bowel disease (IBD). Plasma concentrations of the classical RAS components (angiotensin-converting enzyme (ACE) and angiotensin II (Ang II)) and alternative RAS components (ACE2 and angiotensin (1-7) (Ang (1-7))) were analysed by radioimmuno- and enzymatic assays. Systemic inflammation was assessed using serum C-reactive protein (CRP), white cell count, platelet count and albumin, and intestinal inflammation by faecal calprotectin. Nineteen healthy controls (11 female; mean age 38 years, range 23-68), 19 patients with Crohn's disease (11 female; aged 45 years, range 23-76) and 15 patients with ulcerative colitis (6 female; aged 42 years, 26-64) were studied. Circulating classical RAS component levels were similar across the three groups, whereas ACE2 activity and Ang (1-7) concentrations were higher in patients with IBD compared to controls (ACE2: 21.5 vs 13.3 pmol/ml/min, p<0.05; Ang (1-7): 22.8 vs 14.1 pg/ml, p<0.001). Ang (1-7) correlated weakly with platelet and white cell counts, but not calprotectin or CRP, in patients with IBD. Circulating components of the alternative RAS are increased in patients with IBD. © The Author(s) 2014.

  2. High-intensity interval training has beneficial effects on cardiac remodeling through local renin-angiotensin system modulation in mice fed high-fat or high-fructose diets.

    PubMed

    de Oliveira Sá, Guilherme; Dos Santos Neves, Vívian; de Oliveira Fraga, Shyrlei R; Souza-Mello, Vanessa; Barbosa-da-Silva, Sandra

    2017-11-15

    HIIT (high-intensity interval training) has the potential to reduce cardiometabolic risk factors, but the effects on cardiac remodeling and local RAS (renin-angiotensin system) in mice fed high-fat or high-fructose diets still need to be fully addressed. Sixty male C57BL/6 mice (12weeks old) were randomly divided into three groups, control (C), High-fat (HF), or High-fructose diet (HRU) and were monitored for eight weeks before being submitted to the HIIT. Each group was randomly assigned to 2 subgroups, one subgroup was started on a 12-week HIIT protocol (T=trained group), while the other subgroup remained non-exercised (NT=not-trained group). HIIT reduced BM and systolic blood pressure in high-fat groups, while enhanced insulin sensitivity after high-fat or high-fructose intake. Moreover, HIIT reduced left ventricular hypertrophy in HF-T and HFRU-T. Notably, HIIT modulated key factors in the local left ventricular renin-angiotensin-system (RAS): reduced protein expression of renin, ACE (Angiotensin-converting enzyme), and (Angiotensin type 2 receptor) AT2R in HF-T and HFRU-T groups but reduced (Angiotensin type 1 receptor) AT1R protein expression only in the high-fat trained group. HIIT modulated ACE2/Ang (1-7)/Mas receptor axis. ACE2 mRNA gene expression was enhanced in HF-T and HFRU-T groups, complying with elevated Mas (Mas proto-oncogene, G protein-coupled receptor) receptor mRNA gene expression after HIIT. This study shows the effectiveness of HIIT sessions in producing improvements in insulin sensitivity and mitigating LV hypertrophy, though hypertension was controlled only in the high-fat-fed submitted to HIIT protocol. Local RAS system in the heart mediates these findings and receptor MAS seems to play a pivotal role when it comes to the amelioration of cardiac structural and functional remodeling due to HIIT. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Is there benefit in dual renin-angiotensin-aldosterone system blockade? No, yes and maybe: a guide for the perplexed.

    PubMed

    Wong, Jencia

    2013-05-01

    Since the initial discovery of Angiotensin converting enzyme inhibitors (ACEI) in the 1960s and the launch of Captopril as the first available for clinical use in the 1970s, there now exist three other classes of drugs that block the renin angiotensin aldosterone system (RAAS): the angiotensin II receptor blockers (ARB), aldosterone antagonists (AA) and direct renin inhibitors (DRI). With the proven efficacy of RAAS blockers as monotherapy in many arenas there has been considerable interest in the use of dual therapy combinations of these medications that target different points in the pathway. By potentially offering a more complete RAAS blockade with a commensurate enhanced clinical effect, the strong biological rationale for dual therapy has led to it being embraced by clinicians as a treatment option, for hypertension and nephroprotection in particular. However, the initial enthusiasm for this treatment has been tempered by the recent results from several large trials such as ONTARGET and ALTITUDE, which do not support a specific dual therapy approach. In contrast, there is supportive evidence for dual blockade of specific combinations in selected patient groups and data are lacking for others. In the wake of this complex contemporary evidence, the conundrum now faced by clinicians committed to individualised care is, for which patients dual therapy could still be of benefit. This review examines for the practising clinician the current 'state of play' for dual blockade of various combinations and a perspective on its use in cardio-renal disease and diabetic complications.

  4. Predominance of AT(1) blockade over mas-mediated angiotensin-(1-7) mechanisms in the regulation of blood pressure and renin-angiotensin system in mRen2.Lewis rats.

    PubMed

    Varagic, Jasmina; Ahmad, Sarfaraz; VonCannon, Jessica L; Moniwa, Norihito; Brosnihan, K Bridget; Wysocki, Jan; Batlle, Daniel; Ferrario, Carlos M

    2013-05-01

    We investigated whether the antihypertensive actions of the angiotensin II (Ang II) receptor (AT(1)-R) blocker, olmesartan medoxomil, may in part be mediated by increased Ang-(1-7) in the absence of significant changes in plasma Ang II. mRen2.Lewis congenic hypertensive rats were administered either a vehicle (n = 14) or olmesartan (0.5 mg/kg/day; n = 14) by osmotic minipumps. Two weeks later, rats from both groups were further randomized to receive either the mas receptor antagonist A-779 (0.5 mg/kg/day; n = 7 per group) or its vehicle (n = 7 per group) for the next 4 weeks. Blood pressure was monitored by telemetry, and circulating and tissue components of the renin-angiotensin system (RAS) were measured at the completion of the experiments. Antihypertensive effects of olmesartan were associated with an increase in plasma renin concentration, plasma Ang I, Ang II, and Ang-(1-7), whereas serum aldosterone levels and kidney Ang II content were reduced. Preserved Ang-(1-7) content in kidneys was associated with increases of ACE2 protein but not activity and no changes on serum and kidney ACE activity. There was no change in cardiac peptide levels after olmesartan treatment. The antihypertensive effects of olmesartan were not altered by concomitant administration of the Ang-(1-7) receptor antagonist except for a mild further increase in plasma renin concentration. Our study highlights the independent regulation of RAS among plasma, heart, and kidney tissue in response to AT(1)-R blockade. Ang-(1-7) through the mas receptor does not mediate long-term effects of olmesartan besides counterbalancing renin release in response to AT(1)-R blockade.

  5. Renin-angiotensin-aldosterone system activation in long-standing type 1 diabetes

    PubMed Central

    Lovshin, Julie A.; Boulet, Geneviève; Lytvyn, Yuliya; Lovblom, Leif E.; Bjornstad, Petter; Lai, Vesta; Cham, Leslie; Tse, Josephine; Orszag, Andrej; Scarr, Daniel; Weisman, Alanna; Keenan, Hillary A.; Brent, Michael H.; Paul, Narinder; Perkins, Bruce A.; Cherney, David Z.I.

    2018-01-01

    BACKGROUND. In type 1 diabetes (T1D), adjuvant treatment with inhibitors of the renin-angiotensin-aldosterone system (RAAS), which dilate the efferent arteriole, is associated with prevention of progressive albuminuria and renal dysfunction. Uncertainty still exists as to why some individuals with long-standing T1D develop diabetic kidney disease (DKD) while others do not (DKD resistors). We hypothesized that those with DKD would be distinguished from DKD resistors by the presence of RAAS activation. METHODS. Renal and systemic hemodynamic function was measured before and after exogenous RAAS stimulation by intravenous infusion of angiotensin II (ANGII) in 75 patients with prolonged T1D durations and in equal numbers of nondiabetic controls. The primary outcome was change in renal vascular resistance (RVR) in response to RAAS stimulation, a measure of endogenous RAAS activation. RESULTS. Those with DKD had less change in RVR following exogenous RAAS stimulation compared with DKD resistors or controls (19%, 29%, 31%, P = 0.008, DKD vs. DKD resistors), reflecting exaggerated endogenous renal RAAS activation. All T1D participants had similar changes in renal efferent arteroilar resistance (9% vs. 13%, P = 0.37) irrespective of DKD status, which reflected less change versus controls (20%, P = 0.03). In contrast, those with DKD exhibited comparatively less change in afferent arteriolar vascular resistance compared with DKD resistors or controls (33%, 48%, 48%, P = 0.031, DKD vs. DKD resistors), indicating higher endogenous RAAS activity. CONCLUSION. In long-standing T1D, the intrarenal RAAS is exaggerated in DKD, which unexpectedly predominates at the afferent rather than the efferent arteriole, stimulating vasoconstriction. FUNDING. JDRF operating grant 17-2013-312. PMID:29321380

  6. Living alone and activation of the renin-angiotensin-aldosterone-system: Differential effects depending on alexithymic personality features.

    PubMed

    Terock, Jan; Hannemann, Anke; Janowitz, Deborah; Völzke, Henry; Nauck, Matthias; Freyberger, Harald-Jürgen; Wallaschofski, Henri; Grabe, Hans Jörgen

    2017-05-01

    Living alone is considered as a chronic stress factor predicting different health conditions and particularly cardiovascular disease (CVD). Alexithymia is associated with increased psychological distress, less social skills and fewer close relationships, making alexithymic subjects particularly susceptible to chronic stress imposed by "living alone". Only few studies investigated the renin-angiotensin-aldosterone-system (RAAS) activity in response to chronic stress. We aimed at evaluating the effects of "living alone" as a paradigm for chronic stress on RAAS activity and putatively differential effects depending on alexithymic personality features. Alexithymia and serum concentrations of renin and aldosterone were measured in 944 subjects from the population-based SHIP-1 study. Subgroups were formed using the median of the Toronto Alexithymia Scale-20 (TAS-20) and a cohabitation status of "living alone" or "living together". Analyses were adjusted for various psychosocial, behavioral and metabolic risk factors. "Living alone" was associated with elevated plasma renin (p<0.01, β=0.138) but not aldosterone concentrations in the total sample. On subgroup level, we found associations of "living alone" and elevated renin concentrations only in subjects low in TAS-20 scores (p<0.01, β=0.219). Interactional effects of alexithymia×cohabitation status were found for the aldosterone-to-renin ratio (p=0.02, β=-0.234). The association of chronic stress imposed by "living alone" with increased RAAS activity contributes to explain the relationship of this psychosocial stress condition and increased risk for CVD. In contrast, alexithymic subjects may be less affected by the deleterious effects of "living alone". Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Associations between glycaemic control and activation of the renin-angiotensin-aldosterone system in participants with type 2 diabetes mellitus and hypertension.

    PubMed

    Griffin, T P; Wall, D; Browne, G A; Dennedy, M C; O'Shea, P M

    2018-05-01

    Introduction Hyperglycaemia increases succinate concentrations and succinate receptor activation in the kidney resulting in renin release. The aim of our study was to determine if there is an association between glycaemic control as evidenced by glycated haemoglobin values and activation of the renin-angiotensin-aldosterone system in patients with type 2 diabetes mellitus and hypertension. Methods A cross-sectional study was conducted at Galway University Hospitals between December 2014 and March 2015. Participants ( n = 66) were identified following interrogation of the electronic database for patients with type 2 diabetes mellitus. Baseline clinical demographics, aldosterone, plasma renin activity, direct renin concentration, urea and electrolytes, glycated haemoglobin, cholesterol, urine sodium and albumin creatinine ratio were recorded. Results There was a significant positive linear correlation between glycated haemoglobin and renin (both plasma renin activity [ P = 0.002] and direct renin concentration [ P = 0.008]) and between serum creatinine and aldosterone measured using both radioimmunoassay ( P = 0.008) and immunochemiluminometric assay ( P = 0.008). A significant negative linear correlation was demonstrated between serum sodium and plasma renin activity ( P = 0.005) and direct renin concentration ( P = 0.015) and between estimated glomerular filtration rate and aldosterone measured using radioimmunoassay ( P = 0.02) and immunochemiluminometric assay ( P = 0.016). A significant negative linear correlation existed between urine sodium and plasma renin activity ( P = 0.04) and aldosterone measured using radioimmunoassay ( P = 0.045). Conclusions There is a direct positive association between glycaemic control and renin. We advocate for renin measurement to be part of the diabetologist's armamentarium to assess, guide and optimize therapeutic strategies in patients with diabetes.

  8. Role of the intrarenal renin-angiotensin system in the progression of renal disease.

    PubMed

    Urushihara, Maki; Kagami, Shoji

    2017-09-01

    The intrarenal renin-angiotensin system (RAS) has many well-documented pathophysiologic functions in both blood pressure regulation and renal disease development. Angiotensin II (Ang II) is the major bioactive product of the RAS. It induces inflammation, renal cell growth, mitogenesis, apoptosis, migration, and differentiation. In addition, Ang II regulates the gene expression of bioactive substances and activates multiple intracellular signaling pathways that are involved in renal damage. Activation of the Ang II type 1 (AT1) receptor pathway results in the production of proinflammatory mediators, intracellular formation of reactive oxygen species, cell proliferation, and extracellular matrix synthesis, which in turn facilities renal injury. Involvement of angiotensinogen (AGT) in intrarenal RAS activation and development of renal disease has previously been reported. Moreover, studies have demonstrated that the urinary excretion rates of AGT provide a specific index of the intrarenal RAS status. Enhanced intrarenal AGT levels have been observed in experimental models of renal disease, supporting the concept that AGT plays an important role in the development and progression of renal disease. In this review, we focus on the role of intrarenal RAS activation in the pathophysiology of renal disease. Additionally, we explored the potential of urinary AGT as a novel biomarker of intrarenal RAS status in renal disease.

  9. To live alone and to be depressed, an alarming combination for the renin-angiotensin-aldosterone-system (RAAS).

    PubMed

    Häfner, S; Baumert, J; Emeny, R T; Lacruz, M E; Bidlingmaier, M; Reincke, M; Kuenzel, H; Holle, R; Rupprecht, R; Ladwig, K H

    2012-02-01

    The renin-angiotensin-aldosterone-system (RAAS) is one of the most important systems involved in the pathogenesis of cardiovascular diseases. Its role in stress response has been generally neglected, although the progression of cardiovascular disease is considerably increased in the presence of stress and especially in the presence of depression risk. With the present analysis we aimed to evaluate whether the activity of the RAAS correlates with depressive symptomatology and with chronic stress. Moreover, we aimed to analyse whether stress response is altered in the presence of depressed symptomatology. We chose "living alone" to be our paradigm of chronic stress. Aldosterone and renin levels were assessed in 1743 (829 men, 914 women) from the population-based KORA study (Cooperative Health Research in the Region of Augsburg). The relationship between aldosterone, renin levels and the different combinations of living alone and depressive symptomatology was examined in three different multiple linear regression models adjusted for age, sex, creatinine levels, potassium levels, body mass index (BMI) and bio-behavioural factors. Neither "living alone" nor depressive symptomatology alone were associated with an activation of the RAAS, but the combination of living alone and depressive symptomatology yielded a highly significant increase in the aldosterone (p<0.01) and renin level (p=0.03). Our findings show that depressive symptomatology is associated with a hyper-responsiveness to chronic stress. Under the condition of chronic stress depressed individuals have an activated RAAS. Activation of the RAAS might explain the known increased risk of negative cardiovascular disease outcomes in this group. Copyright © 2011 Elsevier Ltd. All rights reserved.

  10. Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion.

    PubMed

    Mackins, Christina J; Kano, Seiichiro; Seyedi, Nahid; Schäfer, Ulrich; Reid, Alicia C; Machida, Takuji; Silver, Randi B; Levi, Roberto

    2006-04-01

    Having identified renin in cardiac mast cells, we assessed whether its release leads to cardiac dysfunction. In Langendorff-perfused guinea pig hearts, mast cell degranulation with compound 48/80 released Ang I-forming activity. This activity was blocked by the selective renin inhibitor BILA2157, indicating that renin was responsible for Ang I formation. Local generation of cardiac Ang II from mast cell-derived renin also elicited norepinephrine release from isolated sympathetic nerve terminals. This action was mediated by Ang II-type 1 (AT1) receptors. In 2 models of ischemia/reperfusion using Langendorff-perfused guinea pig and mouse hearts, a significant coronary spillover of renin and norepinephrine was observed. In both models, this was accompanied by ventricular fibrillation. Mast cell stabilization with cromolyn or lodoxamide markedly reduced active renin overflow and attenuated both norepinephrine release and arrhythmias. Similar cardioprotection was observed in guinea pig hearts treated with BILA2157 or the AT1 receptor antagonist EXP3174. Renin overflow and arrhythmias in ischemia/reperfusion were much less prominent in hearts of mast cell-deficient mice than in control hearts. Thus, mast cell-derived renin is pivotal for activating a cardiac renin-angiotensin system leading to excessive norepinephrine release in ischemia/reperfusion. Mast cell-derived renin may be a useful therapeutic target for hyperadrenergic dysfunctions, such as arrhythmias, sudden cardiac death, myocardial ischemia, and congestive heart failure.

  11. Chronobiology of the renin-angiotensin-aldosterone system in dogs: relation to blood pressure and renal physiology.

    PubMed

    Mochel, Jonathan P; Fink, Martin; Peyrou, Mathieu; Desevaux, Cyril; Deurinck, Mark; Giraudel, Jérôme M; Danhof, Meindert

    2013-11-01

    The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the regulation of blood pressure and volume homeostasis. Its contribution to the development of cardiovascular diseases has long been recognized. Extensive literature has shown that peptides of the RAAS oscillate with a circadian periodicity in humans, under strong influence of posture, sleep, and age. Although observations of time-variant changes in the renin cascade are available in dogs, no detailed chronobiological investigation has been conducted so far. The present studies were designed to explore the circadian variations of plasma renin activity (RA) and urinary aldosterone-to-creatinine ratio (UA:C) in relation to blood pressure (BP), sodium (UNa, UNa,fe), and potassium (UK, UK,fe) renal handling. Data derived from intensive blood and urine sampling, as well as continuous BP monitoring, were collected throughout a 24-h time period, and analyzed by means of nonlinear mixed-effects models. Differences between the geometric means of day and night observations were compared by parametric statistics. Our results show that variables of the renin cascade, BP, and urinary electrolytes oscillate with significant day-night differences in dogs. An approximately 2-fold (1.6-3.2-fold) change between the average day and night measurements was found for RA (p < 0.001), UA:C (p = 0.01), UK,fe (p = 0.01), and UNa (p = 0.007). Circadian variations in BP, albeit small (less than 10 mm Hg), were statistically significant (p < 0.01) and supported by the model-based analysis. For all variables but UNa and UNa,fe, the levels were higher at night than during the day. The data also indicate that blood pressure oscillates in parallel to the RAAS, such that, as opposed to healthy humans, BP does not drop at night in dogs. The postprandial decrease in RA is assumed to be related to body fluid volume expansion secondary to water and sodium intake, whereas the reduction of UA:C reflects

  12. Renin-angiotensin system (RAS) blockade attenuates growth and metastatic potential of renal cell carcinoma in mice.

    PubMed

    Araújo, Wedson F; Naves, Marcelo A; Ravanini, Juliana N; Schor, Nestor; Teixeira, Vicente P C

    2015-09-01

    Renal cell carcinoma (RCC) is the most frequent type of cancer among renal neoplasms in adults and responds poorly to radiotherapy and chemotherapy. There is evidence that blockade of the renin-angiotensin system (RAS) might have antineoplastic effects. The aim of this study was to investigate the effects of RAS blockade on RCC in a murine model. Murine renal cancer cells (Renca) were injected (1 × 10(5)) into the subcapsular space of the left kidney of BALB/c mice (8 wk of age). The animals were divided into 4 groups: a control group (no treatment), angiotensin-receptor blockers group (losartan 100mg/kg/d), angiotensin-converting enzyme inhibitor group (captopril 10mg/kg/d), and angiotensin-receptor blockers +angiotensin-converting enzyme inhibitor group (losartan 100mg/kg/d +captopril 10mg/kg/d). The animals received the drugs by gavage for 21 days after inoculation, beginning 2 days before tumor induction, and were then euthanized. After killing the animals, the kidneys and lungs were removed, weighed, and processed for histopathological and immunohistochemical analyses. Angiogenesis and vascular microvessels were assessed with the antibodies anti-vascular endothelial growth factor and anti-CD34. Angiotensin II-inoculated animals developed renal tumors. Treated animals presented smaller tumors, regardless of the therapeutic regimen, and far fewer lung metastases in both quantity and dimension compared with the controls. The expression of vascular endothelial growth factor and CD34 were significantly decreased in renal tumors of treated animals compared with the controls. Our findings suggest that blockade of RAS decreases tumor proliferation and metastatic capacity of RCC in this experimental model. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Nephroprotective action of renin-angiotensin-aldosterone system blockade in chronic kidney disease patients: the landscape after ALTITUDE and VA NEPHRON-D trails.

    PubMed

    Rutkowski, Boleslaw; Tylicki, Leszek

    2015-03-01

    The intervention in the renin-angiotensin-aldosterone system (RAAS) is currently the most effective strategy that combines blood pressure lowering and renoprotection. Several large, randomized, controlled trials evidenced the renoprotective potential of the angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in nephropathies of almost any etiology. Mineralocorticoid receptor antagonists and direct renin inhibitor, aliskiren, as add-on treatments to standard therapy including the optimal dose of ACEIs or ARBs reduce albuminuria or proteinuria and slow development of renal dysfunction more than placebo. No clinical evidence is available however about whether these strategies may influence on long-term kidney outcome. Three recent trials suggested that aggressive RAAS blockade, that is, combination of 2 RAAS-blocking agents, does not decrease cardiovascular and renal morbidity and may carry an increased risk of serious complications. This article reviews an evidence-based approach on the use of RAAS-inhibiting agents in chronic kidney disease and considers the implementation of dual RAAS blockade with reference to the results of ALTITUDE and VA NEPHRON-D trails aiming to aid clinicians in their treatment decisions for patients with chronic kidney disease. Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  14. Association Between Pituitary-Adrenal Axis Dominance Over the Renin-Angiotensin-Aldosterone System and Hypertension.

    PubMed

    Daimon, Makoto; Kamba, Aya; Murakami, Hiroshi; Takahashi, Kazuhisa; Otaka, Hideyuki; Makita, Koushi; Yanagimachi, Miyuki; Terui, Ken; Kageyama, Kazunori; Nigawara, Takeshi; Sawada, Kaori; Takahashi, Ippei; Nakaji, Shigeyuki

    2016-03-01

    The hypothalamus-pituitary-adrenal (HPA) axis and the renin-angiotensin aldosterone system (RAAS) are well known to be associated with hypertension. However, the extent of the effects is not yet well elucidated in general conditions. To separately determine the effect of the HPA axis and the RAAS on hypertension in a general population. A population-based study of 859 Japanese individuals enrolled in the 2014 Iwaki study and without hypertension or steroid treatment (age, 50.2 ± 14.7 years). Hypertension prevalence, plasma concentration of aldosterone, ACTH, cortisol, and plasma renin activity. Principal component (PC) analysis using these four hormones identified two PCs (PC1 and PC2), which represent levels of these hormones as a whole, and dominance between the HPA axis (ACTH and cortisol) and the RAAS (plasma renin activity and plasma concentration of aldosterone), respectively. Association between these PCs and hypertension was significant (PC1, high vs low, odds ratio [OR], 1.48; 95% confidence interval [CI], 1.09-2.02; and PC2, HPA axis vs RAAS dominancy, OR, 2.08; and 95% CI, 1.51-2.85). However, association between the hormone levels as a whole and hypertension became insignificant after adjustment for multiple factors including these PCs together. However, association between the HPA axis dominance and hypertension remained significant even after the adjustment (the HPA axis vs the RAAS, OR, 1.73; 95% CI, 1.20-2.48). The HPA axis dominance over the RAAS is significantly associated with hypertension in a Japanese population.

  15. Neuron-specific (pro)renin receptor knockout prevents the development of salt-sensitive hypertension

    PubMed Central

    Li, Wencheng; Peng, Hua; Mehaffey, Eamonn P.; Kimball, Christie D.; Grobe, Justin L.; van Gool, Jeanette M.G.; Sullivan, Michelle N.; Earley, Scott; Danser, A.H. Jan; Ichihara, Atsuhiro; Feng, Yumei

    2013-01-01

    The (pro)renin receptor, which binds both renin and prorenin, is a newly discovered component of the renin angiotensin system that is highly expressed in the central nervous system. The significance of brain PRRs in mediating local angiotensin II formation and regulating blood pressure remains unclear. The current study was performed to test the hypothesis that PRR-mediated, non-proteolytic activation of prorenin is the main source of angiotensin II in the brain. Thus, PRR knockout in the brain is expected to prevent angiotensin II formation and development of deoxycorticosterone acetate salt induced hypertension. A neuron-specific PRR (ATP6AP2) knockout mouse model was generated using the Cre-LoxP system. Physiological parameters were recorded by telemetry. (Pro)renin receptor expression, detected by immunostaining and RT-PCR, was significantly decreased in the brains of knockout compared with wide-type mice. Intracerebroventricular infusion of mouse prorenin increased blood pressure and angiotensin II formation in wild type mice. This hypertensive response was abolished in (pro)renin receptor knockout mice in association with a reduction in angiotensin II levels. Deoxycorticosterone acetate salt increased (pro)renin receptor expression and angiotensin II formation in the brains of wild-type mice, an effect that was attenuated in (pro)renin receptor knockout mice. (Pro)renin receptor knockout in neurons prevented the development of Deoxycorticosterone acetate salt-induced hypertension as well as activation of cardiac and vasomotor sympathetic tone. In conclusion, non-proteolytic activation of prorenin through binding to the PRR mediates angiotensin II formation in the brain. Neuron-specific PRR knockout prevents the development of deoxycorticosterone acetate salt-induced hypertension, possibly through diminished angiotensin II formation. PMID:24246383

  16. The Renin-Angiotensin System, Not the Kinin-Kallikrein System, Affects Post-Exercise Proteinuria.

    PubMed

    Koçer, Günnur; Basralı, Filiz; Kuru, Oktay; Şentürk, Ümit Kemal

    2018-05-17

    Temporary proteinuria post-exercise is common and is caused predominantly by renal haemodynamic alterations. One reason is up-regulation of angiotensin II (Ang II) due to the reducing effect of angiotensin-converting enzyme (ACE) inhibitors. However, another, ignored, reason could be the kininase effect of ACE inhibition. This study investigated how ACE inhibition reduces post-exercise proteinuria: by either Ang II up-regulation inhibition or bradykinin elevation due to kininase activity inhibition. Our study included 10 volunteers, who completed 3 high-intensity exercise protocols involving cycling at 1-week intervals. The first protocol was a control arm, the second evaluated the effect of ACE inhibition and the third examined the effect of angiotensin type 1 receptor blockade. Upon application, both agents reduced systolic and diastolic blood pressure; however, there were no statistically significant -differences. In addition, total protein, microalbumin and -β2-microglobulin excretion levels in urine specimens were analysed before, 30 min after and 120 min after the exercise protocols. Total protein levels in urine samples were elevated in all 3 protocols after 30 min of high-intensity exercise, compared to baseline levels. However, both ACE inhibition and angiotensin type 1 receptor blockade suppressed total protein in the 30th min. In each protocol, total protein levels returned to the baseline after 120 min. Urinary microalbumin and β2-microglobulin levels during the control protocol were significantly higher 30 min post-exercise; however, only angiotensin type 1 receptor blockade suppressed microalbumin levels. The results indicated Ang II up-regulation, not bradykinin elevation, plays a role in post-exercise proteinuria. © 2018 S. Karger AG, Basel.

  17. THE RENIN-ANGIOTENSIN SYSTEM AND THE BIOLOGY OF SKELETAL MUSCLE: MECHANISMS OF MUSCLE WASTING IN CHRONIC DISEASE STATES.

    PubMed

    Delafontaine, Patrice; Yoshida, Tadashi

    2016-01-01

    Sarcopenia and cachexia are muscle-wasting syndromes associated with aging and with many chronic diseases such as congestive heart failure, diabetes, cancer, chronic obstructive pulmonary disease, and renal failure. While mechanisms are complex, these conditions are often accompanied by elevated angiotensin II (Ang II). We found that Ang II infusion in rodents leads to skeletal muscle wasting via alterations in insulin-like growth factor-1 signaling, increased apoptosis, enhanced muscle protein breakdown via the ubiquitin-proteasome system, and decreased appetite resulting from downregulation of hypothalamic orexigenic neuropeptides orexin and neuropeptide Y. Furthermore, Ang II inhibits skeletal muscle stem cell proliferation, leading to lowered muscle regenerative capacity. Distinct stem cell Ang II receptor subtypes are critical for regulation of muscle regeneration. In ischemic mouse congestive heart failure model skeletal muscle wasting and attenuated muscle regeneration are Ang II dependent. These data suggest that the renin-angiotensin system plays a critical role in mechanisms underlying cachexia in chronic disease states.

  18. Potassium handling with dual renin-angiotensin system inhibition in diabetic nephropathy.

    PubMed

    Van Buren, Peter N; Adams-Huet, Beverley; Nguyen, Mark; Molina, Christopher; Toto, Robert D

    2014-02-01

    Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are the cornerstones of pharmacologic therapy in diabetic nephropathy. Mineralocorticoid receptor blockers reduce proteinuria as single agents or add-on therapy to other renin-angiotensin-aldosterone system-inhibiting drugs in these patients. The long-term benefits and ultimate role of mineralocorticoid receptor blockers in diabetic nephropathy remain unknown. A clinical trial previously showed that the kalemic effect of spironolactone is higher than losartan when added to lisinopril in patients with diabetic nephropathy. The purpose of this study was to investigate if renal potassium handling was primarily responsible for that observation. In a blinded, randomized, three-arm placebo-controlled clinical trial, 80 participants with diabetic nephropathy taking lisinopril (80 mg) were randomized to spironolactone (25 mg daily), losartan (100 mg daily), or placebo (trial dates from July of 2003 to December of 2006). Serum potassium, aldosterone, and 24-hour urine sodium, potassium, and creatinine were measured over 48 weeks. Differences were analyzed with repeated measures mixed models. Mean follow-up serum potassium was 5.0 mEq/L for spironolactone, 4.7 mEq/L for losartan (P=0.05 versus spironolactone), and 4.5 mEq/L for placebo (P<0.001 versus spironolactone; P=0.03 versus losartan). The difference in serum potassium was 0.23 mEq/L for losartan versus placebo (P=0.02), 0.43 mEq/L for spironolactone versus placebo (P<0.001), and 0.2 mEq/L for spironolactone versus losartan (P=0.05). Serum and urine potassium excretion and secretion rates were similar between groups throughout the study. Spironolactone raised serum potassium more than losartan in patients with diabetic nephropathy receiving lisinopril, despite similar renal sodium and potassium excretion. This finding suggests that extrarenal potassium homeostasis contributes to hyperkalemia in these patients. A better understanding of

  19. Thyroxine-induced cardiac hypertrophy: influence of adrenergic nervous system versus renin-angiotensin system on myocyte remodeling.

    PubMed

    Hu, L W; Benvenuti, L A; Liberti, E A; Carneiro-Ramos, M S; Barreto-Chaves, M L M

    2003-12-01

    The present study assessed the possible involvement of the renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) in thyroxine (T4)-induced cardiac hypertrophy. Hemodynamic parameters, heart weight (HW), ratio of HW to body weight (HW/BW), and myocyte width were evaluated in absence of thyroid hormone (hypothyroidism) and after T4 administration. Male Wistar rats were used. Some were subjected to thyroidectomies, whereas hyperthyroidism was induced in others via daily intraperitoneal injection of T4 (25 or 100 microg x 100 g BW(-1) x day(-1)) for 7 days. In some cases, T4 administration was combined with the angiotensin I-converting enzyme inhibitor enalapril (Ena), with the angiotensin type 1 (AT1) receptor blocker losartan (Los) or with the beta-adrenergic blocker propanolol (Prop). Hemodynamics and morphology were then evaluated. Systolic blood pressure (SBP) was not altered by administration of either T4 alone or T4 in combination with the specific inhibitors. However, SBP decreased significantly in hypothyroid rats. An increased heart rate was seen after administration of either T4 alone or T4 in combination with either Los or Ena. Although the higher dose of T4 significantly increased HW, HW/BW increased in both T4-treated groups. Ena and Prop inhibited the increase in HW or HW/BW in hyperthyroid rats. Morphologically, both T4 dose levels significantly increased myocyte width, an occurrence prevented by RAS or SNS blockers. There was a good correlation between changes in HW/BW and myocyte width. These results indicate that T4-induced cardiac hypertrophy is associated with both the SNS and the RAS.

  20. Quantification of systemic renin-angiotensin system peptides of hypertensive black and white African men established from the RAS-Fingerprint®.

    PubMed

    van Rooyen, J M; Poglitsch, M; Huisman, H W; Mels, Cmc; Kruger, R; Malan, L; Botha, S; Lammertyn, L; Gafane, L; Schutte, A E

    2016-10-01

    The objective of this study was to make use of a quantitative and qualitative approach comparing the systemic renin-angiotensin system (RAS) of hypertensive black and white African men by using RAS equilibrium analysis. This sub-study involved 23 black (n = 15) and white (n = 8) hypertensive men aged 39.5-41 years, living in the North West Province of South Africa. The RAS-Fingerprinting was determined with LC-MS/MS quantification of angiotensin peptides. Blood pressure and other variables were determined with known methods. The main finding of this study was the significant lower Ang I (<5.0 and 45.1 pg/ml; p = 0.005) and Ang II (15.6 and 123.9 pg/ml; p ⩽ 0.001) encountered in the hypertensive black African men compared to their white counterparts. Levels of Ang 1-5 (downstream metabolite of Ang 1-7) (1.8 and 3.0 pg/ml), were detected in black and white hypertensive men, respectively. The observed differences between circulating RAS components, which are reflected via equilibrium angiotensin levels, point to a distinctive molecular regulation of the RAAS in the two study cohorts. The increased peripheral resistance observed in hypertensive black individuals might take over a dominant role in control of blood pressure in this study population. A novel highly sensitive LC-MS/MS method resolved the issue of peptide recovery variations during sample preparation by using internal standards for each individual angiotensin metabolite. © The Author(s) 2016.

  1. Farmácia Popular Program: pharmaceutical market analysis of antihypertensive acting on the renin-angiotensin system medicines.

    PubMed

    Silva, Rondineli Mendes da; Chaves, Gabriela Costa; Chaves, Luisa Arueira; Campos, Mônica Rodrigues; Luiza, Vera Lucia; Bertoldi, Andréa Dâmaso; Ross-Degnan, Dennis; Emmerick, Isabel Cristina Martins

    2017-08-01

    This paper aims to analyse changes in the retail pharmaceutical market following policy changes in the Farmácia Popular Program (FP), a medicines subsidy program in Brazil. The retrospective longitudinal analyses focus on therapeutic class of agents acting on the renin-angiotensin system. Data obtained from QuintilesIMS (formerly IMS Health) included private retail pharmacy sales volume (pharmaceutical units) and sales values from 2002 to 2013. Analyses evaluated changes in market share following key FP policy changes. The therapeutic class was selected due to its relevance to hypertension treatment. Market share was analysed by therapeutic sub-classes and by individual company. Losartan as a single product accounted for the highest market share among angiotensin II antagonists. National companies had higher sales volume during the study period, while multinational companies had higher sales value. Changes in pharmaceutical market share coincided with the inclusion of specific products in the list of medicines covered by FP and with increases in or exemption from patient copayment.

  2. Hypertrophic response to hemodynamic overload: role of load vs. renin-angiotensin system activation

    NASA Technical Reports Server (NTRS)

    Koide, M.; Carabello, B. A.; Conrad, C. C.; Buckley, J. M.; DeFreyte, G.; Barnes, M.; Tomanek, R. J.; Wei, C. C.; Dell'Italia, L. J.; Cooper, G. 4th; hide

    1999-01-01

    Myocardial hypertrophy is one of the basic mechanisms by which the heart compensates for hemodynamic overload. The mechanisms by which hemodynamic overload is transduced by the cardiac muscle cell and translated into cardiac hypertrophy are not completely understood. Candidates include activation of the renin-angiotensin system (RAS) and angiotensin II receptor (AT1) stimulation. In this study, we tested the hypothesis that load, independent of the RAS, is sufficient to stimulate cardiac growth. Four groups of cats were studied: 14 normal controls, 20 pulmonary artery-banded (PAB) cats, 7 PAB cats in whom the AT1 was concomitantly and continuously blocked with losartan, and 8 PAB cats in whom the angiotensin-converting enzyme (ACE) was concomitantly and continuously blocked with captopril. Losartan cats had at least a one-log order increase in the ED50 of the blood pressure response to angiotensin II infusion. Right ventricular (RV) hypertrophy was assessed using the RV mass-to-body weight ratio and ventricular cardiocyte size. RV hemodynamic overload was assessed by measuring RV systolic and diastolic pressures. Neither the extent of RV pressure overload nor RV hypertrophy that resulted from PAB was affected by AT1 blockade with losartan or ACE inhibition with captopril. RV systolic pressure was increased from 21 +/- 3 mmHg in normals to 68 +/- 4 mmHg in PAB, 65 +/- 5 mmHg in PAB plus losartan and 62 +/- 3 mmHg in PAB plus captopril. RV-to-body weight ratio increased from 0.52 +/- 0.04 g/kg in normals to 1.11 +/- 0.06 g/kg in PAB, 1.06 +/- 0.06 g/kg in PAB plus losartan and 1.06 +/- 0.06 g/kg in PAB plus captopril. Thus 1) pharmacological modulation of the RAS with losartan and captopril did not change the extent of the hemodynamic overload or the hypertrophic response induced by PAB; 2) neither RAS activation nor angiotensin II receptor stimulation is an obligatory and necessary component of the signaling pathway that acts as an intermediary coupling load to the

  3. A high sodium intake reduces antiproteinuric response to renin-angiotensin-aldosterone system blockade in kidney transplant recipients.

    PubMed

    Monfá, Elena; Rodrigo, Emilio; Belmar, Lara; Sango, Cristina; Moussa, Fozi; Ruiz San Millán, Juan Carlos; Piñera, Celestino; Fernández-Fresnedo, Gema; Arias, Manuel

    Post-transplant proteinuria is associated with lower graft and patient survival. Renin-angiotensin-aldosterone system blockers are used to reduce proteinuria and improve renal outcome. Although it is known that a high salt intake blunts the antiproteinuric effect of ACEI and ARB drugs in non-transplant patients, this effect has not been studied in kidney transplant recipients. To analyse the relationship between sodium intake and the antiproteinuric effect of ACEI/ARB drugs in kidney transplant recipients. We selected 103 kidney transplant recipients receiving ACEI/ARB drugs for more than 6 months due to proteinuria>1 g/day. Proteinuria was analysed at baseline and at 6 months after starting ACEI/ARB treatment. Salt intake was estimated by urinary sodium to creatinine ratio (uNa/Cr). Proteinuria fell to less than 1g/day in 46 patients (44.7%). High uNa/Cr was associated with a smaller proteinuria decrease (r=-0.251, P=.011). The percentage proteinuria reduction was significantly lower in patients in the highest uNa/Cr tertile [63.9% (IQR 47.1%), 60.1% (IQR 55.4%), 38.9% (IQR 85.5%), P=.047]. High uNa/Cr independently relates (OR 2.406 per 100 mEq/g, 95% CI: 1.008-5.745, P=.048) to an antiproteinuric response <50% after renin-angiotensin-aldosterone system blockade. A high salt intake results in a smaller proteinuria decrease in kidney transplant recipients with proteinuria treated with ACEI/ARB drugs. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

  4. Long-Term Regulation of the Local Renin-Angiotensin System in the Myocardium of Spontaneously Hypertensive Rats by Feeding Bioactive Peptides Derived from Spirulina platensis.

    PubMed

    Pan, Huanglei; She, Xingxing; Wu, Hongli; Ma, Jun; Ren, Difeng; Lu, Jun

    2015-09-09

    This study investigated the long-term (8 weeks) anti-hypertensive effects of 10 mg/kg tripeptides isolated from Spirulina platensis, Ile-Gln-Pro (IQP) and Val-Glu-Pro (VEP), and S. platensis hydrolysates (SH) on spontaneously hypertensive rats. The treatment period was 6 weeks, and observation continued for another 2 weeks. After treatment, weighted systolic blood pressure, weighted diastolic blood pressure, left ventricular mass index, and right ventricular mass index of groups treated with IQP, VEP, and SH were significantly lower than those of the group treated with distilled water, even when the treatments had been withdrawn for 2 weeks. Quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blotting showed the mRNA expression levels and protein/peptide concentrations of the main components of the renin angiotensin system in myocardium were significantly affected by treatment: angiotensin converting enzyme, angiotensin II, and angiotensin type 1 receptor were down-regulated, whereas angiotensin type 2 receptor, angiotensin converting enzyme 2, angiotensin-(1-7), and Mas receptor were up-regulated.

  5. The renin-angiotensin system in thyroid disorders and its role in cardiovascular and renal manifestations.

    PubMed

    Vargas, Félix; Rodríguez-Gómez, Isabel; Vargas-Tendero, Pablo; Jimenez, Eugenio; Montiel, Mercedes

    2012-04-01

    Thyroid disorders are among the most common endocrine diseases and affect virtually all physiological systems, with an especially marked impact on cardiovascular and renal systems. This review summarizes the effects of thyroid hormones on the renin-angiotensin system (RAS) and the participation of the RAS in the cardiovascular and renal manifestations of thyroid disorders. Thyroid hormones are important regulators of cardiac and renal mass, vascular function, renal sodium handling, and consequently blood pressure (BP). The RAS acts globally to control cardiovascular and renal functions, while RAS components act systemically and locally in individual organs. Various authors have implicated the systemic and local RAS in the mediation of functional and structural changes in cardiovascular and renal tissues due to abnormal thyroid hormone levels. This review analyzes the influence of thyroid hormones on RAS components and discusses the role of the RAS in BP, cardiac mass, vascular function, and renal abnormalities in thyroid disorders.

  6. A potential pathophysiological role for galectins and the renin-angiotensin system in preeclampsia.

    PubMed

    Blois, Sandra M; Dechend, Ralf; Barrientos, Gabriela; Staff, Anne Cathrine

    2015-01-01

    This review discusses a potential role of galectins and the renin-angiotensin system (RAS) in the pathophysiology of preeclampsia (PE). Preeclampsia affects between 3 and 5 % of all pregnancies and is a heterogeneous disease, which may be caused by multiple factors. The only cure is the delivery of the placenta, which may result in a premature delivery and baby. Probably due to its heterogeneity, PE studies in human have hitherto only led to the identification of a limited number of factors involved in the pathogenesis of the disease. Animal models, particularly in mice and rats, have been used to gain further insight into the molecular pathology behind PE. In this review, we discuss the picture emerging from human and animal studies pointing to galectins and the RAS being associated with the PE syndrome and affecting a broad range of cellular signaling components. Moreover, we review the epidemiological evidence for PE increasing the risk of future cardiovascular disease later in life.

  7. Therapeutic perspectives in hypertension: novel means for renin-angiotensin-aldosterone system modulation and emerging device-based approaches.

    PubMed

    Unger, Thomas; Paulis, Ludovit; Sica, Domenic A

    2011-11-01

    The conventional antihypertensive therapies including renin-angiotensin-aldosterone system antagonists (converting enzyme inhibitors, receptor blockers, renin inhibitors, and mineralocorticoid receptor blockers), diuretics, β-blockers, and calcium channel blockers are variably successful in achieving the challenging target blood pressure values in hypertensive patients. Difficult to treat hypertension is still a commonly observed problem world-wide. A number of drugs are considered to be used as novel therapies for hypertension. Renalase supplementation, vasopeptidase inhibitors, endothelin antagonists, and especially aldosterone antagonists (aldosterone synthase inhibitors and novel selective mineralocorticoid receptor blockers) are considered an option in resistant hypertension. In addition, the aldosterone antagonists as well as (pro)renin receptor blockers or AT(2) receptor agonists might attenuate end-organ damage. This array of medications has now been complemented by a number of new approaches of non-pharmacological strategies including vaccination, genomic interference, controlled breathing, baroreflex activation, and probably most successfully renal denervation techniques. However, the progress on innovative therapies seems to be slow and the problem of resistant hypertension and proper blood pressure control appears to be still persisting. Therefore the regimens of currently available drugs are being fine-tuned, resulting in the establishment of several novel fixed-dose combinations including triple combinations with the aim to facilitate proper blood pressure control. It remains an exciting question which approach will confer the best blood pressure control and risk reduction in this tricky disease.

  8. Effects of aqueous extract of Hibiscus sabdariffa on the renin-angiotensin-aldosterone system of Nigerians with mild to moderate essential hypertension: A comparative study with lisinopril

    PubMed Central

    Nwachukwu, Daniel Chukwu; Aneke, Eddy Ikemefuna; Obika, Leonard Fidelis; Nwachukwu, Nkiru Zuada

    2015-01-01

    Objectives: The present study investigated the effects of aqueous extract of Hibiscus sabdariffa (HS) on the three basic components of renin-angiotensin-aldosterone system: Plasma renin, serum angiotensin-converting enzyme (ACE), and plasma aldosterone (PA) in mild to moderate essential hypertensive Nigerians and compared with that of lisinopril, an ACE inhibitor. Materials and Methods: A double-blind controlled randomized clinical study was used. Seventy-eight newly diagnosed but untreated mild to moderate hypertensive subjects attending Medical Outpatients Clinic of Enugu State University Teaching Hospital, Enugu were recruited for the study. Those in Group A received placebo (150 mg/kg/day), Group B were given lisinopril (10 mg once daily) while those in Group C received aqueous extract of HS (150 mg/kg/day). After 4 weeks of treatment, the levels of plasma renin, serum ACE, and PA were determined. Results: HS and lisinopril significantly (P < 0.001) reduced PA compared to placebo by 32.06% and 30.01%, respectively. Their effects on serum ACE and plasma renin activity (PRA) were not significant compared to placebo; they reduced ACE by 6.63% and 5.67% but increased plasma PRA by 2.77% and 5.36%, respectively. Conclusion: HS reduced serum ACE and PA in mild to moderate hypertensive Nigerians with equal efficacy as lisinopril. These actions are possibly due to the presence of anthocyanins in the extract. PMID:26600645

  9. Effects of aqueous extract of Hibiscus sabdariffa on the renin-angiotensin-aldosterone system of Nigerians with mild to moderate essential hypertension: A comparative study with lisinopril.

    PubMed

    Nwachukwu, Daniel Chukwu; Aneke, Eddy Ikemefuna; Obika, Leonard Fidelis; Nwachukwu, Nkiru Zuada

    2015-01-01

    The present study investigated the effects of aqueous extract of Hibiscus sabdariffa (HS) on the three basic components of renin-angiotensin-aldosterone system: Plasma renin, serum angiotensin-converting enzyme (ACE), and plasma aldosterone (PA) in mild to moderate essential hypertensive Nigerians and compared with that of lisinopril, an ACE inhibitor. A double-blind controlled randomized clinical study was used. Seventy-eight newly diagnosed but untreated mild to moderate hypertensive subjects attending Medical Outpatients Clinic of Enugu State University Teaching Hospital, Enugu were recruited for the study. Those in Group A received placebo (150 mg/kg/day), Group B were given lisinopril (10 mg once daily) while those in Group C received aqueous extract of HS (150 mg/kg/day). After 4 weeks of treatment, the levels of plasma renin, serum ACE, and PA were determined. HS and lisinopril significantly (P < 0.001) reduced PA compared to placebo by 32.06% and 30.01%, respectively. Their effects on serum ACE and plasma renin activity (PRA) were not significant compared to placebo; they reduced ACE by 6.63% and 5.67% but increased plasma PRA by 2.77% and 5.36%, respectively. HS reduced serum ACE and PA in mild to moderate hypertensive Nigerians with equal efficacy as lisinopril. These actions are possibly due to the presence of anthocyanins in the extract.

  10. A local renal renin-angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats.

    PubMed

    Tojo, Akihiro; Kinugasa, Satoshi; Fujita, Toshiro; Wilcox, Christopher S

    2016-01-01

    The mechanism of activation of local renal renin-angiotensin system (RAS) has not been clarified in diabetes mellitus (DM). We hypothesized that the local renal RAS will be activated via increased glomerular filtration and tubular uptake of prorenin and angiotensinogen in diabetic kidney with microalbuminuria. Streptozotocin (STZ)-induced DM and control rats were injected with human prorenin and subsequently with human angiotensinogen. Human prorenin uptake was increased in podocytes, proximal tubules, macula densa, and cortical collecting ducts of DM rats where prorenin receptor (PRR) was expressed. Co-immunoprecipitation of kidney homogenates in DM rats revealed binding of human prorenin to the PRR and to megalin. The renal uptake of human angiotensinogen was increased in DM rats at the same nephron sites as prorenin. Angiotensin-converting enzyme was increased in podocytes, but decreased in the proximal tubules in DM rats, which may have contributed to unchanged renal levels of angiotensin despite increased angiotensinogen. The systolic blood pressure increased more after the injection of 20 μg of angiotensinogen in DM rats than in controls, accompanied by an increased uptake of human angiotensinogen in the vascular endothelium. In conclusion, endocytic uptake of prorenin and angiotensinogen in the kidney and vasculature in DM rats was contributed to increased tissue RAS and their pressor response to angiotensinogen.

  11. Expression of renin-angiotensin system signalling compounds in maternal protein-restricted rats: effect on renal sodium excretion and blood pressure.

    PubMed

    Mesquita, Flávia Fernandes; Gontijo, José Antonio Rocha; Boer, Patrícia Aline

    2010-02-01

    Intrauterine growth restriction due to low maternal dietary protein during pregnancy is associated with retardation of foetal growth, renal alterations and adult hypertension. The renin-angiotensin system (RAS) is a coordinated hormonal cascade in the control of cardiovascular, renal and adrenal function that governs body fluid and electrolyte balance, as well as arterial pressure. In the kidney, all the components of the renin-angiotensin system including angiotensin II type 1 (AT1) and type 2 (AT2) receptors are expressed locally during nephrogenesis. Hence, we investigated whether low protein diet intake during pregnancy altered kidney and adrenal expression of AT1(R) and AT2(R) receptors, their pathways and if the modified expression of the RAS compounds occurs associated with changes in urinary sodium and in arterial blood pressure in sixteen-week-old males' offspring of the underfed group. The pregnancy dams were divided in two groups: with normal protein diet (pups named NP) (17% protein) or low protein diet (pups LP) (6% protein) during all pregnancy. The present data confirm a significant enhancement in arterial pressure in the LP group. Furthermore, the study showed a significantly decreased expression of RAS pathway protein and Ang II receptors in the kidney and an increased expression in the adrenal of LP rats. The detailed immunohistochemical analysis of RAS signalling proteins in the kidney confirm the immunoblotting results for both groups. The present investigation also showed a pronounced decrease in fractional urinary sodium excretion in maternal protein-restricted offspring, compared with the NP age-matched group. This occurred despite unchanged creatinine clearance. The current data led us to hypothesize that foetal undernutrition could be associated with decreased kidney expression of AT(R) resulting in the inability of renal tubules to handle the hydro-electrolyte balance, consequently causing arterial hypertension.

  12. Activation of renin-angiotensin-aldosterone system (RAAS) in the lung of smoking-induced pulmonary arterial hypertension (PAH) rats.

    PubMed

    Yuan, Yi-Ming; Luo, Li; Guo, Zhen; Yang, Ming; Ye, Ren-Song; Luo, Chuan

    2015-06-01

    To explore the role of the renin-angiotensin-aldosterone system (RAAS) in the pathogenesis of pulmonary arterial hypertension (PAH) induced by chronic exposure to cigarette smoke. 48 healthy male SD rats were randomly divided into four groups (12/group): control group (group A); inhibitor alone group (group B); cigarette induction group (group C); cigarette induction + inhibitor group (group D). After the establishment of smoking-induced PAH rat model, the right ventricular systolic pressure (RVSP) was detected using an inserted catheter; western blotting was used to detect the protein expression of angiotensin-converting enzyme-2 (ACE2) and angiotensin-converting enzyme (ACE); expression levels of angiotensin II (AngII) in lung tissue were measured by radioimmunoassay. After six months of cigarette exposure, the RVSP of chronic cigarette induction group was significantly higher than that of the control group; expression levels of AngII and ACE increased in lung tissues, but ACE2 expression levels reduced. Compared with cigarette exposure group, after losartan treatment, RVSP, ACE and AngII obviously decreased (P<0.05), and ACE2 expression levels significantly increased. Chronic cigarette exposure may result in PAH and affect the protein expression of ACE2 and ACE in lung tissue, suggesting that ACE2 and ACE play an important role in the pathogenesis of smoking-induced PAH. © The Author(s) 2015.

  13. Effect of Sodium-Glucose Co-Transporter 2 Inhibitor, Dapagliflozin, on Renal Renin-Angiotensin System in an Animal Model of Type 2 Diabetes.

    PubMed

    Shin, Seok Joon; Chung, Sungjin; Kim, Soo Jung; Lee, Eun-Mi; Yoo, Young-Hye; Kim, Ji-Won; Ahn, Yu-Bae; Kim, Eun-Sook; Moon, Sung-Dae; Kim, Myung-Jun; Ko, Seung-Hyun

    2016-01-01

    Renal renin-angiotensin system (RAS) activation is one of the important pathogenic mechanisms in the development of diabetic nephropathy in type 2 diabetes. The aim of this study was to investigate the effects of a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, dapagliflozin, on renal RAS in an animal model with type 2 diabetes. Dapagliflozin (1.0 mg/kg, OL-DA) or voglibose (0.6 mg/kg, OL-VO, diabetic control) (n = 10 each) was administered to Otsuka Long-Evans Tokushima Fatty (OLETF) rats for 12 weeks. We used voglibose, an alpha-glucosidase inhibitor, as a comparable counterpart to SGLT2 inhibitor because of its postprandial glucose-lowering effect without proven renoprotective effects. Control Long-Evans Tokushima Otsuka (LT) and OLETF (OL-C) rats received saline (n = 10, each). Changes in blood glucose, urine albumin, creatinine clearance, and oxidative stress were measured. Inflammatory cell infiltration, mesangial widening, and interstitial fibrosis in the kidney were evaluated by histological analysis. The effects of dapagliflozin on renal expression of the RAS components were evaluated by quantitative RT-PCR in renal tissue. After treatment, hyperglycemia and urine microalbumin levels were attenuated in both OL-DA and OL-VO rather than in the OL-C group (P < 0.05). The urine angiotensin II (Ang II) and angiotensinogen levels were significantly decreased following treatment with dapagliflozin or voglibose, but suppression of urine Ang II level was more prominent in the OL-DA than the OL-VO group (P < 0.05). The expressions of angiotensin type 1 receptor and tissue oxidative stress markers were markedly increased in OL-C rats, which were reversed by dapagliflozin or voglibose (P < 0.05, both). Inflammatory cell infiltration, mesangial widening, interstitial fibrosis, and total collagen content were significantly increased in OL-C rats, which were attenuated in OL-DA group (P < 0.05). Dapagliflozin treatment showed beneficial effects on diabetic

  14. Vitamin D receptor deficit induces activation of renin angiotensin system via SIRT1 modulation in podocytes.

    PubMed

    Chandel, Nirupama; Ayasolla, Kamesh; Wen, Hongxiu; Lan, Xiqian; Haque, Shabirul; Saleem, Moin A; Malhotra, Ashwani; Singhal, Pravin C

    2017-02-01

    Vitamin D receptor (VDR) deficient status has been shown to be associated with the activation of renin angiotensin system (RAS). We hypothesized that lack of VDR would enhance p53 expression in podocytes through down regulation of SIRT1; the former would enhance the transcription of angiotensinogen (Agt) and angiotensinogen II type 1 receptor (AT1R) leading to the activation of RAS. Renal tissues of VDR mutant (M) mice displayed increased expression of p53, Agt, renin, and AT1R. In vitro studies, VDR knockout podocytes not only displayed up regulation p53 but also displayed enhanced expression of Agt, renin and AT1R. VDR deficient podocytes also displayed an increase in mRNA expression for p53, Agt, renin, and AT1R. Interestingly, renal tissues of VDR-M as well as VDR heterozygous (h) mice displayed attenuated expression of deacetylase SIRT1. Renal tissues of VDR-M mice showed acetylation of p53 at lysine (K) 382 residues inferring that enhanced p53 expression in renal tissues could be the result of ongoing acetylation, a consequence of SIRT1 deficient state. Notably, podocytes lacking SIRT1 not only showed acetylation of p53 at lysine (K) 382 residues but also displayed enhanced p53 expression. Either silencing of SIRT1/VDR or treatment with high glucose enhanced podocyte PPAR-y expression, whereas, immunoprecipitation (IP) of their lysates with anti-retinoid X receptor (RXR) antibody revealed presence of PPAR-y. It appears that either the deficit of SIRT1 has de-repressed expression of PPAR-y or enhanced podocyte expression of PPAR-y (in the absence of VDR) has contributed to the down regulation of SIRT1. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Changes in the renin angiotensin system during the development of colorectal cancer liver metastases.

    PubMed

    Neo, Jaclyn H; Ager, Eleanor I; Angus, Peter W; Zhu, Jin; Herath, Chandana B; Christophi, Christopher

    2010-04-10

    Blockade of the renin angiotensin system (RAS) via angiotensin I converting enzyme (ACE) inhibition reduces growth of colorectal cancer (CRC) liver metastases in a mouse model. In this work we defined the expression of the various components of the RAS in both tumor and liver during the progression of this disease. Immunohistochemistry and quantitative RT-PCR was used to examine RAS expression in a mouse CRC liver metastases model. CRC metastases and liver tissue was assessed separately at key stages of CRC liver metastases development in untreated (control) mice and in mice treated with the ACE inhibitor captopril (750 mg/kg/day). Non-tumor induced (sham) mice indicated the effect of tumors on normal liver RAS. The statistical significance of multiple comparisons was determined using one-way analysis of variance followed by Bonferroni adjustment with SAS/STAT software. Reduced volume of CRC liver metastases with captopril treatment was evident. Local RAS of CRC metastases differed from the surrounding liver, with lower angiotensin II type 1 receptor (AT1R) expression but increased ANG-(1-7) receptor (MasR) compared to the liver. The AT1R localised to cancer and stromal infiltrating cells, while other RAS receptors were detected in cancer cells only. Tumor induction led to an initial increase in AT1R and ACE expression while captopril treatment significantly increased ACE expression in the final stages of tumor growth. Conversely, captopril treatment decreased expression of AT1R and angiotensinogen. These results demonstrate significant changes in RAS expression in the tumor-bearing captopril treated liver and in CRC metastases. The data suggests the existence of a tumor-specific RAS that can be independently targeted by RAS blockade.

  16. Shifts in renin-angiotensin system components, angiogenesis, and oxidative stress-related protein expression in the lamina cribrosa region of streptozotocin-induced diabetic mice.

    PubMed

    Qian, Xiaobing; Lin, Leilei; Zong, Yao; Yuan, Yongguang; Dong, Yanmin; Fu, Yue; Shao, Wanwen; Li, Yujie; Gao, Qianying

    2018-03-01

    This study aimed to analyse shifts in renin-angiotensin system (RAS) components, angiogenesis, and oxidative stress-related protein expression in the lamina cribrosa (LC) region in streptozotocin (STZ)-induced diabetic mice. Six months after diabetes induction, the retinal vessels of male C57BL/6 J mice were observed by colour photography, fundus fluorescein angiography (FFA), and immunofluorescent staining following incubation with CD31. Immunofluorescence for glial fibrillary acidic protein (GFAP), alpha-smooth muscle actin (α-SMA),and NG2 was also performed. Angiotensin-converting enzyme 1 (ACE1), angiotensin II type I receptor (AT1R), renin, hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR2), and haeme oxygenase 1 (HO-1) expression levels were confirmed by immunohistochemical and western blotting analyses. Compared with control mice, diabetic mice had significantly higher blood glucose concentrations (p < 0.001) and significantly lower body weights (p < 0.001). Colour photography and FFA did not reveal any vessel abnormalities in the diabetic mice; however, immunostaining of whole-mount retinas revealed an increased number of retinal vessels. Furthermore, histopathological staining showed significant reduction in the whole retinal thickness. GFAP expression was slightly higher, whereas fewer NG2 + pericytes were observed in diabetic mice than in control mice. ACE1, AT1R, renin, HIF-1α, VEGF, VEGFR2, and HO-1 expression were up-regulated in the LC of the STZ-induced diabetic mice. Collectively, ACE 1, AT1R, HIF-1α, VEGF, VEGFR2, and HO-1 activation in the LC region in diabetic mice may be involved in diabetes via the RAS and induction of angiogenesis and oxidative stress.

  17. Renin-angiotensin system inhibitors prevent the recurrence of atrial fibrillation: a meta-analysis of randomized controlled trials.

    PubMed

    Han, Min; Zhang, Yong; Sun, Shujuan; Wang, Zhongsu; Wang, Jiangrong; Xie, Xinxing; Gao, Mei; Yin, Xiangcui; Hou, Yinglong

    2013-10-01

    This study was designed to assess whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) could prevent the recurrence of atrial fibrillation (AF). A systemic literature search of PubMed, EMBASE, and Cochrane Controlled Trials Register till 2012 was performed to identify randomized controlled trials involving the prevention of recurrence of AF with renin-angiotensin system blockade therapy. Subgroup analysis and meta-regression were performed. Publication bias was checked through funnel plot and Egger's test. Twenty-one randomized controlled trials including 13,184 patients with AF were identified. Overall, the recurrence of AF was significantly reduced in patients using ACEI/ARBs [odds ratio (OR), 0.43; 95% confidence interval (CI), 0.32-0.56; P < 0.00001], especially both in irbesartan subgroup (OR, 0.38; 95% CI, 0.21-0.68; P = 0.001) and in patients receiving antiarrhythmic drug (AAD) (OR, 0.37; 95% CI, 0.29-0.48; P < 0.00001), and there was no significant difference between ACEIs and ARBs (ACEIs: OR, 0.42; 95% CI, 0.31-0.57 and ARBs: OR, 0.42; 95% CI, 0.31-0.57). Moreover, it was found that the benefits of ACEI/ARBs revealed positive correlation to systolic blood pressure (regression coefficient: -0.0700257, P = 0.000) in no-AAD users. ACEI/ARBs are effective on the secondary prevention of AF, especially in patients receiving AAD and suffering from hypertension.

  18. Relationship between drugs affecting the renin-angiotensin system and colorectal cancer: The MCC-Spain study.

    PubMed

    Dierssen-Sotos, Trinidad; Gómez-Acebo, Inés; Palazuelos, Camilo; Rodriguez-Moranta, Francisco; Pérez-Gómez, Beatriz; Fernández Vazquez, José Pedro; Amiano, Pilar; Barricarte, Aurelio; Mirón-Pozo, Benito; Tardon, Adonina; Capelo, Rocío; Peiro Pérez, Rosana; Huerta, José María; Andreu, Montserrat; Sierra, Mª Ángeles; Castañón López, Carmen; Ruiz, Irune; Moreno-Iribas, Concepción; Olmedo-Requena, Rocío; Castaño-Vinyals, Gemma; Aragonés, Nuria; Kogevinas, Manolis; Pollán, Marina; Llorca, Javier

    2017-06-01

    The potential protective effect of renin-angiotensin system (RAS) inhibitors is a subject of increasing interest due to their possible role as chemopreventive agents against colorectal cancer (CRC). To evaluate this association, we conducted a case-control study with 2165 cases of colorectal cancer, diagnosed between 2007 and 2012, and 3912 population controls frequency matched (by age, sex and region) from the Spanish multicenter case-control study MCC-Spain. We found a significant protective effect of the angiotensin-converting enzyme Inhibitors (ACEIs) against CRC, limited to the under-65years group (OR=0.65 95%CI (0.48-0.89)) and to a lesser degree to men (OR=0.81 95%CI (0.66-0.99). In contrast, the angiotensin receptor blockers (ARBs) did not show a significant effect. Regarding the duration of use, a greater protection was observed in men as the length of consumption increases. In contrast, in the under-65 stratum, the strongest association was found in short-term treatments. Finally, by analyzing ACEIs effect by colon subsite, we found no differences, except for under 65years old, where the maximum protection was seen in the proximal intestine, descending in the distal and rectum (without statistical significance). In conclusion, our study shows a protective effect on CRC of the ACEis limited to males and people under 65years old, which increases in proximal colon in the latter. If confirmed, these results may suggest a novel approach to proximal CRC prevention, given the shortcomings of colonoscopy screening in this location. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Acute lead exposure increases arterial pressure: role of the renin-angiotensin system.

    PubMed

    Simões, Maylla Ronacher; Ribeiro Júnior, Rogério F; Vescovi, Marcos Vinícius A; de Jesus, Honério C; Padilha, Alessandra S; Stefanon, Ivanita; Vassallo, Dalton V; Salaices, Mercedes; Fioresi, Mirian

    2011-04-11

    Chronic lead exposure causes hypertension and cardiovascular disease. Our purpose was to evaluate the effects of acute exposure to lead on arterial pressure and elucidate the early mechanisms involved in the development of lead-induced hypertension. Wistar rats were treated with lead acetate (i.v. bolus dose of 320 µg/Kg), and systolic arterial pressure, diastolic arterial pressure and heart rate were measured during 120 min. An increase in arterial pressure was found, and potential roles of the renin-angiotensin system, Na(+),K(+)-ATPase and the autonomic reflexes in this change in the increase of arterial pressure found were evaluated. In anesthetized rats, lead exposure: 1) produced blood lead levels of 37±1.7 µg/dL, which is below the reference blood concentration (60 µg/dL); 2) increased systolic arterial pressure (Ct: 109±3 mmHg vs Pb: 120±4 mmHg); 3) increased ACE activity (27% compared to Ct) and Na(+),K(+)-ATPase activity (125% compared to Ct); and 4) did not change the protein expression of the α1-subunit of Na(+),K(+)-ATPase, AT(1) and AT(2). Pre-treatment with an AT(1) receptor blocker (losartan, 10 mg/Kg) or an ACE inhibitor (enalapril, 5 mg/Kg) blocked the lead-induced increase of arterial pressure. However, a ganglionic blockade (hexamethonium, 20 mg/Kg) did not prevent lead's hypertensive effect. Acute exposure to lead below the reference blood concentration increases systolic arterial pressure by increasing angiotensin II levels due to ACE activation. These findings offer further evidence that acute exposure to lead can trigger early mechanisms of hypertension development and might be an environmental risk factor for cardiovascular disease.

  20. Angioedema Triggered by Medication Blocking the Renin/Angiotensin System: Retrospective Study Using the French National Pharmacovigilance Database.

    PubMed

    Faisant, Charles; Armengol, Guillaume; Bouillet, Laurence; Boccon-Gibod, Isabelle; Villier, Céline; Lévesque, Hervé; Cottin, Judith; Massy, Nathalie; Benhamou, Ygal

    2016-01-01

    Bradykinin-mediated angioedema (AE) is a rare side effect of some medications, including angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB). In France, side-effects to treatments are reported to the national pharmacovigilance database. The national MedDRA database was searched using the term "angioedema". Patients were included if they met the clinical criteria corresponding to bradykinin-mediated AE, if their C1-inhibitor levels were normal, and if they were treated with an ACEi or an ARB. 7998 cases of AE were reported between 1994 and 2013. Among these, 112 met the criteria for bradykinin-mediated AE with normal C1-inhibitor levels. On the 112 drug-AE, patients were treated with an ARB in 21% of cases (24 patients), or an ACEi in 77% of cases (88 patients), in combination with another treatment in 17 cases (mTORi for 3 patients, iDPP-4 for 1 patient, hormonal treatment for 7 patients). ENT involvement was reported in 90% of cases (tongue: 48.2%, larynx: 23.2%). The median duration of treatment before the first attack was 720 days, and the mean duration of attacks was 36.6 h. Forty-one percent (19/46) of patients relapsed after discontinuing treatment. Angioedema triggered by medication blocking the renin/angiotensin system is rare but potentially severe, with a high risk of recurrence despite cessation of the causative drug.

  1. Decongestion Strategies and Renin-Angiotensin-Aldosterone System Activation in Acute Heart Failure

    PubMed Central

    Mentz, Robert J.; Stevens, Susanna R.; DeVore, Adam D.; Lala, Anuradha; Vader, Justin M.; AbouEzzeddine, Omar F.; Khazanie, Prateeti; Redfield, Margaret M.; Stevenson, Lynne W.; O'Connor, Christopher M.; Goldsmith, Steven R.; Bart, Bradley A.; Anstrom, Kevin J.; Hernandez, Adrian F.; Braunwald, Eugene; Felker, G. Michael

    2014-01-01

    Background High dose diuretics in patients with acute heart failure (AHF) are thought to activate the renin-angiotensin-aldosterone system (RAAS), and alternative decongestion strategies, such as ultrafiltration (UF), have been proposed to mitigate this RAAS activation. Methods We analyzed 427 AHF patients enrolled in the DOSE-AHF and CARRESS-HF trials. We assessed the relationship between two markers of RAAS activation (plasma renin activity [PRA] and aldosterone) from baseline to 72-96h and decongestion strategy; high vs. low-dose and continuous infusion vs. bolus furosemide for DOSE-AHF and UF vs. stepped pharmacologic care for CARRESS-HF. We determined the relationship between RAAS biomarkers and 60-day outcomes. Results Patients with greater RAAS activation at baseline had lower blood pressures, lower serum sodium, and higher BUN. Continuous infusion furosemide and UF were associated with greater PRA increases (median +1.66 vs. +0.66 ng/mL/h with continuous vs. bolus, P=0.021; +4.05 vs. +0.56 ng/mL/h with UF vs. stepped care, P=0.014). There was no significant difference in RAAS biomarker change with high vs. low-dose diuretics (both P>0.5). Neither baseline log PRA nor log aldosterone was associated with increased death/HF hospitalization (HR for a doubling 1.05; 95% CI: 0.98-1.13, P=0.18 and HR 1.13; 95% CI: 0.99-1.28, P=0.069, respectively). The change in RAAS biomarkers from baseline to 72-96 h was not associated with outcomes (both P>0.5). Conclusions High-dose loop diuretics did not result in greater RAAS activation than low-dose diuretics. UF resulted in greater PRA increase than stepped pharmacologic care. Neither PRA nor aldosterone was significantly associated with short-term outcomes in this cohort. PMID:25543972

  2. Molecular characterization and transcriptional regulation of the renin-angiotensin system genes in Senegalese sole (Solea senegalensis Kaup, 1858): differential gene regulation by salinity.

    PubMed

    Armesto, Paula; Cousin, Xavier; Salas-Leiton, Emilio; Asensio, Esther; Manchado, Manuel; Infante, Carlos

    2015-06-01

    In this work, the complete cDNA sequence encoding angiotensinogen (agt) in the euryhaline flatfish Senegalese sole was obtained. Additionally, putative coding sequences belonging to other renin-angiotensin system (RAS) genes including renin (ren), angiotensin-converting enzyme (ace), angiotensin-converting enzyme 2 (ace2), as well as angiotensin II receptor type I (agtr1) and type II (agtr2), were also identified. In juvenile tissues, agt transcripts were mainly detected in liver, ren in kidney, ace and ace2 in intestine, agtr1 in kidney and brain, and agtr2 in liver and kidney. Expression analysis of the six RAS genes after a salinity shift revealed a clear increase of agt mRNA abundance in liver just after transferring soles to high salinity water (60 ppt) with a peak at 48 h. Moreover, gene expression analysis in gills showed transcriptional regulation of ace and agtr1 at 48 h and agtr2 at 96 h after transferring soles to 60 ppt. Incubation of larvae before mouth opening (until 3 days post hatch; dph) at low salinity (10 ppt) resulted in a coordinated transcriptional up-regulation of RAS genes. Nevertheless, no differences in mRNA abundance between salinities were observed when larvae were cultivated to low salinity after mouth opening. Whole-mount in situ hybridization (WISH) signal for agt and ace in 3 dph larvae incubated at 10 ppt and 35 ppt confirmed that the former gene was mainly expressed in liver whereas the later gene was mainly located in pharynx and posterior gut, without pronounced differences in intensity between salinities. Possible physiological significance of all these results is discussed. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Emerging Therapies for Diabetic Nephropathy Patients: Beyond Blockade of the Renin-Angiotensin System

    PubMed Central

    Tanios, Bassem Y.; Ziyadeh, Fuad N.

    2012-01-01

    Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. The mainstay of treatment has been glycemic control and blood pressure lowering using agents blocking the renin-angiotensin system. Clinical trials are currently under way using novel agents for the treatment of patients with diabetic nephropathy. Promising agents emerging from some of the completed trials include pirfenidone and bardoxolone methyl, which have been shown in two recent randomized controlled trials in patients with diabetic nephropathy to result in an improved estimated glomerular filtration rate compared to placebo. Also, paricalcitol has been shown to decrease the urinary albumin-to-creatinine ratio, whereas sulodexide failed to do so in a large randomized double-blind placebo-controlled trial. Of note, pyridoxamine has also shown promise in the treatment of diabetic nephropathy if started early in the disease course. These preliminary trials have shown significant promise for managing patients with diabetic nephropathy, sparking active research in this field and providing the rationale for further clinical testing in long-term, hard-outcomes trials. PMID:23599705

  4. Changes in the renin angiotensin system during the development of colorectal cancer liver metastases

    PubMed Central

    2010-01-01

    Background Blockade of the renin angiotensin system (RAS) via angiotensin I converting enzyme (ACE) inhibition reduces growth of colorectal cancer (CRC) liver metastases in a mouse model. In this work we defined the expression of the various components of the RAS in both tumor and liver during the progression of this disease. Methods Immunohistochemistry and quantitative RT-PCR was used to examine RAS expression in a mouse CRC liver metastases model. CRC metastases and liver tissue was assessed separately at key stages of CRC liver metastases development in untreated (control) mice and in mice treated with the ACE inhibitor captopril (750 mg/kg/day). Non-tumor induced (sham) mice indicated the effect of tumors on normal liver RAS. The statistical significance of multiple comparisons was determined using one-way analysis of variance followed by Bonferroni adjustment with SAS/STAT software. Results Reduced volume of CRC liver metastases with captopril treatment was evident. Local RAS of CRC metastases differed from the surrounding liver, with lower angiotensin II type 1 receptor (AT1R) expression but increased ANG-(1-7) receptor (MasR) compared to the liver. The AT1R localised to cancer and stromal infiltrating cells, while other RAS receptors were detected in cancer cells only. Tumor induction led to an initial increase in AT1R and ACE expression while captopril treatment significantly increased ACE expression in the final stages of tumor growth. Conversely, captopril treatment decreased expression of AT1R and angiotensinogen. Conclusions These results demonstrate significant changes in RAS expression in the tumor-bearing captopril treated liver and in CRC metastases. The data suggests the existence of a tumor-specific RAS that can be independently targeted by RAS blockade. PMID:20380732

  5. New agents modulating the renin-angiotensin-aldosterone system—Will there be a new therapeutic option?

    PubMed Central

    Szoka, Piotr; Kolodziejczyk, Patrycjusz; Kramkowski, Karol; Wojewodzka-Zelezniakowicz, Marzena; Chabielska, Ewa

    2016-01-01

    The renin-angiotensin-aldosterone system (RAAS) is more complex than it was originally regarded. According to the current subject knowledge, there are two main axes of the RAAS: (1) angiotensin-converting enzyme (ACE)-angiotensin II-AT1 receptor axis and (2) ACE2-angiotensin-(1-7)-Mas receptor axis. The activation of the first axis leads to deleterious effects, including vasoconstriction, endothelial dysfunction, thrombosis, inflammation, and fibrosis; therefore, blocking the components of this axis is a highly rational and commonly used therapeutic procedure. The ACE2-Ang-(1-7)-Mas receptor axis has a different role, since it often opposes the effects induced by the classical ACE-Ang II-AT1 axis. Once the positive effects of the ACE2-Ang-(1-7)-Mas axis were discovered, the alternative ways of pharmacotherapy activating this axis of RAAS appeared. This article briefly describes new molecules affecting the RAAS, namely: recombinant human ACE2, ACE2 activators, angiotensin-(1-7) peptide and non-peptide analogs, aldosterone synthase inhibitors, and the third and fourth generation of mineralocorticoid receptor antagonists. The results of the experimental and clinical studies are encouraging, which leads us to believe that these new molecules can support the treatment of cardiovascular diseases as well as cardiometabolic disorders. PMID:27439538

  6. Circadian rhythm of blood pressure and the renin-angiotensin system in the kidney.

    PubMed

    Ohashi, Naro; Isobe, Shinsuke; Ishigaki, Sayaka; Yasuda, Hideo

    2017-05-01

    Activation of the intrarenal renin-angiotensin system (RAS) has a critical role in the pathophysiology of the circadian rhythm of blood pressure (BP) and renal injury, independent of circulating RAS. Although it is clear that the circulating RAS has a circadian rhythm, reports of a circadian rhythm in tissue-specific RAS are limited. Clinical studies evaluating intrarenal RAS activity by urinary angiotensinogen (AGT) levels have indicated that urinary AGT levels were equally low during both the daytime and nighttime in individuals without chronic kidney disease (CKD) and that urinary AGT levels were higher during the daytime than at nighttime in patients with CKD. Moreover, urinary AGT levels of the night-to-day (N/D) ratio of urinary AGT were positively correlated with the levels of N/D of urinary protein, albumin excretion and BP. In addition, animal studies have demonstrated that the expression of intrarenal RAS components, such as AGT, angiotensin II (AngII) and AngII type 1 receptor proteins, increased and peaked at the same time as BP and urinary protein excretion during the resting phase, and the amplitude of the oscillations of these proteins was augmented in a chronic progressive nephritis animal compared with a control. Thus, the circadian rhythm of intrarenal RAS activation may lead to renal damage and hypertension, which both are associated with diurnal variations in BP. It is possible that augmented glomerular permeability increases AGT excretion levels into the tubular lumen and that circadian fluctuation of glomerular permeability influences the circadian rhythm of the intrarenal RAS.

  7. Maternal hyperthyroidism alters the pattern of expression of cardiac renin-angiotensin system components in rat offspring.

    PubMed

    Lino, Caroline A; Shibata, Caroline E R; Barreto-Chaves, Maria Luiza M

    2014-03-01

    Changes in perinatal environment can lead to physiological, morphological, or metabolic alterations in adult life. It is well known that thyroid hormones (TH) are critical for the development, growth, and maturation of organs and systems. In addition, TH interact with the renin-angiotensin system (RAS), and both play a critical role in adult cardiovascular function. The objective of this study was to evaluate the effect of maternal hyperthyroidism on cardiac RAS components in pups during development. From gestational day nine (GD9), pregnant Wistar rats received thyroxine (T4, 12 mg/l in tap water; Hyper group) or vehicle (control group). Dams and pups were killed on GD18 and GD20. Serum concentrations of triiodothyronine (T3) and T4 were higher in the Hyper group than in the control group dams. Cardiac hypertrophy was observed in Hyper pups on GD20. Cardiac angiotensin-converting enzyme (ACE) activity was significantly lower in Hyper pups on both GD18 and GD20, but there was no difference in Ang I/Ang II levels. Ang II receptors expression was higher in the Hyper pup heart on GD18. Maternal hyperthyroidism is associated with alterations in fetal development and altered pattern of expression in RAS components, which in addition to cardiac hypertrophy observed on GD20 may represent an important predisposing factor to cardiovascular diseases in adult life.

  8. The blockade of renin-angiotensin-aldosterone system in hemodialysis patients to control hypertension and prevent cardiovascular disease: optimal pharmacotherapy.

    PubMed

    Morishita, Yoshiyuki; Kusano, Eiji

    2011-10-01

    Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in hemodialysis (HD) patients. Hypertension (HT) is a major risk factor for CVD. The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of HT in HD patients. Previous studies suggested that the blockade of RAAS may be effective to control blood pressure (BP) and to prevent CVD in HD patients. A certain level of preventive effects against CVD by RAAS blockade in HD patients has been reported independently from a BP lowering effect. This review focuses on the effect of blocking RAAS in HD patients for the control of HT and the prevention of CVD.

  9. Chronic Renin-Angiotensin System (RAS) Blockade May Not Induce Hypotension During Anaesthesia for Bariatric Surgery.

    PubMed

    Salvetti, Guido; Di Salvo, Claudio; Ceccarini, Giovanni; Abramo, Antonio; Fierabracci, Paola; Magno, Silvia; Piaggi, Paolo; Vitti, Paolo; Santini, Ferruccio

    2016-06-01

    The use of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) for the treatment of hypertensive obese patients is steadily increasing. Some studies have reported that the use of these drugs was associated with an increased risk of hypotensive episodes, during general anaesthesia. The number of bariatric procedures is also increasing worldwide, but there is a lack of studies investigating the hypotensive effect of renin-angiotensin system (RAS) blockers in severely obese patients during general anaesthesia for bariatric surgery. The aim of this pilot study was to evaluate hemodynamic changes induced by general anaesthesia in obese patients chronically treated with ACE-I or ARB compared to a control group not treated with antihypertensive therapy. Fourteen obese subjects (mean body mass index (BMI) 47.5 kg/m(2)) treated with ACE-I or ARB and twelve obese (mean BMI 45.7 kg/m2) controls not treated with antihypertensive therapy underwent general anaesthesia to perform laparoscopic bariatric surgery. Systolic blood pressure, diastolic blood pressure, and heart rate were monitored continuously and registered at different time points: T0 before induction, then at 2, 5, 7, 10, 15, 20, 30, 60, 90, 120, and 150 min after induction, and the last time point taken following recovery from anaesthesia. A progressive reduction of both systolic and diastolic blood pressure values was observed without significant differences between the two groups. A similar trend of heart rate values was observed. In conclusion, our pilot study suggests that RAS blockers may be continued during the perioperative period in patients undergoing bariatric surgery, without increasing the risk of hypotensive episodes.

  10. Involvement of skeletal renin-angiotensin system and kallikrein-kinin system in bone deteriorations of type 1 diabetic mice with estrogen deficiency.

    PubMed

    Zhang, Yan; Wang, Liang; Liu, Jin-Xin; Wang, Xin-Luan; Shi, Qi; Wang, Yong-Jun

    This study was aimed to investigate the involvement of skeletal renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) in bone deteriorations of mice in response to the combination treatment of estrogen deficiency and hyperglycemia. The female C57BL/6J mice were sham-operated or ovariectomized with vehicle or streptozotocin (STZ) treatment. Two weeks later, the biochemistries in serum and urine were determined by standard colorimetric methods or ELISA. The H&E and TRAP staining were performed at the tibial proximal metaphysis. The polymerase chain reaction and immunoblotting were applied for molecular analysis on mRNA and protein expression. The mice after treating with ovariectomy and STZ showed the decreased level of serum Ca and the increased level of serum PTH and urine Ca. The H&E staining showed trabecular bone abnormalities as demonstrated by the loss, disconnection and separation of trabecular bone network as well as the loss of chondrocytes and appearance of chondrocyte cluster at growth plate of tibia. The significant increase of matured osteoclast number was shown in group with double treatments. The combination treatment significantly up-regulated mRNA expression of AGT, ACE, renin receptor, MMP-9 and CAII, and protein expression of renin, and decreased the ratio of OPG/RANKL and the expression of bradykinin receptors in bone tissue. Ovariectomy combined with STZ induction produced more detrimental actions on bone through the activation of local bone RAS and the down-regulation of bradykinin receptors, as compared to the respective single treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Soya protein attenuates abnormalities of the renin-angiotensin system in adipose tissue from obese rats.

    PubMed

    Frigolet, María E; Torres, Nimbe; Tovar, Armando R

    2012-01-01

    Several metabolic disturbances during obesity are associated with adipose tissue-altered functions. Adipocytes contain the renin-angiotensin system (RAS), which regulates signalling pathways that control angiogenesis via Akt in an autocrine fashion. Soya protein (Soy) consumption modifies the gene expression pattern in adipose tissue, resulting in an improved adipocyte function. Therefore, the aim of the present work is to study whether dietary Soy regulates the expression of RAS and angiogenesis-related genes and its association with the phosphorylated state of Akt in the adipose tissue of obese rats. Animals were fed a 30 % Soy or casein (Cas) diet containing 5 or 25 % fat for 160 d. mRNA abundance was studied in the adipose tissue, and Akt phosphorylation and hormone release were measured in the primary adipocyte culture. The present results show that Soy treatment in comparison with Cas consumption induces lower angiotensin release and increased insulin-stimulated Akt activation in adipocytes. Furthermore, Soy consumption varies the expression of RAS and angiogenesis-related genes, which maintain cell size and vascularity in the adipose tissue of rats fed a high-fat diet. Thus, adipocyte hypertrophy and impaired angiogenesis, which are frequently observed in dysfunctional adipose tissue, were avoided by consuming dietary Soy. Taken together, these findings suggest that Soy can be used as a dietary strategy to preserve adipocyte functionality and to prevent obesity abnormalities.

  12. Response of the kallikrein-kinin and renin-angiotensin systems to saline infusion and upright posture.

    PubMed Central

    Wong, P Y; Talamo, R C; Williams, G H; Colman, R W

    1975-01-01

    The possibility that bradykinin, a potent vasodilator, might be a physiological antagonist of the renin-angiotensin system was investigated. 11 norman subjects, ranging in age from 21 to 33 yr were studied. Seven of the subjects were given a 10 meq sodium, 100 meq potassium, 2500 ml isocaloric diet. After metabolic balance was achieved, they were infused with either 1 liter of 5 per cent glucose over 2 h or 2 liters of 0.9 per cent saline over 4 h. During the infusions, plasma renin activity (PRA), angiotensin II (A II), prekallikrein, bradykinin, and aldosterone levels were frequently determined. Plasma prekallikrein and kallikrein inhibitor did not change during the infusion of either glucose or saline. In subjects receiving saline, plasma bradykinin fell from 3.9 plus or minus 1.5 (SEM) ng/ml at 0 min to 0.93 plus or minus 0.2 at 30 min and 0.95 plus or minus 0.3 at 120 min. These changes paralleled the decrease in PRA over the same period (7.9 plus or minus 1.3 ng/ml/h to 5.6 plus or minus 0.8 at 30 min and 3.5 plus or minus 0.7 at 120 min). Similarly, A II fell from 113 plus or minus 12 pg/ml to 62 plus or minus 10 and 48 plus or minus 5, respectively, at 30 and 120 min. In contrast, the control group infused with glucose showed no change in bradykinin, A II, or PRA. Another four subjects were given a constant 200 meq sodium/100 meq potassium isocaloric diet. After metabolic balance was achieved, they were kept supine and fasting overnight. At 9 a.m. they assumed an upright position and began walking a fixed distance (200 ft) at a normal rate (3-4 ft/s). Plasma prekallikrein and kallikrein inhibitor did not change during the posture study. The plasma bradykinin rose from a base line of 0.54 plus or minus 0.01 (SEM) ng/ml to 0.96 plus or minus 0.13 at 20 min. 0.77 plus or minus 0.18 at 60 min, and 0.96 plus or minus 0.07 at 120 min. These changes parallel the increase in PRA over the same period (1.65 plus or minus 3.3 ng/ml/h to 3.6 plus or minus 0.85 at 20

  13. Maternal corticosterone exposure in the mouse programs sex-specific renal adaptations in the renin-angiotensin-aldosterone system in 6-month offspring.

    PubMed

    Cuffe, James S M; Burgess, Danielle J; O'Sullivan, Lee; Singh, Reetu R; Moritz, Karen M

    2016-04-01

    Short-term maternal corticosterone (Cort) administration at mid-gestation in the mouse reduces nephron number in both sexes while programming renal and cardiovascular dysfunction in 12-month male but not female offspring. The renal renin-angiotensin-aldosterone system (RAAS), functions in a sexually dimorphic manner to regulate both renal and cardiovascular physiology. This study aimed to identify if there are sex-specific differences in basal levels of the intrarenal RAAS and to determine the impact of maternal Cort exposure on the RAAS in male and female offspring at 6 months of age. While intrarenal renin concentrations were higher in untreated females compared to untreated males, renal angiotensin II concentrations were higher in males than females. Furthermore, basal plasma aldosterone concentrations were greater in females than males. Cort exposed male but not female offspring had reduced water intake and urine excretion. Cort exposure increased renal renin concentrations and elevated mRNA expression of Ren1, Ace2, and Mas1 in male but not female offspring. In addition, male Cort exposed offspring had increased expression of the aldosterone receptor, Nr3c2 and renal sodium transporters. In contrast, Cort exposure increased Agtr1a mRNA levels in female offspring only. This study demonstrates that maternal Cort exposure alters key regulators of renal function in a sex-specific manner at 6 months of life. These finding likely contribute to the disease outcomes in male but not female offspring in later life and highlights the importance of renal factors other than nephron number in the programming of renal and cardiovascular disease. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  14. Pharmacodynamic effects of C-domain-specific ACE inhibitors on the renin-angiotensin system in myocardial infarcted rats.

    PubMed

    Sharp, Sarah; Poglitsch, Marko; Zilla, Peter; Davies, Neil H; Sturrock, Edward D

    2015-12-01

    The renin-angiotensin system (RAS) is a dynamic network that plays a critical role in blood pressure regulation and fluid and electrolyte homeostasis. Modulators of the RAS, such as angiotensin-converting enzyme (ACE) inhibitors, are widely used to treat hypertension, heart failure and myocardial infarction. The effect of ACE inhibitors (lisinopril and C-domain-selective LisW-S) on the constituent peptides of the RAS following myocardial infarction was examined in rats. Ten angiotensin peptides were analysed using a sensitive LC-MS/MS-based assay to examine both the circulating and equilibrium levels of these peptides. Administration of lisinopril or LisW-S caused a significant decrease in Ang 1-8/Ang 1-10 ratios as determined by circulating and equilibrium peptide level analysis. Furthermore, Ang 1-7 levels were elevated by both ACE inhibitors, but only lisinopril decreased the Ang 1-5/Ang 1-7 ratio. This indicates LisW-S C-domain specificity as Ang 1-5 is generated by hydrolysis of Ang 1-7 by the N-domain. Further corroboration of LisW-S C-domain specificity is that only lisinopril increased the circulating levels of the N-domain ACE substrate Ac-SDKP. LisW-S is able to effectively block ACE in vivo by C-domain-selective inhibition. The LC-MS/MS-based assay allows the evaluation of the pharmacologic impact of RAS inhibitors in different pathophysiological conditions. © The Author(s) 2015.

  15. Clinical pharmacokinetics and efficacy of renin inhibitors.

    PubMed

    Rongen, G A; Lenders, J W; Smits, P; Thien, T

    1995-07-01

    The successful introduction of angiotensin converting enzyme (ACE) inhibitors in the treatment of patients with essential hypertension or heart failure has increased interest in the (patho)physiological role of the renin-angiotensin system (RAS). ACE is not only involved in the formation of angiotensin II from angiotensin I, but also inactivates vasoactive substances such as bradykinin and substance P. Accumulation of these substances during treatment with ACE inhibitors may contribute to both their therapeutic action and certain adverse effects associated with their use, such as cough and angioneurotic oedema. Renin inhibitors offer an alternative approach to inhibit the RAS. The major advantage of these, still experimental, drugs is their high specificity for the RAS since angiotensinogen is the only known substrate of renin. The currently available renin inhibitors are pseudopeptides that are rapidly taken up by the liver and excreted in the bile. Consequently, these drugs are subjected to a considerable first pass effect which limits their oral bioavailability. Additionally, plasma elimination half-life times are short and the duration of action is limited. Despite these shortcomings, single oral or intravenous administration results in a 80 to 90% inhibition of plasma renin activity and a slight reduction in blood pressure in patients with hypertension. The extent of blood pressure reduction is dependent on the patient's salt balance. After 1 week of oral treatment with the renin inhibitor remikiren, the antihypertensive effect was reduced in salt-repleted hypertensive patients. Subsequent intravenous administration of the drug did not further affect blood pressure, indicating that it was not the first pass effect that was limiting the efficacy of remikiren.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Statins, the renin-angiotensin-aldosterone system and hypertension - a tale of another beneficial effect of statins.

    PubMed

    Drapala, Adrian; Sikora, Mariusz; Ufnal, Marcin

    2014-09-01

    Statins, a class of lipid lowering drugs, decrease mortality associated with cardiovascular events. As hypercholesterolemia is often accompanied by hypertension, a large number of patients receive therapy with statins and antihypertensive drugs which act via the renin-angiotensin-aldosterone system (RAAS). New guidelines published by the American Heart Association and American College of Cardiology on the treatment of dyslipidaemia and the reduction of atherosclerotic cardiovascular risk, which use a risk prediction algorithm based on risk factors such as hypertension but not low-density lipoprotein (LDL) level, may even further increase the number of patients receiving such concomitant therapy. In this paper we review studies on an interaction between statins, the RAAS and antihypertensive drugs acting via the RAAS. Accumulating evidence suggests that the combination of statins and drugs affecting the RAAS exerts a synergistic effect on the circulatory system. For example, statins may lower arterial blood pressure and augment the effect of antihypertensive drugs acting via the RAAS. Statins may interact with the RAAS in a number of ways i.e. to decrease the expression of receptors for angiotensin II (Ang II), inhibit the Ang II-dependent intracellular signalling, reduce the RAAS-dependent oxidative stress and inflammation as well as inhibit the synthesis of Ang II and aldosterone. Although statins given either alone or together with antihypertensive drugs acting via the RAAS may lower arterial blood pressure, further research is needed to evaluate the mechanisms and their therapeutic significance. © The Author(s) 2014.

  17. Renin angiotensin system blockage associates with insertion/deletion polymorphism of angiotensin-converting enzyme in patients with hypertensive emergency.

    PubMed

    Vilela-Martin, José F; Vaz-de-Melo, Renan O; Cosenso-Martin, Luciana N; Kuniyoshi, Cristina H; Yugar-Toledo, Juan C; Pinhel, Marcela A S; de Souza, Gisele F; Souza, Dorotéia R S; Pimenta, Eduardo; Moreno, Heitor; Cipullo, José P

    2013-09-01

    Hypertensive crisis (HC) stands out as a form of acute elevation of blood pressure (BP). It can manifest itself as hypertensive emergency (HE) or hypertensive urgency (HU), which is usually accompanied with levels of diastolic BP ≥120 mmHg. Angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism may influence manifestations of HC. Thus, this study evaluated the influence of ACE I/D polymorphism in individuals with HC. A total of 187 patients admitted with HC (HU [n=69] and HE [n=118]) and 75 normotensive individuals were included in the study. Peripheral blood was drawn for a biochemical and genetic analysis of the ACE I/D polymorphism by Polymerase Chain Reaction. HC group showed higher systolic BP, body mass index (BMI), glycemia, creatinine, and lower high-density lipoprotein (HDL) cholesterol compared with normotensive individuals. The use of renin-angiotensin system (RAS) blockers was more frequent in the HU group than in the HE group (p=0.020). The II genotype was more predominant in normotensive and HU individuals than among HE individuals (18.7%, 11.6%, and 2.5%, respectively; p=0.004). Higher BMI and glycemia were associated with HC in the logistic regression model. ACE II genotype (odds ratio [OR] 0.14; 95% confidence interval [CI] 0.04-0.51) and HDL cholesterol were protective for the development of HE. ACE II genotype was present in the HU group, compared with the HE group (OR 0.18; 95% CI 0.04-0.88). This study shows an association between the low prevalence of ACE I/D polymorphism II genotype and a greater occurrence of HE in Brazilian individuals. The lower blockage of RAS, which was detected in the HE group, may interact with the low frequency of II genotype, conferring an increased risk for HE.

  18. Renal BOLD-MRI relates to kidney function and activity of the renin-angiotensin-aldosterone system in hypertensive patients.

    PubMed

    Vink, Eva E; de Boer, Anneloes; Hoogduin, Hans J M; Voskuil, Michiel; Leiner, Tim; Bots, Michiel L; Joles, Jaap A; Blankestijn, Peter J

    2015-03-01

    The renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system are key factors in the pathophysiology of hypertension. Renal hypoxia is the putative mechanism stimulating both systems. Blood oxygen level-dependent MRI (BOLD-MRI) provides a noninvasive tool to determine renal oxygenation in humans. The aim of the current study was to investigate the relation between blood pressure (BP) and kidney function with renal BOLD-MRI. Moreover, the relation between direct and indirect variables of the RAAS and sympathetic nervous system and renal BOLD-MRI was studied. Seventy-five hypertensive patients (38 men) were included. Antihypertensive medication was temporarily stopped. Patients collected urine during 24 h (sodium, catecholamines), blood samples were taken (creatinine, renin, aldosterone), a captopril challenge test was performed, and ambulatory BP was measured. Mean age was 58 (±11) years, day-time BP was 167 (±19)/102 (±16) mmHg, and estimated glomerular filtration rate was 75 (±18) ml/min per 1.73 m). In multivariable regression analysis, renal medullary R2*-values inversely related to estimated glomerular filtration rate (P = 0.02). Moreover, the BP-lowering effect of captopril positively related to cortical (P = 0.02) and medullary (P = 0.008) R2*-values, as well as to P90 (P = 0.02). In patients with hypertension, kidney function relates to medullary R2*-values. Activation of the RAAS is also positively related to the renal R2*-values.

  19. Novel inhibitors of the cellular renin-angiotensin system components, poricoic acids, target Smad3 phosphorylation and Wnt/β-catenin pathway against renal fibrosis.

    PubMed

    Wang, Ming; Chen, Dan-Qian; Chen, Lin; Cao, Gang; Zhao, Hui; Liu, Dan; Vaziri, Nosratola D; Guo, Yan; Zhao, Ying-Yong

    2018-07-01

    Tubulo-interstitial fibrosis is the final pathway in the progression of chronic kidney disease (CKD) to kidney failure. The renin-angiotensin system (RAS) plays a major role in CKD progression. Hence, we determined the efficacy of novel RAS inhibitors isolated from Poria cocos against renal fibrosis. Effects of three novel tetracyclic triterpenoid compounds, poricoic acid ZC (PZC), poricoic acid ZD (PZD) and poricoic acid ZE (PZE), were investigated on TGFβ1- and angiotensin II (AngII)-treated HK-2 cells and unilateral ureteral obstruction (UUO) in mice. Immunofluorescence staining, quantitative real-time PCR, siRNA, co-immunoprecipitation and Western blot analyses were used to evaluate expression of key molecules in RAS, Wnt/β-catenin and TGFβ/Smad pathways. Addition of the above compounds to culture media and their administration to UUO mice: (i) significantly attenuated epithelial-to-mesenchymal transition and extracellular matrix production in TGFβ1- and AngII-treated HK-2 cells and UUO mice by inhibiting Wnt/β-catenin pathway activation and Smad3 phosphorylation; (ii) selectively inhibited Smad3 phosphorylation by blocking the interaction of TGFBR1 with Smad3; and (iii) specifically inhibited Smad3 activation. PZC and PZD showed a strong inhibitory effect on all RAS components, and PZE showed a strong inhibitory effect on renin. Furthermore, the secolanostane tetracyclic triterpenoids, PZC and PZD, showed a stronger inhibitory effect than the lanostane tetracyclic triterpenoid PZE. Therefore, compounds with secolanostance skeleton showed stronger bioactivity than those with lanostance skeleton. The secolanostane tetracyclic triterpenoids effectively blocked RAS by simultaneously targeting multiple RAS components and lanostane tetracyclic triterpenoids inhibited renin and protected against tubulo-interstitial fibrosis. © 2018 The British Pharmacological Society.

  20. Renin inhibition improves metabolic syndrome, and reduces angiotensin II levels and oxidative stress in visceral fat tissues in fructose-fed rats.

    PubMed

    Chou, Chu-Lin; Lin, Heng; Chen, Jin-Shuen; Fang, Te-Chao

    2017-01-01

    Renin-angiotensin system in visceral fat plays a crucial role in the pathogenesis of metabolic syndrome in fructose-fed rats. However, the effects of renin inhibition on visceral adiposity in metabolic syndrome are not fully investigated. We investigated the effects of renin inhibition on visceral adiposity in fructose-fed rats. Male Wistar-Kyoto rats were divided into 4 groups for 8-week experiments: Group Con (standard chow diet), Group Fru (high-fructose diet; 60% fructose), Group FruA (high-fructose diet and concurrent aliskiren treatment; 100 mg/kg body weight [BW] per day), and Group FruB (high-fructose diet and subsequent, i.e. 4 weeks after initiating high-fructose feeding, aliskiren treatment; 100 mg/kg BW per day). The high-fructose diet induced metabolic syndrome, increased visceral fat weights and adipocyte sizes, and augmented angiotensin II (Ang II), NADPH oxidase (NOX) isoforms expressions, oxidative stress, and dysregulated production of adipocytokines from visceral adipose tissues. Concurrent and subsequent aliskiren administration ameliorated metabolic syndrome, dysregulated adipocytokines, and visceral adiposity in high fructose-fed hypertensive rats, and was associated with reducing Ang II levels, NOX isoforms expressions and oxidative stress in visceral fat tissues. Therefore, this study demonstrates renin inhibition could improve metabolic syndrome, and reduce Ang II levels and oxidative stress in visceral fat tissue in fructose-fed rats, and suggests that visceral adipose Ang II plays a crucial role in the pathogenesis of metabolic syndrome in fructose-fed rats.

  1. Activation of calpain by renin-angiotensin system in pleural mesothelial cells mediates tuberculous pleural fibrosis

    PubMed Central

    Yang, Jie; Xiang, Fei; Cai, Peng-Cheng; Lu, Yu-Zhi; Xu, Xiao-Xiao; Yu, Fan; Li, Feng-Zhi; Greer, Peter A.; Shi, Huan-Zhong; Zhou, Qiong; Xin, Jian-Bao; Ye, Hong; Su, Yunchao

    2016-01-01

    Pleural fibrosis is defined as an excessive deposition of extracellular matrix (ECM) components that results in destruction of the normal pleural tissue architecture. It can result from diverse inflammatory conditions, especially tuberculous pleurisy. Pleural mesothelial cells (PMCs) play a pivotal role in pleural fibrosis. Calpain is a family of calcium-dependent endopeptidases, which plays an important role in ECM remodeling. However, the role of calpain in pleural fibrosis remains unknown. In the present study, we found that tuberculous pleural effusion (TPE) induced calpain activation in PMCs and that inhibition of calpain prevented TPE-induced collagen-I synthesis and cell proliferation of PMCs. Moreover, our data revealed that the levels of angiotensin (ANG)-converting enzyme (ACE) were significantly higher in pleural fluid of patients with TPE than those with malignant pleural effusion, and ACE-ANG II in TPE resulted in activation of calpain and subsequent triggering of the phosphatidylinositol 3-kinase (PI3K)/Akt/NF-κB signaling pathway in PMCs. Finally, calpain activation in PMCs and collagen depositions were confirmed in pleural biopsy specimens from patients with tuberculous pleurisy. Together, these studies demonstrated that calpain is activated by renin-angiotensin system in pleural fibrosis and mediates TPE-induced collagen-I synthesis and proliferation of PMCs via the PI3K/Akt/NF-κB signaling pathway. Calpain in PMCs might be a novel target for intervention in tuberculous pleural fibrosis. PMID:27261452

  2. The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system on hyperkalaemia and acute kidney injury: systematic review and meta-analysis

    PubMed Central

    Gilbert, Cameron; Wald, Ron; Bell, Chaim; Perl, Jeff; Juurlink, David; Beyene, Joseph; Shah, Prakesh S

    2012-01-01

    Objective To examine the safety of using aliskiren combined with agents used to block the renin-angiotensin system. Design Systematic review and meta-analysis of randomised controlled trials. Data sources Medline, Embase, the Cochrane Library, and two trial registries, published up to 7 May 2011. Study selection Published and unpublished randomised controlled trials that compared combined treatment using aliskiren and angiotensin converting enzyme inhibitors or angiotensin receptor blockers with monotherapy using these agents for at least four weeks and that provided numerical data on the adverse event outcomes of hyperkalaemia and acute kidney injury. A random effects model was used to calculate pooled risk ratios and 95% confidence intervals for these outcomes. Results 10 randomised controlled studies (4814 participants) were included in the analysis. Combination therapy with aliskiren and angiotensin converting enzyme inhibitors or angiotensin receptor blockers significantly increased the risk of hyperkalaemia compared with monotherapy using angiotensin converting enzymes or angiotensin receptor blockers (relative risk 1.58, 95% confidence interval 1.24 to 2.02) or aliskiren alone (1.67, 1.01 to 2.79). The risk of acute kidney injury did not differ significantly between the combined therapy and monotherapy groups (1.14, 0.68 to 1.89). Conclusion Use of aliskerin in combination with angiotensin converting enzyme inhibitors or angiotensin receptor blockers is associated with an increased risk for hyperkalaemia. The combined use of these agents warrants careful monitoring of serum potassium levels. PMID:22232539

  3. Progression of hypertension and kidney disease in aging fawn-hooded rats is mediated by enhanced influence of renin-angiotensin system and suppression of nitric oxide system and epoxyeicosanoids.

    PubMed

    Doleželová, Šárka; Jíchová, Šárka; Husková, Zuzana; Vojtíšková, Alžběta; Kujal, Petr; Hošková, Lenka; Kautzner, Josef; Sadowski, Janusz; Červenka, Luděk; Kopkan, Libor

    The fawn-hooded hypertensive (FHH) rat serves as a genetic model of spontaneous hypertension associated with glomerular hyperfiltration and proteinuria. However, the knowledge of the natural course of hypertension and kidney disease in FHH rats remains fragmentary and the underlying pathophysiological mechanisms are unclear. In this study, over the animals' lifetime, we followed the survival rate, blood pressure (telemetry), indices of kidney damage, the activity of renin-angiotensin (RAS) and nitric oxide (NO) systems, and CYP450-epoxygenase products (EETs). Compared to normotensive controls, no elevation of plasma and renal RAS was observed in prehypertensive and hypertensive FHH rats; however, RAS inhibition significantly reduced systolic blood pressure (137 ± 9 to 116 ± 8, and 159 ± 8 to 126 ± 4 mmHg, respectively) and proteinuria (62 ± 2 to 37 ± 3, and 132 ± 8 to 87 ± 5 mg/day, respectively). Moreover, pharmacological RAS inhibition reduced angiotensin (ANG) II and increased ANG 1-7 in the kidney and thereby may have delayed the progression of kidney disease. Furthermore, renal NO and EETs declined in the aging FHH rats but not in the control strain. The present results, especially the demonstration of exaggerated vascular responsiveness to ANG II, indicate that RAS may contribute to the development of hypertension and kidney disease in FHH rats. The activity of factors opposing the development of hypertension and protecting the kidney declined with age in this model. Therefore, therapeutic enhancement of this activity besides RAS inhibition could be attempted in the therapy of human hypertension associated with kidney disease.

  4. Renin-angiotensin and sympathetic nervous system contribution to high blood pressure in Schlager mice.

    PubMed

    Palma-Rigo, Kesia; Jackson, Kristy L; Davern, Pamela J; Nguyen-Huu, Thu-Phuc; Elghozi, Jean-Luc; Head, Geoffrey A

    2011-11-01

    Schlager hypertensive (BPH/2J) mice have been suggested to have high blood pressure (BP) due to an overactive sympathetic nervous system (SNS), but the contribution of the renin-angiotensin system (RAS) is unclear. In the present study, we examined the cardiovascular effects of chronically blocking the RAS in BPH/2J mice. Schlager normotensive (BPN/3J, n = 6) and BPH/2J mice (n = 8) received the angiotensin AT 1A-receptor antagonist losartan (150 mg/kg per day) in drinking water for 2 weeks. Pre-implanted telemetry devices were used to record mean arterial pressure (MAP), heart rate (HR) and locomotor activity. MAP was reduced by losartan treatment in BPN/3J (-23 mmHg, P < 0.01) and in BPH/2J mice (-25 mmHg, P < 0.001), whereas HR was increased. Losartan had little effect on initial pressor responses to feeding or to stress, but did attenuate the sustained pressor response to cage-switch stress. During the active period, the hypotension to sympathetic blockade with pentolinium was greater in BPH/2J than BPN/3J (suggesting neurogenic hypertension), but was not affected by losartan. During the inactive period, a greater depressor response to pentolinium was observed in losartan-treated animals. The hypotensive actions of losartan suggest that although the RAS provides an important contribution to BP, it contributes little, if at all, to the hypertension-induced or the greater stress-induced pressor responses in Schlager mice. The effects of pentolinium suggest that the SNS is mainly responsible for hypertension in BPH/2J mice. However, the RAS inhibits sympathetic vasomotor tone during inactivity and prolongs sympathetic activation during periods of adverse stress, indicating an important sympatho-modulatory role.

  5. The critical role of the central nervous system (pro)renin receptor in regulating systemic blood pressure

    PubMed Central

    Xu, Quanbin; Jensen, Dane D.; Peng, Hua; Feng, Yumei

    2016-01-01

    The systemic renin–angiotensin system (RAS) has long been recognized as a critically important system in blood pressure (BP) regulation. However, extensive evidence has shown that a majority of RAS components are also present in many tissues and play indispensable roles in BP regulation. Here, we review evidence that RAS components, notably including the newly identified (pro)renin receptor (PRR), are present in the brain and are essential for the central regulation of BP. Binding of the PRR to its ligand, prorenin or renin, increases BP and promotes progression of cardiovascular diseases in an angiotensin II-dependent and -independent manner, establishing the PRR a promising antihypertensive drug target. We also review the existing PRR blockers, including handle region peptide and PRO20, and propose a rationale for blocking prorenin/PRR activation as a therapeutic approach that does not affect the actions of the PRR in vacuolar H+-ATPase and development. Finally, we summarize categories of currently available antihypertensive drugs and consider future perspectives. PMID:27113409

  6. Blocking the RAAS at different levels: an update on the use of the direct renin inhibitors alone and in combination.

    PubMed

    Cagnoni, Francesca; Njwe, Christian Achiri Ngu; Zaninelli, Augusto; Ricci, Alessandra Rossi; Daffra, Diletta; D'Ospina, Antonio; Preti, Paola; Destro, Maurizio

    2010-08-09

    The renin-angiotensin-aldosterone system (RAAS), an important regulator of blood pressure and mediator of hypertension-related complications, is a prime target for cardiovascular drug therapy. Angiotensin-converting enzyme inhibitors (ACEIs) were the first drugs to be used to block the RAAS. Angiotensin II receptor blockers (ARBs) have also been shown to be equally effective for treatment. Although these drugs are highly effective and are widely used in the management of hypertension, current treatment regimens with ACEIs and ARBs are unable to completely suppress the RAAS. Combinations of ACEIs and ARBs have been shown to be superior than to either agent alone for some, but certainly not all, composite cardiovascular and kidney outcomes, but dual RAAS blockade with the combination of an ACEI and an ARB is sometimes associated with an increase in the risk for adverse events, primarily hyperkalemia and worsening renal function. The recent introduction of the direct renin inhibitor, aliskiren, has made available new combination strategies to obtain a more complete blockade of the RAAS with fewer adverse events. Renin system blockade with aliskiren and another RAAS agent has been, and still is, the subject of many large-scale clinical trials and furthermore, is already available in some countries as a fixed combination.

  7. Angiotensin-(1-7): A Novel Peptide to Treat Hypertension and Nephropathy in Diabetes?

    PubMed

    Padda, Ranjit Singh; Shi, Yixuan; Lo, Chao-Sheng; Zhang, Shao-Ling; Chan, John S D

    2015-10-14

    The renin-angiotensin system (RAS) plays a pivotal role in mammalian homeostasis physiology. The RAS can be delineated into a classical RAS (the pressor arm) including angiotensinogen (Agt), renin, angiotensin-converting enzyme (ACE), angiotensin II (Ang II) and angiotensin type 1 receptor (AT1R), and a counterbalancing novel RAS (the depressor arm) including Agt, renin, angiotensin-converting enzyme-2 (ACE-2), angiotensin-(1-7) (Ang 1-7) and Ang 1-7 receptor (or Mas receptor (MasR)). Hyperglycemia (diabetes) induces severe tissue oxidative stress, which stimulates the pressor arm of the renal RAS axis and leads to an increase in ACE/ACE-2 ratio, with excessive formation of Ang II. There is a growing body of evidence for beneficial effects of the depressor arm of RAS (ACE-2/Ang 1-7/MasR) axis in diabetes, hypertension and several other diseased conditions. Evidence from in vitro, in vivo and clinical studies reflects anti-oxidant, anti-fibrotic, and anti-inflammatory properties of Ang 1-7. Most of the currently available therapies only target suppression of the pressor arm of RAS with angiotensin receptor blockers (ARBs) and ACE inhibitors (ACEi). However, it is time to consider simultaneous activation of the depressor arm for more effective outcomes. This review summarizes the recent updates on the protective role of Ang 1-7 in hypertension and kidney injury in diabetes, as well as the possible underlying mechanism(s) of Ang 1-7 action, suggesting that the ACE-2/Ang 1-7/MasR axis can be developed as a therapeutic target for the treatment of diabetes-induced hypertension and renal damage.

  8. Angiotensin-(1-7): A Novel Peptide to Treat Hypertension and Nephropathy in Diabetes?

    PubMed Central

    Padda, Ranjit Singh; Shi, Yixuan; Lo, Chao-Sheng; Zhang, Shao-Ling; Chan, John S.D.

    2015-01-01

    The renin-angiotensin system (RAS) plays a pivotal role in mammalian homeostasis physiology. The RAS can be delineated into a classical RAS (the pressor arm) including angiotensinogen (Agt), renin, angiotensin-converting enzyme (ACE), angiotensin II (Ang II) and angiotensin type 1 receptor (AT1R), and a counterbalancing novel RAS (the depressor arm) including Agt, renin, angiotensin-converting enzyme-2 (ACE-2), angiotensin-(1-7) (Ang 1-7) and Ang 1-7 receptor (or Mas receptor (MasR)). Hyperglycemia (diabetes) induces severe tissue oxidative stress, which stimulates the pressor arm of the renal RAS axis and leads to an increase in ACE/ACE-2 ratio, with excessive formation of Ang II. There is a growing body of evidence for beneficial effects of the depressor arm of RAS (ACE-2/Ang 1-7/MasR) axis in diabetes, hypertension and several other diseased conditions. Evidence from in vitro, in vivo and clinical studies reflects anti-oxidant, anti-fibrotic, and anti-inflammatory properties of Ang 1-7. Most of the currently available therapies only target suppression of the pressor arm of RAS with angiotensin receptor blockers (ARBs) and ACE inhibitors (ACEi). However, it is time to consider simultaneous activation of the depressor arm for more effective outcomes. This review summarizes the recent updates on the protective role of Ang 1-7 in hypertension and kidney injury in diabetes, as well as the possible underlying mechanism(s) of Ang 1-7 action, suggesting that the ACE-2/Ang 1-7/MasR axis can be developed as a therapeutic target for the treatment of diabetes-induced hypertension and renal damage. PMID:26793405

  9. Antenatal corticosteroids and the renin-angiotensin-aldosterone system in adolescents born preterm.

    PubMed

    South, Andrew M; Nixon, Patricia A; Chappell, Mark C; Diz, Debra I; Russell, Gregory B; Snively, Beverly M; Shaltout, Hossam A; Rose, James C; O'Shea, T Michael; Washburn, Lisa K

    2017-01-01

    Antenatal corticosteroid (ANCS) treatment hastens fetal lung maturity and improves survival of premature infants, but the long-term effects of ANCS are not well-described. Animal models suggest that ANCS increases the risk of cardiovascular disease through programmed changes in the renin-angiotensin (Ang)-aldosterone system (RAAS). We hypothesized that ANCS exposure alters the RAAS in adolescents born prematurely. A cohort of 173 adolescents born prematurely was evaluated, of whom 92 were exposed to ANCS. We measured plasma and urine Ang II and Ang-(1-7) and calculated Ang II/Ang-(1-7) ratios. We used general linear regression models to estimate the difference in the RAAS between the ANCS-exposed and unexposed groups, adjusting for confounding variables. In unadjusted analyses, and after adjustment for sex, race, and maternal hypertension, ANCS exposure was associated with increased urinary Ang II/Ang-(1-7) (estimate 0.27 (95% CI 0.03, 0.5), P = 0.03), increased plasma Ang-(1-7) (0.66 (0.26, 1.07), P = 0.002), and decreased plasma Ang II/Ang-(1-7) (-0.48 (-0.91, -0.06), P = 0.03). These alterations indicate an imbalance in the urinary RAAS, promoting the actions of Ang II at the expense of Ang-(1-7), which over time may increase the risk of renal inflammation and fibrosis and ultimately hypertension and renal disease.

  10. Big angiotensin-25: a novel glycosylated angiotensin-related peptide isolated from human urine.

    PubMed

    Nagata, Sayaka; Hatakeyama, Kinta; Asami, Maki; Tokashiki, Mariko; Hibino, Hajime; Nishiuchi, Yuji; Kuwasako, Kenji; Kato, Johji; Asada, Yujiro; Kitamura, Kazuo

    2013-11-29

    The renin-angiotensin system (RAS), including angiotensin II (Ang II), plays an important role in the regulation of blood pressure and body fluid balance. Consequently, the RAS has emerged as a key target for treatment of kidney and cardiovascular disease. In a search for bioactive peptides using an antibody against the N-terminal portion of Ang II, we identified and characterized a novel angiotensin-related peptide from human urine as a major molecular form. We named the peptide Big angiotensin-25 (Bang-25) because it consists of 25 amino acids with a glycosyl chain and added cysteine. Bang-25 is rapidly cleaved by chymase to Ang II, but is resistant to cleavage by renin. The peptide is abundant in human urine and is present in a wide range of organs and tissues. In particular, immunostaining of Bang-25 in the kidney is specifically localized to podocytes. Although the physiological function of Bang-25 remains uncertain, our findings suggest it is processed from angiotensinogen and may represent an alternative, renin-independent path for Ang II synthesis in tissue. Copyright © 2013. Published by Elsevier Inc.

  11. Impact of The Protective Renin-Angiotensin System (RAS) on The Vasoreparative Function of CD34+ CACs in Diabetic Retinopathy

    NASA Technical Reports Server (NTRS)

    Duan, Yaqian; Moldovan, Leni; Miller, Rehae C.; Beli, Eleni; Salazar, Tatiana; Hazra, Sugata; Al-Sabah, Jude; Chalam, KV; Raghunandan, Sneha; Vyas, Ruchi; hide

    2016-01-01

    Purpose: In diabetes, the impaired vasoreparative function of Circulating Angiogenic Cells (CACs) is believed to contribute to the progression of diabetic retinopathy (DR). Accumulating evidence suggests that the protective arm of renin-angiotensin system (RAS) ACE2 Angiotensin-(1-7) Mas plays an important role in restoring the function of diabetic CACs. We examined the protective RAS in CACs in diabetic individuals with different stages of retinopathy. Methods: Study subjects (n43) were recruited as controls or diabetics with either no DR, mild non-proliferative DR (NPDR), moderate NPDR, severe NPDR or proliferative DR (PDR). Fundus photography and fluorescein angiograms were analyzed using Vessel Generation Analysis (VESGEN) software in a cohort of subjects. CD34+ CACs were isolated from peripheral blood of diabetics and control subjects. RAS gene expressions in CACs were measured by qPCR. The vasoreparative function of CACs was assessed by migration ability toward CXCL12 using the QCM 5M 96-well chemotaxis cell migration assay. Results: ACE2 gene is a key enzyme converting the deleterious Angiotensin II to the beneficial Angiotensin-(1-7). ACE2 expression in CACs from diabetic subjects without DR was increased compared to controls, suggestive of compensation (p0.0437). The expression of Mas (Angiotensin-(1-7) receptor) in CACs was also increased in diabetics without DR, while was reduced in NPDR compared to controls (p0.0002), indicating a possible loss of compensation of the protective RAS at this stage of DR. The presence of even mild NPDR was associated with CD34+ CAC migratory dysfunction. When pretreating CACs of DR subjects with Angiotensin-(1-7), migratory ability to a chemoattractant CXCL12 was restored (p0.0008). By VESGEN analysis, an increase in small vessel density was observed in NPDR subjects when compared with the controls. Conclusions: These data suggest the protective RAS axis within diabetic CACs may help maintain their vasoreparative potential

  12. Selective Deletion of the Brain-Specific Isoform of Renin Causes Neurogenic Hypertension.

    PubMed

    Shinohara, Keisuke; Liu, Xuebo; Morgan, Donald A; Davis, Deborah R; Sequeira-Lopez, Maria Luisa S; Cassell, Martin D; Grobe, Justin L; Rahmouni, Kamal; Sigmund, Curt D

    2016-12-01

    The renin-angiotensin system (RAS) in the brain is a critical determinant of blood pressure, but the mechanisms regulating RAS activity in the brain remain unclear. Expression of brain renin (renin-b) occurs from an alternative promoter-first exon. The predicted translation product is a nonsecreted enzymatically active renin whose function is unknown. We generated a unique mouse model by selectively ablating the brain-specific isoform of renin (renin-b) while preserving the expression and function of the classical isoform expressed in the kidney (renin-a). Preservation of renal renin was confirmed by measurements of renin gene expression and immunohistochemistry. Surprisingly, renin-b-deficient mice exhibited hypertension, increased sympathetic nerve activity to the kidney and heart, and impaired baroreflex sensitivity. Whereas these mice displayed decreased circulating RAS activity, there was a paradoxical increase in brain RAS activity. Physiologically, renin-b-deficient mice exhibited an exaggerated depressor response to intracerebroventricular administration of losartan, captopril, or aliskiren. At the molecular level, renin-b-deficient mice exhibited increased expression of angiotensin-II type 1 receptor in the paraventricular nucleus, which correlated with an increased renal sympathetic nerve response to leptin, which was dependent on angiotensin-II type 1 receptor activity. Interestingly, despite an ablation of renin-b expression, expression of renin-a was significantly increased in rostral ventrolateral medulla. These data support a new paradigm for the genetic control of RAS activity in the brain by a coordinated regulation of the renin isoforms, with expression of renin-b tonically inhibiting expression of renin-a under baseline conditions. Impairment of this control mechanism causes neurogenic hypertension. © 2016 American Heart Association, Inc.

  13. Effect of endogenous angiotensin II on the frequency response of the renal vasculature.

    PubMed

    Dibona, Gerald F; Sawin, Linda L

    2004-12-01

    The renal vasculature functions as an efficient low-pass filter of the multiple frequencies contained within renal sympathetic nerve activity. This study examined the effect of angiotensin II on the frequency response of the renal vasculature. Physiological changes in the activity of the endogenous renin-angiotensin system were produced by alterations in dietary sodium intake. The frequency response of the renal vasculature was evaluated using pseudorandom binary sequence renal nerve stimulation, and the role of angiotensin II was evaluated by the administration of the angiotensin II AT(1)-receptor antagonist losartan. In low-sodium-diet rats with increased renin-angiotensin system activity, losartan steepened the renal vascular frequency response (i.e., greater attenuation); this was not seen in normal- or high-sodium-diet rats with normal or decreased renin-angiotensin system activity. Analysis of the transfer function from arterial pressure to renal blood flow, i.e., dynamic autoregulation, showed that the tubuloglomerular feedback but not the myogenic component was enhanced in low- and normal- but not in high-sodium-diet rats and that this was reversed by losartan administration. Thus physiological increases in endogenous renin-angiotensin activity inhibit the renal vascular frequency response to renal nerve stimulation while selectively enhancing the tubuloglomerular feedback component of dynamic autoregulation of renal blood flow.

  14. Combination use of medicines from two classes of renin-angiotensin system blocking agents: risk of hyperkalemia, hypotension, and impaired renal function.

    PubMed

    Esteras, Raquel; Perez-Gomez, Maria Vanessa; Rodriguez-Osorio, Laura; Ortiz, Alberto; Fernandez-Fernandez, Beatriz

    2015-08-01

    European and United States regulatory agencies recently issued warnings against the use of dual renin-angiotensin system (RAS) blockade therapy through the combined use of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs) or aliskiren in any patient, based on absence of benefit for most patients and increased risk of hyperkalemia, hypotension, and renal failure. Special emphasis was made not to use these combinations in patients with diabetic nephropathy. The door was left open to therapy individualization, especially for patients with heart failure, when the combined use of an ARB and ACEI is considered absolutely essential, although renal function, electrolytes and blood pressure should be closely monitored. Mineralocorticoid receptor antagonists were not affected by this warning despite increased risk of hyperkalemia. We now critically review the risks associated with dual RAS blockade and answer the following questions: What safety issues are associated with dual RAS blockade? Can the safety record of dual RAS blockade be improved? Is it worth trying to improve the safety record of dual RAS blockade based on the potential benefits of the combination? Is dual RAS blockade dead? What is the role of mineralocorticoid antagonists in combination with other RAS blocking agents: RAAS blockade?

  15. Enhanced peripheral dopamine impairs post-ischemic healing by suppressing angiotensin receptor type 1 expression in endothelial cells and inhibiting angiogenesis.

    PubMed

    Sarkar, Chandrani; Ganju, Ramesh K; Pompili, Vincent J; Chakroborty, Debanjan

    2017-02-01

    Increased circulating catecholamines have been linked with cardiovascular anomalies as well as with peripheral vascular diseases. Although the roles of epinephrine and norepinephrine have received considerable attention, the role of the other catecholamine, dopamine, has been less studied. Since dopamine is a potent endogenous inhibitor of angiogenesis and as angiogenesis is essential for ischemic healing, we therefore studied the role played by dopamine during ischemic healing using dopamine D 2 receptor knockout (KOD2) mice. Although concentration of dopamine and its rate-limiting enzyme, tyrosine hydroxylase, was considerably high in the muscle tissues of wild-type and KOD2 mice with unilateral hind limb ischemia (HLI), recovery was significantly faster in the KOD2 mice compared to the wild-type controls, thereby indicating that peripheral dopamine might have a role in this healing process. In addition, we observed significant differences in post-ischemic angiogenesis between these two groups. Our study further revealed that elevated dopamine independently suppressed activation of local tissue-based renin-angiotensin system (RAS), a critical growth factor system stimulating angiogenesis in ischemia. Angiotensin II (ATII) and its receptor, angiotensin receptor type 1 (AT1R), are the key players in RAS-mediated angiogenesis. Dopamine acting through its D 2 receptors in endothelial cells inhibited ATII-mediated angiogenesis by suppressing the expression of AT1R in these cells. This study thus for the first time demonstrates the role played by dopamine in prolonging post-ischemic recovery. Therefore, pharmacological intervention inhibiting the action of dopamine holds promise as future therapeutic strategy for the treatment of HLI and other peripheral arterial diseases.

  16. Combined effects of aging and inflammation on renin-angiotensin system mediate mitochondrial dysfunction and phenotypic changes in cardiomyopathies.

    PubMed

    Burks, Tyesha N; Marx, Ruth; Powell, Laura; Rucker, Jasma; Bedja, Djahida; Heacock, Elisa; Smith, Barbara J; Foster, D Brian; Kass, David; O'Rourke, Brian; Walston, Jeremy D; Abadir, Peter M

    2015-05-20

    Although the effects of aging and inflammation on the health of the cardiac muscle are well documented, the combined effects of aging and chronic inflammation on cardiac muscle are largely unknown. The renin-angiotensin system (RAS) has been linked independently to both aging and inflammation, but is understudied in the context of their collective effect. Thus, we investigated localized cardiac angiotensin II type I and type II receptors (AT(1)R, AT(2)R), downstream effectors, and phenotypic outcomes using mouse models of the combination of aging and inflammation and compared it to a model of aging and a model of inflammation. We show molecular distinction in the combined effect of aging and inflammation as compared to each independently. The combination maintained an increased AT(1)R:AT(2)R and expression of Nox2 and exhibited the lowest activity of antioxidants. Despite signaling pathway differences, the combined effect shared phenotypic similarities with aging including oxidative damage, fibrosis, and hypertrophy. These phenotypic similarities have dubbed inflammatory conditions as premature aging, but they are, in fact, molecularly distinct. Moreover, treatment with an AT(1)R blocker, losartan, selectively reversed the signaling changes and ameliorated adverse phenotypic effects in the combination of aging and inflammation as well as each independently.

  17. Combined effects of aging and inflammation on renin-angiotensin system mediate mitochondrial dysfunction and phenotypic changes in cardiomyopathies

    PubMed Central

    Burks, Tyesha N.; Marx, Ruth; Powell, Laura; Rucker, Jasma; Bedja, Djahida; Heacock, Elisa; Smith, Barbara J.; Foster, D. Brian; Kass, David; O'Rourke, Brian; Walston, Jeremy D.; Abadir, Peter M.

    2015-01-01

    Although the effects of aging and inflammation on the health of the cardiac muscle are well documented, the combined effects of aging and chronic inflammation on cardiac muscle are largely unknown. The renin-angiotensin system (RAS) has been linked independently to both aging and inflammation, but is understudied in the context of their collective effect. Thus, we investigated localized cardiac angiotensin II type I and type II receptors (AT1R, AT2R), downstream effectors, and phenotypic outcomes using mouse models of the combination of aging and inflammation and compared it to a model of aging and a model of inflammation. We show molecular distinction in the combined effect of aging and inflammation as compared to each independently. The combination maintained an increased AT1R:AT2R and expression of Nox2 and exhibited the lowest activity of antioxidants. Despite signaling pathway differences, the combined effect shared phenotypic similarities with aging including oxidative damage, fibrosis, and hypertrophy. These phenotypic similarities have dubbed inflammatory conditions as premature aging, but they are, in fact, molecularly distinct. Moreover, treatment with an AT1R blocker, losartan, selectively reversed the signaling changes and ameliorated adverse phenotypic effects in the combination of aging and inflammation as well as each independently. PMID:26221650

  18. Protection against death and renal failure by renin-angiotensin system blockers in patients with diabetes and kidney disease.

    PubMed

    Shen, Jian; Huang, Yan-Mei; Song, Xin-Nan; Hong, Xue-Zhi; Wang, Min; Ling, Wei; Zhang, Xiao-Xi; Zhao, Hai-Lu

    2016-07-01

    Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are widely used to block the renin-angiotensin system (RAS). Yet it remains uncertain whether these drugs are equally effective and safe. Systematic reviews and meta-analyses of ACEis/ARBs in diabetes and kidney disease published in PubMed, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases were searched for clinical outcomes including all-cause mortality, end-stage renal disease (ESRD), hyperkalemia and cough. Eight meta-analyses included 2177-61,264 patients with follow-up of 6-108 months. RAS blockers reduced mortality (relative risk ratio (RR), 0.90, 95% confidence interval (CI), 0.86-0.95) without heterogeneity. The death protection was significant specifically with ACEis (RR, 0.85, 95% CI, 0.79-0.91), but not with ARBs. Protection against ESRD was homogenously evident by ARBs (RR, 0.79, 95% CI, 0.73-0.87), ACEis (RR, 0.79, 95% , 0.64-0.94), and both (RR, 0.79, 95% CI, 0.73-0.87). Significant side effects were hyperkalemia by ARBs (RR, 2.44, 95% CI, 1.13-5.26), and cough by ACEis (RR, 2.38, 95% CI, 1.75-3.22) CONCLUSIONS: In patients with diabetes and kidney disease, ACEis and ARBs are consistently protective for the development of ESRD. Use of ACEis alone additionally reduces deaths and increases the risk for cough. Use of ARBs alone increases the risk for hyperkalemia without additional benefit of death protection. © The Author(s) 2016.

  19. Administration of exogenous 1,25(OH)2D3 normalizes overactivation of the central renin-angiotensin system in 1α(OH)ase knockout mice.

    PubMed

    Zhang, Wei; Chen, Lulu; Zhang, Luqing; Xiao, Ming; Ding, Jiong; Goltzman, David; Miao, Dengshun

    2015-02-19

    Previously, we reported that active vitamin D deficiency in mice causes secondary hypertension and cardiac dysfunction, but the underlying mechanism remains largely unknown. To clarify whether exogenous active vitamin D rescues hypertension by normalizing the altered central renin-angiotensin system (RAS) via an antioxidative stress mechanism, 1-alpha-hydroxylase [1α(OH)ase] knockout mice [1α(OH)ase(-/-)] and their wild-type littermates were fed a normal diet alone or with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], or a high-calcium, high-phosphorus "rescue" diet with or without antioxidant N-acetyl-l-cysteine (NAC) supplementation for 4 weeks. Compared with their wild-type littermates, 1α(OH)ase(-/-)mice had high mean arterial pressure, increased levels of renin, angiotensin II (Ang II), and Ang II type 1 receptor, and increased malondialdehyde levels, but decreased anti-peroxiredoxin I and IV proteins and the antioxidative genes glutathione reductase (Gsr) and glutathione peroxidase 4 (Gpx4) in the brain samples. Except Ang II type 1 receptor, these pathophysiological changes were rescued by exogenous 1,25(OH)2D3 or NAC plus rescue diet, but not by rescue diet alone. We conclude that 1,25(OH)2D3 normalizes the altered central RAS in 1α(OH)ase(-/-)mice, at least partially, through a central antioxidative mechanism. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. [Elevated serum aldosterone levels in dialysis patients: Are we underusing renin-angiotensin-aldosterone system blockers?

    PubMed

    Fernández-Reyes, M J; Velasco, S; Gutierrez, C; Gonzalez Villalba, M J; Heras, M; Molina, A; Callejas, R; Rodríguez, A; Calle, L; Lopes, V

    Serum aldosteronelevels (SA) are a marker of cardiovascular (CV) risk in the general population. To analyze SA levels in dialysis patients and its relationship with characteristics of dialysis; comorbidity; blood pressure and the use of blocking renin-angiotensin-aldosterone system agents (BSRAA). We determined SA in 102 patients: 81 on hemodialysis (HD) and 21 on peritoneal dialysis. Mean age 71.4±12 years; 54.9% male; 29.4% diabetics. Mean time on dialysis 59.3±67 months. In 44 HD patients plasma renin activity (PRA) was measured. Mean SA was 72.6±114.9ng/dl (normal range 1.17-23.6ng/dl). A total of 57.8% of patients had above normal levels which were not related to dialysis characteristics or comorbidity. Only 21% of patients with heart failure and 19.2% with ischemic heart disease used BSRAA. A number of 25 patients treated with BSRAA had significantly lower levels of SA. There was an inverse correlation between AS and systolic blood pressure (SBP), and direct with PRA. The logistic regression analysis conducted to find SA levels above the median associated factors showed that SBP was the only independent risk variable in the overall population (OR 0.97; P=.022); in the 44 patients in whom PRA was determined this was the only independent risk factor (OR 2.24; P=.012). A high percentage of dialysis patients have elevated levels of SA that are associated to diminished SBP and activated PRA and not to dialysis characteristics. In patients with a history of heart disease we underuse BSRAA. Copyright © 2016 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.

  1. The relationship between vitamin D and the renin-angiotensin system in the pathophysiology of hypertension, kidney disease, and diabetes.

    PubMed

    Vaidya, Anand; Williams, Jonathan S

    2012-04-01

    Vitamin D has been implicated in the pathophysiology of extraskeletal conditions such as hypertension, kidney disease, and diabetes via its ability to negatively regulate the renin-angiotensin system (RAS). This article reviews the evidence supporting a link between vitamin D and the RAS in these conditions, with specific emphasis on translational observations and their limitations. A literature review of animal and human studies evaluating the role of vitamin D in hypertension, kidney disease, and diabetes was performed. Excess activity of the RAS has been implicated in the pathogenesis of hypertension, chronic kidney disease, decreased insulin secretion, and insulin resistance. Animal studies provide strong support for 1,25-dihydroxyvitamin D(3)-mediated downregulation of renin expression and RAS activity via its interaction with the vitamin D receptor. Furthermore, the activity of vitamin D metabolites in animals is associated with reductions in blood pressure, proteinuria and renal injury, and with improved β-cell function. Many observational, and a few interventional, studies in humans have supported these findings; however, there is a lack of well-designed prospective human interventional studies to definitively assess clinical outcomes. There is a need for more well-designed prospective interventional studies to validate this hypothesis in human clinical outcomes. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Effect of Uric Acid Lowering on Renin-Angiotensin-System Activation and Ambulatory BP: A Randomized Controlled Trial

    PubMed Central

    Borgi, Lea; Fisher, Naomi; Curhan, Gary; Forman, John

    2017-01-01

    Background and objectives Higher serum uric acid levels, even within the reference range, are strongly associated with increased activity of the renin-angiotensin system (RAS) and risk of incident hypertension. However, the effect of lowering serum uric acid on RAS activity in humans is unknown, although the data that lowering serum uric acid can reduce BP are conflicting. Design, setting, participants, & measurements In a double-blind placebo-controlled trial conducted from 2011 to 2015, we randomly assigned 149 overweight or obese adults with serum uric acid ≥5.0 mg/dl to uric acid lowering with either probenecid or allopurinol, or to placebo. The primary endpoints were kidney-specific and systemic RAS activity. Secondary endpoints included mean 24-hour systolic BP, mean awake and asleep BP, and nocturnal dipping. Results Allopurinol and probenecid markedly lowered serum uric acid after 4 and 8 weeks compared with placebo (mean serum uric acid in allopurinol, probenecid, and placebo at 8 weeks was 2.9, 3.5, and 5.6 mg/dl, respectively). The change in kidney-specific RAS activity, measured as change in the median (interquartile range) renal plasma flow response to captopril (in ml/min per 1.73 m2) from baseline to 8 weeks, was −4 (−25 to 32) in the probenecid group (P=0.83), −4 (−16 to 9) in the allopurinol group (P=0.32), and 1 (−21 to 17) in the placebo group (P=0.96), with no significant treatment effect (P=0.77). Similarly, plasma renin activity and plasma angiotensin II levels did not significantly change with treatment. The change in mean (±SD) 24-hour systolic BPs from baseline to 8 weeks was −1.6±10.1 with probenecid (P=0.43), −0.4±6.1 with allopurinol (P=0.76), and 0.5±6.0 with placebo (P=0.65); there was no significant treatment effect (P=0.58). Adverse events occurred in 9%, 12%, and 2% of those given probenecid, allopurinol, or placebo, respectively. Conclusions In contrast to animal experiments and observational studies, this

  3. Effect of Uric Acid Lowering on Renin-Angiotensin-System Activation and Ambulatory BP: A Randomized Controlled Trial.

    PubMed

    McMullan, Ciaran J; Borgi, Lea; Fisher, Naomi; Curhan, Gary; Forman, John

    2017-05-08

    Higher serum uric acid levels, even within the reference range, are strongly associated with increased activity of the renin-angiotensin system (RAS) and risk of incident hypertension. However, the effect of lowering serum uric acid on RAS activity in humans is unknown, although the data that lowering serum uric acid can reduce BP are conflicting. In a double-blind placebo-controlled trial conducted from 2011 to 2015, we randomly assigned 149 overweight or obese adults with serum uric acid ≥5.0 mg/dl to uric acid lowering with either probenecid or allopurinol, or to placebo. The primary endpoints were kidney-specific and systemic RAS activity. Secondary endpoints included mean 24-hour systolic BP, mean awake and asleep BP, and nocturnal dipping. Allopurinol and probenecid markedly lowered serum uric acid after 4 and 8 weeks compared with placebo (mean serum uric acid in allopurinol, probenecid, and placebo at 8 weeks was 2.9, 3.5, and 5.6 mg/dl, respectively). The change in kidney-specific RAS activity, measured as change in the median (interquartile range) renal plasma flow response to captopril (in ml/min per 1.73 m 2 ) from baseline to 8 weeks, was -4 (-25 to 32) in the probenecid group ( P =0.83), -4 (-16 to 9) in the allopurinol group ( P =0.32), and 1 (-21 to 17) in the placebo group ( P =0.96), with no significant treatment effect ( P =0.77). Similarly, plasma renin activity and plasma angiotensin II levels did not significantly change with treatment. The change in mean (±SD) 24-hour systolic BPs from baseline to 8 weeks was -1.6±10.1 with probenecid ( P =0.43), -0.4±6.1 with allopurinol ( P =0.76), and 0.5±6.0 with placebo ( P =0.65); there was no significant treatment effect ( P =0.58). Adverse events occurred in 9%, 12%, and 2% of those given probenecid, allopurinol, or placebo, respectively. In contrast to animal experiments and observational studies, this randomized, placebo-controlled trial found that uric acid lowering had no effect on kidney

  4. Effect of maternal renin-angiotensin-aldosterone system activation on social coping strategies and gene expression of oxytocin and vasopressin in the brain of rat offspring in adulthood.

    PubMed

    Senko, Tomáš; Svitok, Pavel; Kršková, Lucia

    2017-10-01

    The intrauterine condition in which the mammalian foetus develops has an important role in prenatal programming. The aim of this study was to determine the extent to which activation of the maternal renin-angiotensin-aldosterone system (RAAS) could influence social behaviour strategies in offspring via changes in social neurotransmitters in the brain. Pregnant female Wistar rats were implanted with osmotic minipumps which continually released angiotensin II for 14 days at concentration of 2 μg/kg/h. The adult offspring (angiotensin and control groups) underwent a social interaction test. The mRNA expression of vasopressin, oxytocin and the oxytocin receptor in selected brain areas was measured by in situ hybridisation. Prenatal exposure to higher levels of angiotensin II resulted in a strong trend toward decreased total social interaction time and significantly decreased time spent in close proximity and frequency of mutual sniffing. The angiotensin group showed no changes in oxytocin mRNA expression in the hypothalamic paraventricular or supraoptic nuclei, but this group had reduced vasopressin mRNA expression in the same areas. We concluded that maternal activation of RAAS (via higher levels of angiotensin II) caused inhibition of some socio-cohesive indicators and decreased vasopressinergic activity of offspring. Taken together, these results suggest a reactive rather than proactive social coping strategy.

  5. Distribution of renin activity and angiotensinogen in rat brain. Effects of dietary sodium chloride intake on brain renin.

    PubMed Central

    Genain, C P; Van Loon, G R; Kotchen, T A

    1985-01-01

    The purpose of this study was to investigate the biochemistry and the regulation of the brain renin-angiotensin system in the Sprague-Dawley rat. Renin activity and angiotensinogen concentrations (direct and indirect radioimmunoassays) were measured in several brain areas and in neuroendocrine glands. Regional renin activities were measured in separate groups of rats on high and low NaCl diets. Mean tissue renin activities ranged from 2.2 +/- 0.6 to 54.4 +/- 19.7 fmol/mg protein per h (mean of 7 +/- SD), with the highest amounts in pineal, pituitary, and pons-medulla. NaCl depletion increased renin activity in selected regions; based on estimates of residual plasma contamination (despite perfusion of brains with saline), increased renin activity of pineal gland and posterior pituitary was attributed to higher plasma renin. To eliminate contamination by plasma renin, 16-h-nephrectomized rats were also studied. In anephric rats, NaCl depletion increased renin activity by 92% in olfactory bulbs and by 97% in anterior pituitary compared with NaCl-replete state. These elevations could not be accounted for by hyperreninemia. Brain renin activity was low and was unaffected by dietary NaCl in amygdala, hypothalamus, striatum, frontal cortex, and cerebellum. In contrast to renin, highest angiotensinogen concentrations were measured in hypothalamus and cerebellum. Overall, angiotensinogen measurements with the direct and the indirect assays were highly correlated (n = 56, r = 0.96, P less than 0.001). We conclude that (a) NaCl deprivation increases renin in olfactory bulbs and anterior pituitary of the rat, unrelated to contamination by plasma renin; and (b) the existence of angiotensinogen, the precursor of angiotensins, is demonstrated by direct radioimmunoassay throughout the brain and in neuroendocrine glands. PMID:3902894

  6. The (pro)renin receptor and body fluid homeostasis

    PubMed Central

    Cao, Theresa

    2013-01-01

    The renin-angiotensin system (RAS) has long been established as one of the major mechanisms of hypertension through the increased levels of angiotensin (ANG) II and its resulting effect on the sympathetic nerve activity, arterial vasoconstriction, water reabsorption, and retention, etc. In the central nervous system, RAS activation affects body fluid homeostasis through increases in sympathetic nerve activity, water intake, food intake, and arginine vasopressin secretion. Previous studies, however, have shown that ANG II can be made in the brain, and it could possibly be through a new component called the (pro)renin receptor. This review intends to summarize the central and peripheral effects of the PRR on body fluid homeostasis. PMID:23678024

  7. Angiotensin II and its different receptor subtypes in placenta and fetal membranes.

    PubMed

    Kalenga, M K; de Gasparo, M; Thomas, K; de Hertogh, R

    1996-01-01

    The recent discovery of a local renin-angiotensin system in trophoblastic tissues has raised many questions regarding its role in the physiology of normal gestation and its implications in the pathophysiology of hypertension during pregnancy. In this article, the authors first review the most interesting aspects of the chorioplacental renin-angiotensin system, dwelling on the tissue distribution of angiotensin II and its receptor subtypes in the placenta and fetal membranes of different species. The relationship between angiotensin II and other locally synthesized chorioplacental substances is also analysed and the therapeutic implications of phenomena observed in pregnancy-associated hypertension are discussed.

  8. Low-protein diet supplemented with ketoacids ameliorates proteinuria in 3/4 nephrectomised rats by directly inhibiting the intrarenal renin-angiotensin system.

    PubMed

    Zhang, Jia-Ying; Yin, Ying; Ni, Li; Long, Quan; You, Li; Zhang, Qian; Lin, Shan-Yan; Chen, Jing

    2016-11-01

    Low-protein diet plus ketoacids (LPD+KA) has been reported to decrease proteinuria in patients with chronic kidney diseases (CKD). However, the mechanisms have not been clarified. As over-activation of intrarenal renin-angiotensin system (RAS) has been shown to play a key role in the progression of CKD, the current study was performed to investigate the direct effects of LPD+KA on intrarenal RAS, independently of renal haemodynamics. In this study, 3/4 subtotal renal ablated rats were fed 18 % normal-protein diet (Nx-NPD), 6 % low-protein diet (Nx-LPD) or 5 % low-protein diet plus 1 % ketoacids (Nx-LPD+KA) for 12 weeks. Sham-operated rats fed NPD served as controls. The level of proteinuria and expression of renin, angiotensin II (AngII) and its type 1 receptors (AT1R) in the renal cortex were markedly higher in Nx-NPD group than in the sham group. LPD+KA significantly decreased the proteinuria and inhibited intrarenal RAS activation. To exclude renal haemodynamic impact on intrarenal RAS, the serum samples derived from the different groups were added to the culture medium of mesangial cells. It showed that the serum from Nx-NPD directly induced higher expression of AngII, AT1R, fibronectin and transforming growth factor-β1 in the mesangial cells than in the control group. Nx-LPD+KA serum significantly inhibited these abnormalities. Then, proteomics and biochemical detection suggested that the mechanisms underlying these beneficial effects of LPD+KA might be amelioration of the nutritional metabolic disorders and oxidative stress. In conclusion, LPD+KA could directly inhibit the intrarenal RAS activation, independently of renal haemodynamics, thus attenuating the proteinuria in CKD rats.

  9. Low birth weight in response to salt restriction during pregnancy is not due to alterations in uterine-placental blood flow or the placental and peripheral renin-angiotensin system.

    PubMed

    Leandro, Sandra Márcia; Furukawa, Luzia Naôko Shinohara; Shimizu, Maria Heloisa Massola; Casarini, Dulce Elena; Seguro, Antonio Carlos; Patriarca, Giuliana; Coelho, Michella Soares; Dolnikoff, Miriam Sterman; Heimann, Joel Claudio

    2008-09-03

    A number of studies conducted in humans and in animals have observed that events occurring early in life are associated with the development of diseases in adulthood. Salt overload and restriction during pregnancy and lactation are responsible for functional (hemodynamic and hormonal) and structural alterations in adult offspring. Our group observed that lower birth weight and insulin resistance in adulthood is associated with salt restriction during pregnancy. On the other hand, perinatal salt overload is associated with higher blood pressure and higher renal angiotensin II content in adult offspring. Therefore, we hypothesised that renin-angiotensin system (RAS) function is altered by changes in sodium intake during pregnancy. Such changes may influence fetoplacental blood flow and thereby fetal nutrient supply, with effects on growth in utero and, consequently, on birth weight. Female Wistar rats were fed low-salt (LS), normal-salt (NS), or high-salt (HS) diet, starting before conception and continuing until day 19 of pregnancy. Blood pressure, heart rate, fetuses and dams' body weight, placentae weight and litter size were measured on day 19 of pregnancy. Cardiac output, uterine and placental blood flow were also determined on day 19. Expressions of renin-angiotensin system components and of the TNF-alpha gene were evaluated in the placentae. Plasma renin activity (PRA) and plasma and tissue angiotensin-converting enzyme (ACE) activity, as well as plasma and placental levels of angiotensins I, II, and 1-7 were measured. Body weight and kidney mass were greater in HS than in NS and LS dams. Food intake did not differ among the maternal groups. Placental weight was lower in LS dams than in NS and HS dams. Fetal weight was lower in the LS group than in the NS and HS groups. The PRA was greater in LS dams than in NS and HS dams, although ACE activity (serum, cardiac, renal, and placental) was unaffected by the level of sodium intake. Placental levels of

  10. Effects of Olmesartan and Azilsartan on Albuminuria and the Intrarenal Renin-Angiotensin System

    PubMed Central

    Takami, Takeshi; Okada, Sadanori; Saito, Yoshihiko; Nishijima, Yoko; Kobori, Hiroyuki; Nishiyama, Akira

    2018-01-01

    Purpose Olmesartan and azilsartan decrease blood pressure more effectively than other angiotensin receptor blockers (ARBs). ARBs additionally decrease the urinary albumin to creatinine ratio (UACR), a urinary albumin marker, and urinary angiotensinogen (u-AGT), an intrarenal renin-angiotensin system activity marker. We examined the effects of these ARBs on blood pressure, UACR, and u-AGT in patients with uncontrolled hypertension. Methods Patients with uncontrolled hypertension treated with conventional ARBs, excluding olmesartan and azilsartan, for over 8 weeks were enrolled. We randomly switched patients from their prior ARBs to either olmesartan or azilsartan, and followed them for 24 weeks. Results Systolic blood pressure (SBP), diastolic blood pressure (DBP), and central systolic blood pressure (cSBP) significantly decreased at 24 weeks. UACR and u-AGT also decreased at 24 weeks in both groups. There were no significant differences in SBP, DBP, cSBP, UACR, or u-AGT between the groups. Therefore, we combined both groups for further analyses. After combining, SBP (160.5 ± 16.4 to 139.6 ± 15.6 mm Hg, P < 0.0001), DBP (88.4 ± 13.7 to 80.7 ± 13.2 mm Hg, P = 0.008), cSBP (167.4 ± 20.8 to 146.6 ± 24.6 mm Hg, P < 0.0001), UACR (13.8 to 9.0 mg/g Cre, P = 0.0096), and u-AGT (4.13 to 2.32 μg/g Cre, P = 0.0074) significantly decreased at 24 weeks. Patients with microalbuminuria (UACR ≥ 30 mg/g Cre) had significantly greater ΔUACR (−39.4 vs 0.27, P = 0.0024) and Δu-AGT (−11.9 vs −0.61, P = 0.0235) than patients without microalbuminuria. The changes in u-AGT were significantly associated with changes in UACR (r = 0.411, P = 0.046); however, there was no significant relationship between the changes in u-AGT and those in SBP or DBP. Conclusion Olmesartan and azilsartan decreased blood pressure, UACR, and u-AGT more than the other ARBs, and exerted depressor and renoprotective effects. PMID:29683146

  11. Effects of Olmesartan and Azilsartan on Albuminuria and the Intrarenal Renin-Angiotensin System.

    PubMed

    Takami, Takeshi; Okada, Sadanori; Saito, Yoshihiko; Nishijima, Yoko; Kobori, Hiroyuki; Nishiyama, Akira

    2018-01-01

    Olmesartan and azilsartan decrease blood pressure more effectively than other angiotensin receptor blockers (ARBs). ARBs additionally decrease the urinary albumin to creatinine ratio (UACR), a urinary albumin marker, and urinary angiotensinogen (u-AGT), an intrarenal renin-angiotensin system activity marker. We examined the effects of these ARBs on blood pressure, UACR, and u-AGT in patients with uncontrolled hypertension. Patients with uncontrolled hypertension treated with conventional ARBs, excluding olmesartan and azilsartan, for over 8 weeks were enrolled. We randomly switched patients from their prior ARBs to either olmesartan or azilsartan, and followed them for 24 weeks. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and central systolic blood pressure (cSBP) significantly decreased at 24 weeks. UACR and u-AGT also decreased at 24 weeks in both groups. There were no significant differences in SBP, DBP, cSBP, UACR, or u-AGT between the groups. Therefore, we combined both groups for further analyses. After combining, SBP (160.5 ± 16.4 to 139.6 ± 15.6 mm Hg, P < 0.0001), DBP (88.4 ± 13.7 to 80.7 ± 13.2 mm Hg, P = 0.008), cSBP (167.4 ± 20.8 to 146.6 ± 24.6 mm Hg, P < 0.0001), UACR (13.8 to 9.0 mg/g Cre, P = 0.0096), and u-AGT (4.13 to 2.32 μg/g Cre, P = 0.0074) significantly decreased at 24 weeks. Patients with microalbuminuria (UACR ≥ 30 mg/g Cre) had significantly greater ΔUACR (-39.4 vs 0.27, P = 0.0024) and Δu-AGT (-11.9 vs -0.61, P = 0.0235) than patients without microalbuminuria. The changes in u-AGT were significantly associated with changes in UACR (r = 0.411, P = 0.046); however, there was no significant relationship between the changes in u-AGT and those in SBP or DBP. Olmesartan and azilsartan decreased blood pressure, UACR, and u-AGT more than the other ARBs, and exerted depressor and renoprotective effects.

  12. Renin-angiotensin system blockers regulate the metabolism of isolated fat cells in vitro

    PubMed Central

    Caminhotto, R de O.; Sertié, R.A.L.; Andreotti, S.; Campaãa, A.B.; Lima, F.B.

    2016-01-01

    Due to the presence of the renin-angiotensin system (RAS) in tissues and its specific influence on white adipose tissue, fat cells are possible targets of pharmacological RAS blockers commonly used as anti-hypertensive drugs. In the present study, we investigated the effects of different RAS blockers on fat cell metabolism, more specifically on lipolysis, lipogenesis and oxidation of energy substrates. Isolated primary adipocytes were incubated with different RAS blockers (aliskiren, captopril and losartan) in vitro for 24 h and lipolysis, lipogenesis and glucose oxidation capacities were determined in dose-response assays to a β-adrenergic agonist and to insulin. Although no change was found in lipolytic capacity, the RAS blockers modulated lipogenesis and glucose oxidation in a different way. While captopril decreased insulin-stimulated lipogenesis (−19% of maximal response and −60% of insulin responsiveness) due to reduced glucose derived glycerol synthesis (−19% of maximal response and 64% of insulin responsiveness), aliskiren increased insulin-stimulated glucose oxidation (+49% of maximal response and +292% of insulin responsiveness) in fat cells. Our experiments demonstrate that RAS blockers can differentially induce metabolic alterations in adipocyte metabolism, characterized by a reduction in lipogenic responsiveness or an increase in glucose oxidation. The impact of RAS blockers on adipocyte metabolism may have beneficial implications on metabolic disorders during their therapeutic use in hypertensive patients. PMID:27487419

  13. Renin inhibition improves metabolic syndrome, and reduces angiotensin II levels and oxidative stress in visceral fat tissues in fructose-fed rats

    PubMed Central

    Chen, Jin-Shuen

    2017-01-01

    Renin–angiotensin system in visceral fat plays a crucial role in the pathogenesis of metabolic syndrome in fructose-fed rats. However, the effects of renin inhibition on visceral adiposity in metabolic syndrome are not fully investigated. We investigated the effects of renin inhibition on visceral adiposity in fructose-fed rats. Male Wistar–Kyoto rats were divided into 4 groups for 8-week experiments: Group Con (standard chow diet), Group Fru (high-fructose diet; 60% fructose), Group FruA (high-fructose diet and concurrent aliskiren treatment; 100 mg/kg body weight [BW] per day), and Group FruB (high-fructose diet and subsequent, i.e. 4 weeks after initiating high-fructose feeding, aliskiren treatment; 100 mg/kg BW per day). The high-fructose diet induced metabolic syndrome, increased visceral fat weights and adipocyte sizes, and augmented angiotensin II (Ang II), NADPH oxidase (NOX) isoforms expressions, oxidative stress, and dysregulated production of adipocytokines from visceral adipose tissues. Concurrent and subsequent aliskiren administration ameliorated metabolic syndrome, dysregulated adipocytokines, and visceral adiposity in high fructose-fed hypertensive rats, and was associated with reducing Ang II levels, NOX isoforms expressions and oxidative stress in visceral fat tissues. Therefore, this study demonstrates renin inhibition could improve metabolic syndrome, and reduce Ang II levels and oxidative stress in visceral fat tissue in fructose-fed rats, and suggests that visceral adipose Ang II plays a crucial role in the pathogenesis of metabolic syndrome in fructose-fed rats. PMID:28700686

  14. Vascular endothelial growth factor during hypoglycemia in patients with type 1 diabetes mellitus: relation to cognitive function and renin-angiotensin system activity.

    PubMed

    Kristensen, Peter Lommer; Høi-Hansen, Thomas; Boomsma, Frans; Pedersen-Bjergaard, Ulrik; Thorsteinsson, Birger

    2009-10-01

    In healthy adults, levels of vascular endothelial growth factor (VEGF) increase in response to mild hypoglycemia. VEGF is implicated in glucose transport over the blood-brain barrier, and the increase during hypoglycemia has been positively correlated with preservation of cognitive function during hypoglycemia. High activity in the renin-angiotensin system (RAS) is associated with an increased risk of severe hypoglycemia in patients with type 1 diabetes mellitus. Renin-angiotensin system possibly exerts its mechanism in hypoglycemia via VEGF. We studied the impact of mild hypoglycemia on plasma VEGF in patients with type 1 diabetes mellitus and high or low RAS activity and analyzed associations between VEGF levels and cognitive function during hypoglycemia. Eighteen patients with type 1 diabetes mellitus-9 with high and 9 with low RAS activity-underwent a single-blinded, placebo-controlled, crossover study with either mild hypoglycemia or stable glycemia. Cognitive function was assessed by the California Cognitive Assessment Package and the Alzheimer Quick Test. Nadir plasma glucose was 2.2 (0.3) mmol/L. During the control study, plasma VEGF did not change. During hypoglycemia, plasma VEGF increased from 39 to 58 pg/L in the high-RAS group (P = .004) and from 76 to 109 pg/L in the low-RAS group (P = .01), with no difference between RAS groups (P = .9). A weak association between reduced preservation of cognitive function during hypoglycemia and low VEGF response was observed. Plasma VEGF levels increase during mild, short-term hypoglycemia in patients with type 1 diabetes mellitus. The VEGF response is not dependent on RAS activity and only weakly associated with preservation of cognitive function during hypoglycemia. Thus, the previously described association between low RAS activity and better cognitive performance during hypoglycemia does not seem to be mediated by VEGF.

  15. Angiotensin receptor blockers: Focus on cardiac and renal injury.

    PubMed

    Arumugam, Somasundaram; Sreedhar, Remya; Thandavarayan, Rajarajan A; Karuppagounder, Vengadeshprabhu; Krishnamurthy, Prasanna; Suzuki, Kenji; Nakamura, Masahiko; Watanabe, Kenichi

    2016-04-01

    Angiotensin II, an important component of renin angiotensin system, is a potent vasopressor and its actions are mostly mediated via angiotensin II type 1 receptor (AT1R) and role of AT2R in counterbalancing the actions of AT1R stimulation are under extensive research. In addition to its physiological actions, angiotensin II plays important roles in the pathogenesis of atherosclerosis, hypertension, left ventricular hypertrophy, and heart failure. The effects of angiotensin II can be blocked by either suppressing its production by blocking angiotensin converting enzyme or by antagonizing its actions on AT1R using angiotensin II receptor blockers (ARBs). Instead of the extensive use of ARBs in the treatment of various cardiovascular diseases, proper selection of a particular ARB is crucial as the clinical condition of individual patient is different and also their economic status would play an essential role in medication compliance. Thus a critical review of the proven and promising actions of ARBs against various pathological conditions will be of great importance for the clinicians as well as for the researchers. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Excessive Catecholamine Secretion and the Activation of the Renin-Angiotensin-Aldosterone-System in Patients with Pheochromocytoma: A Single Center Experience and Overview of the Literature.

    PubMed

    Haase, Matthias; Dringenberg, Till; Allelein, Stephanie; Willenberg, Holger S; Schott, Matthias

    2017-10-01

    Catecholamines stimulate renin-secretion in the juxtaglomerular cells of the kidney and a number of case reports suggest an association between pheochromocytoma and activation of the RAAS. Therefore, it could be asked whether patients suffering from pheochromocytoma with high concentrations of circulating catecholamines present with oversecretion of renin and aldosterone. We identified twelve patients with excessive catecholamine secretion due to pheochromocytoma and compared them to a group of twelve patients with essential hypertension (EH) with regard to the activation of the renin-angiotensin-aldosterone-system (RAAS). The PubMed database was screened for studies that investigate the association between pheochromocytoma and activation of the RAAS. The plasma concentrations of metanephrines (19.9-fold) and normetanephrines (29.5-fold) were significantly higher in the pheochromocytoma group than in the EH group. Renin and aldosterone levels were 1.3-fold and 1.6-fold higher, respectively, as compared to the EH group, whereas the differences were not statistically significant. There was no significant correlation between plasma metanephrine or normetanephrine levels and the plasma renin concentration (r s =0.077, r s =0.049, respectively) in our patients. The data from our institution and from review of literature suggest that an association between pheochromocytoma in the context of high plasma catecholamine levels and activation of the RAAS is present. However, results have not been consistent. Thus, other causes of RAAS-activation should be considered also in the presence of pheochromocytoma or reinvestigation for aldosteronism should be offered to such patients after removal of the catecholamine-producing tumour. © Georg Thieme Verlag KG Stuttgart · New York.

  17. Expression and nutritional regulation of the (pro)renin receptor in rat visceral adipose tissue.

    PubMed

    Achard, V; Tassistro, V; Boullu-Ciocca, S; Grino, M

    2011-12-01

    Early life nutritional environment plays an important role in the development of visceral adipose tissue and interacts with nutritional regulations in adulthood, leading to metabolic dysregulations. We hypothesized that the renin-angiotensin system may play a role in the programming-induced development of visceral adipose tissue. We studied, using a model of programming of overweight and glucose intolerance, obtained by post-natal overfeeding with consecutive highfat diet, the status of plasma renin activity and mesenteric adipose renin-angiotensin system, including the recently identified (pro)renin receptor, in adult rats. Post-natal overfeeding or high-fat feeding lead to overweight with increased visceral fat mass and adipocytes surface. When both paradigms were associated, adipocytes surface showed a disproportionate increase. A strong immunoreactivity for (pro)renin receptor was found in stromal cells. Plasma renin activity increased in programmed animals whereas (pro)renin receptor expressing cells density was stimulated by high-fat diet. There was a positive, linear relationship between plasma renin activity and (pro)renin receptor expressing cells density and adipocytes surface. Our experiments demonstrate that association of post-natal overfeeding and high-fat diet increased plasma renin activity and adipose (pro)renin receptor expression. Such phenomenon could explain, at least in part, the associated disproportionate adipocyte hypertrophy and its accompanying increased glucose intolerance.

  18. Hypertension and depressed symptomatology: a cluster related to the activation of the renin-angiotensin-aldosterone system (RAAS). Findings from population based KORA F4 study.

    PubMed

    Häfner, S; Baumert, J; Emeny, R T; Lacruz, M E; Bidlingmaier, M; Reincke, M; Ladwig, K H

    2013-10-01

    Preliminary evidence points to aldosterone being not only prominently involved in the systemic regulation of the blood pressure but also to play a role in the pathophysiology of depression. We evaluated whether the combination of hypertension and depressed symptomatology is useful to screen for individuals suffering an activation of the renin-angiotensin-aldosterone system (RAAS). We conducted a cross-sectional analysis in participants from the Cooperative Health Research in the Region of Augsburg (KORA) F4 Study conducted between 2006 and 2008 in Southern Germany. A total of 1805 participants of the F4 study were included in the study. The association between aldosterone and renin levels and the different combinations of hypertension and depressed symptomatology was examined in four different models of multiple linear regression adjusted for age, sex, creatinine levels, potassium levels, body mass index (BMI) and behavioural risk factors. Individuals suffering both, depressed symptomatology and hypertension exhibited highly significantly increased aldosterone levels (p<0.001) and slightly, not significantly increased renin levels (p=0.08) compared to individuals with no depressed symptomatology and no hypertension. No significant activation of the RAAS was seen in only depressed or only hypertensive individuals. The finding of highly significantly increased aldosterone levels and increased renin levels in individuals suffering both, depressed symptomatology and hypertension provides further evidence for the involvement of the RAAS in the pathogenesis of depressed symptomatology. These findings have important implications for future research concerning the pathophysiological pathways that link depression and cardiovascular disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. [Changes of concentration of renin-angiotensin system components during vibration and their correction in experiment].

    PubMed

    Kapanadze, N A

    2007-04-01

    The aim of the research was investigation of the state of rennin-angiotensin system during the vibration in rats. 40 (180-200gr) pubertal male rats were studied. One hour vibro seance was conducted every day during two months. The 60 animals were divided into 3 groups (20 rats in each group); the third was control group. On 20th , 40th and 60th days of the experiment the decapitation of the animals was done under general narcosis. the Concentrations of rennin, angiotensin II and angiotensin converted ensyme in the blood plasma was determined using the method of radio immunoassay, The significant changes in concentrations of rennin-angiotensin system components have been manifested. The research showed the destruction in regulation of rennin-angiotensin system. It is concluded, that the vibration provokes the destruction of reciprocal feed-back of rennin-angiotensin system in the rats.

  20. The role of angiotensin II in the renal responses to somatic nerve stimulation in the rat.

    PubMed Central

    Handa, R K; Johns, E J

    1987-01-01

    1. Electrical stimulation of the brachial nerves at 3 Hz (15 V, 0.2 ms), in sodium pentobarbitone-anaesthetized rats whose renal arterial pressure was held constant, elicited a 26% increase in systemic blood pressure, a 15% rise in heart rate, an 11% reduction in renal blood flow, did not alter glomerular filtration rate and significantly reduced absolute and fractional sodium excretions and urine flow by 44, 49 and 31%, respectively. 2. In a separate group of rats, brachial nerve stimulation at 3 Hz increased plasma renin activity approximately 2-fold, while in animals in which the brachial nerves were not stimulated plasma renin activity did not change. 3. Following inhibition of the renin-angiotensin system with captopril or sar-1-ile-8-angiotensin II, brachial nerve stimulation resulted in similar increases in systemic blood pressure and heart rate as in the animals with an intact renin-angiotensin system but, in captopril-infused rats, did not change renal haemodynamics or urine flow while absolute and fractional sodium excretions were reduced by 20 and 25%, respectively. In sar-1-ile-8-angiotensin II-infused animals, similar nerve stimulation decreased renal blood flow by 12%, glomerular filtration rate by 7% and absolute and fractional sodium excretions and urine flow by 25, 18 and 18%, respectively. These decreases in sodium and water output were significantly smaller than those observed in animals with an intact renin-angiotensin system. 4. Stimulation of the brachial nerves increased post-ganglionic efferent renal nerve activity by 20% and the magnitude of this response was unaffected following inhibition of the renin-angiotensin system. 5. The results show that low rates of brachial nerve stimulation in the rat can increase efferent renal nerve activity and result in an antinatriuresis and antidiuresis which is dependent on the presence of angiotensin II, and appears to be due to an action of angiotensin II at the level of the kidney. PMID:3328780

  1. Combined treatment with dipeptidyl peptidase-4 inhibitor (sitagliptin) and angiotensin-II type 1 receptor blocker (losartan) suppresses progression in a non-diabetic rat model of steatohepatitis.

    PubMed

    Okura, Yasushi; Namisaki, Tadashi; Moriya, Kei; Kitade, Mitsuteru; Takeda, Kosuke; Kaji, Kosuke; Noguchi, Ryuichi; Nishimura, Norihisa; Seki, Kenichiro; Kawaratani, Hideto; Takaya, Hiroaki; Sato, Shinya; Sawada, Yasuhiko; Shimozato, Naotaka; Furukawa, Masanori; Nakanishi, Keisuke; Saikawa, Soichiro; Kubo, Takuya; Asada, Kiyoshi; Yoshiji, Hitoshi

    2017-11-01

    Dipeptidyl peptidase-4 (DPP4) inhibitors (DPP4-I) are oral glucose-lowering drugs for type 2 diabetes mellitus. Previously, we reported that DPP4-I (sitagliptin) exerted suppressive effects on experimental liver fibrosis in rats. Blockade of the renin-angiotensin system by angiotensin-II type 1 receptor blocker (losartan), commonly used in the management of hypertension, has been shown to significantly alleviate hepatic fibrogenesis and carcinogenesis. We aimed to elucidate the effects and possible mechanisms of a sitagliptin + losartan combination on the progression of non-diabetic non-alcoholic steatohepatitis (NASH) in a rat model. To induce NASH, Fischer 344 rats were fed a choline-deficient L-amino acid-defined diet for 12 weeks. We elucidated the chemopreventive effects of sitagliptin + losartan, especially in conjunction with hepatic stellate cell (HSC) activation, angiogenesis, and oxidative stress, all known to play important roles in the progression of NASH. Sitagliptin + losartan suppressed choline-deficient L-amino acid-defined diet-induced hepatic fibrogenesis and carcinogenesis. The combination treatment exerted a greater inhibitory effect than monotherapy. These inhibitory effects occurred almost concurrently with the suppression of HSC activation, neovascularization, and oxidative stress. In vitro studies showed that sitagliptin + losartan inhibited angiotensin II-induced proliferation and expression of transforming growth factor-β1 and α1 (I)-procollagen mRNA of activated HSC and in vitro angiogenesis, in parallel with the suppression observed in in vivo studies. The widely and safely used sitagliptin + losartan combination treatment in clinical practice could be an effective strategy against NASH. © 2016 The Japan Society of Hepatology.

  2. Angiotensin II Receptor Blockers

    MedlinePlus

    ... 2010. Mann JFE, et al. Renin-angiotensin system inhibition in the treatment of hypertension. http://www.uptodate. ... profit organization and proceeds from Web advertising help support our mission. Mayo Clinic does not endorse any ...

  3. Hypohydration and Heat Acclimation: Plasma Renin and Aldosterone during Exercise,

    DTIC Science & Technology

    1983-01-01

    vasoconstriction in heat-stressed men: role of McGraw-Hill, 1964, p. 419-423. renin - angiotensin system . J. AppL PhysioL: Respirat. Environ. 13. LINDQUIST, E...AL.A137 365 HYPOHYDRATION AND HEAT ACCLIMATION: PLASMA RENIN AND I/ ALDOSTERONE DURING EXERCISE(U) ARMY RESEARCH INST OF ENVIRONMENTAL MEDICINE...heat acclimation:plasma renin dependent not only on the mode of exercise but also the and aldosterone during exercise. J. Appl. Physiol.: Respirat

  4. New and old roles of the peripheral and brain renin-angiotensin-aldosterone system (RAAS): Focus on cardiovascular and neurological diseases.

    PubMed

    Mascolo, A; Sessa, M; Scavone, C; De Angelis, A; Vitale, C; Berrino, L; Rossi, F; Rosano, G; Capuano, A

    2017-01-15

    It is commonly accepted that the renin-angiotensin-aldosterone system (RAAS) is a cardiovascular circulating hormonal system that plays also an important role in the modulation of several patterns in the brain. The pathway of the RAAS can be divided into two classes: the traditional pathway of RAAS, also named classic RAAS, and the non-classic RAAS. Both pathways play a role in both cardiovascular and neurological diseases through a peripheral or central control. In this regard, renewed interest is growing in the last years for the consideration that the brain RAAS could represent a new important therapeutic target to regulate not only the blood pressure via central nervous control, but also neurological diseases. However, the development of compounds able to cross the blood-brain barrier and to act on the brain RAAS is challenging, especially if the metabolic stability and the half-life are taken into consideration. To date, two drug classes (aminopeptidase type A inhibitors and angiotensin IV analogues) acting on the brain RAAS are in development in pre-clinical or clinical stages. In this article, we will present an overview of the biological functions played by peripheral and brain classic and non-classic pathways of the RAAS in several clinical conditions, focusing on the brain RAAS and on the new pharmacological targets of the RAAS. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. Renin-angiotensin-aldosterone system activity in hyperthyroid cats with and without concurrent hypertension.

    PubMed

    Williams, T L; Elliott, J; Syme, H M

    2013-01-01

    Hypertension is present in some hyperthyroid cats at diagnosis or can develop after treatment for hyperthyroidism. Activation of the renin-angiotensin-aldosterone system (RAAS) could be involved in the pathogenesis of hypertension. Hyperthyroid cats that develop hypertension before or after treatment for hyperthyroidism will have greater RAAS activation than normotensive cats. Ninety-nine hyperthyroid cats. Retrospective case-control study. Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured in untreated hyperthyroid hypertensive cats (HT-Pre group), initially normotensive hyperthyroid cats that develop hypertension after treatment (HT-Post group), and hyperthyroid cats that are normotensive (NT group). Data are presented as median [25th, 75th percentile]. Baseline PRA was not significantly different among the 3 groups (HT-Pre group 1.50 [0.05, 2.37] ng/mL/h, HT-Post group 0.66 [0.17, 2.31] ng/mL/h, NT group 1.11 [0.57, 2.18] ng/mL/h; P = .44). PRA decreased significantly after treatment in the NT group (1.09 [0.53, 2.47] versus 0.22 [0.05, 0.76] ng/mL/h; P < .001) and the HT-Post group (0.71 [0.17, 2.33] versus 0.28 [0.07, 0.57] ng/mL/h; P = .006). Baseline PAC was not significantly different among the 3 groups (HT-Pre group 72.2 [40.0, 145.6] pg/mL, HT-Post group 69.7 [43.3, 142.6] pg/mL, NT group 109.0 [68.2, 184.6] pg/mL; P = .10). PAC decreased significantly after treatment in the NT group (114.4 [56.6, 204.1] versus 59.5 [32.4, 98.2] pg/mL; P < .001) but did not change significantly in the HT-Post group (61.2 [44.9, 124.0] versus 58.4 [42.0, 97.7] pg/mL; P = .59). RAAS activation occurs in hyperthyroid cats, but is not associated with the development of hypertension. PAC is not influenced by changes in PRA in hyperthyroid cats that develop hypertension after treatment, perhaps indicating RAAS dysfunction in these cats. Copyright © 2013 by the American College of Veterinary Internal Medicine.

  6. Human interventions to characterize novel relationships between the renin-angiotensin-aldosterone system and parathyroid hormone.

    PubMed

    Brown, Jenifer M; Williams, Jonathan S; Luther, James M; Garg, Rajesh; Garza, Amanda E; Pojoga, Luminita H; Ruan, Daniel T; Williams, Gordon H; Adler, Gail K; Vaidya, Anand

    2014-02-01

    Observational studies in primary hyperaldosteronism suggest a positive relationship between aldosterone and parathyroid hormone (PTH); however, interventions to better characterize the physiological relationship between the renin-angiotensin-aldosterone system (RAAS) and PTH are needed. We evaluated the effect of individual RAAS components on PTH using 4 interventions in humans without primary hyperaldosteronism. PTH was measured before and after study (1) low-dose angiotensin II (Ang II) infusion (1 ng/kg per minute) and captopril administration (25 mg×1); study (2) high-dose Ang II infusion (3 ng/kg per minute); study (3) blinded crossover randomization to aldosterone infusion (0.7 µg/kg per hour) and vehicle; and study (4) blinded randomization to spironolactone (50 mg/daily) or placebo for 6 weeks. Infusion of Ang II at 1 ng/kg per minute acutely increased aldosterone (+148%) and PTH (+10.3%), whereas Ang II at 3 ng/kg per minute induced larger incremental changes in aldosterone (+241%) and PTH (+36%; P<0.01). Captopril acutely decreased aldosterone (-12%) and PTH (-9.7%; P<0.01). In contrast, aldosterone infusion robustly raised serum aldosterone (+892%) without modifying PTH. However, spironolactone therapy during 6 weeks modestly lowered PTH when compared with placebo (P<0.05). In vitro studies revealed the presence of Ang II type I and mineralocorticoid receptor mRNA and protein expression in normal and adenomatous human parathyroid tissues. We observed novel pleiotropic relationships between RAAS components and the regulation of PTH in individuals without primary hyperaldosteronism: the acute modulation of PTH by the RAAS seems to be mediated by Ang II, whereas the long-term influence of the RAAS on PTH may involve aldosterone. Future studies to evaluate the impact of RAAS inhibitors in treating PTH-mediated disorders are warranted.

  7. Buffering of blood pressure variability by the renin-angiotensin system in the conscious dog

    PubMed Central

    Just, Armin; Kirchheim, Hartmut R; Ehmke, Heimo

    1998-01-01

    The renin-angiotensin system (RAS) participates in the compensation of major blood pressure disturbances such as haemorrhage and is involved in the tonic long-term (> 1 day) maintenance of mean arterial blood pressure (MABP). Since its contribution to the short-term (< 1 h) buffering of normal blood pressure variability is not known, this was investigated in resting conscious dogs.The regulatory efficiency and the response time of the RAS were studied by an acute step reduction of renal artery pressure to 70 mmHg for 1 h using a suprarenal aortic cuff. After a delay of at least 100 s, MABP rose exponentially by 22 ± 5 mmHg in normal dogs (n = 4), by 6 ± 3 mmHg after angiotensin converting enzyme (ACE) inhibition (n = 4), and by 25 ± 5 mmHg after ganglionic blockade (n = 4). MABP returned to control after release of the cuff with similar time courses. The time constants of the MABP responses were in the range of 20 min. Thus, possible feedback oscillations of the RAS would be expected around 0.0025 Hz (1/(4 × 100 s)); a buffering effect would be possible below this frequency.Blood pressure variability was investigated by spectral analysis of MABP from 3.75 h recordings in the frequency ranges of 0.002–0.003 Hz (feedback oscillations) and below 0.002 Hz (buffering effect).ACE inhibition (n = 7) decreased MABP by 11 ± 2 mmHg (P < 0.05), but in both frequency ranges integrated spectral density was not affected. ACE inhibition also failed to significantly change spectral density in either of the two frequency ranges under the following conditions: (1) during ganglionic blockade (n = 7), (2) during a low-sodium diet (except for a very slight elevation below 0.002 Hz) (n = 7), and (3) when the fall of MABP induced by ACE inhibition was compensated by an angiotensin II infusion (n = 7).It is concluded that in spite of its high regulatory efficiency with an adequate response time the RAS does not directly contribute to the short-term buffering of blood pressure

  8. A novel interaction between sympathetic overactivity and aberrant regulation of renin by miR-181a in BPH/2J genetically hypertensive mice.

    PubMed

    Jackson, Kristy L; Marques, Francine Z; Watson, Anna M D; Palma-Rigo, Kesia; Nguyen-Huu, Thu-Phuc; Morris, Brian J; Charchar, Fadi J; Davern, Pamela J; Head, Geoffrey A

    2013-10-01

    Genetically hypertensive mice (BPH/2J) are hypertensive because of an exaggerated contribution of the sympathetic nervous system to blood pressure. We hypothesize that an additional contribution to elevated blood pressure is via sympathetically mediated activation of the intrarenal renin-angiotensin system. Our aim was to determine the contribution of the renin-angiotensin system and sympathetic nervous system to hypertension in BPH/2J mice. BPH/2J and normotensive BPN/3J mice were preimplanted with radiotelemetry devices to measure blood pressure. Depressor responses to ganglion blocker pentolinium (5 mg/kg i.p.) in mice pretreated with the angiotensin-converting enzyme inhibitor enalaprilat (1.5 mg/kg i.p.) revealed a 2-fold greater sympathetic contribution to blood pressure in BPH/2J mice during the active and inactive period. However, the depressor response to enalaprilat was 4-fold greater in BPH/2J compared with BPN/3J mice, but only during the active period (P=0.01). This was associated with 1.6-fold higher renal renin messenger RNA (mRNA; P=0.02) and 0.8-fold lower abundance of micro-RNA-181a (P=0.03), identified previously as regulating human renin mRNA. Renin mRNA levels correlated positively with depressor responses to pentolinium (r=0.99; P=0.001), and BPH/2J mice had greater renal sympathetic innervation density as identified by tyrosine hydroxylase staining of cortical tubules. Although there is a major sympathetic contribution to hypertension in BPH/2J mice, the renin-angiotensin system also contributes, doing so to a greater extent during the active period and less during the inactive period. This is the opposite of the normal renin-angiotensin system circadian pattern. We suggest that renal hyperinnervation and enhanced sympathetically induced renin synthesis mediated by lower micro-RNA-181a contributes to hypertension in BPH/2J mice.

  9. Renin-Angiotensin-Aldosterone Genotype Influences Ventricular Remodeling in Infants with Single Ventricle

    PubMed Central

    Mital, Seema; Chung, Wendy K.; Colan, Steven D.; Sleeper, Lynn A.; Manlhiot, Cedric; Arrington, Cammon B.; Cnota, James F.; Graham, Eric M.; Mitchell, Michael E.; Goldmuntz, Elizabeth; Li, Jennifer S.; Levine, Jami C.; Lee, Teresa M.; Margossian, Renee; Hsu, Daphne T.

    2011-01-01

    Background We investigated the effect of polymorphisms in the renin-angiotensin-aldosterone system (RAAS) genes on ventricular remodeling, growth, renal function and response to enalapril in infants with single ventricle. Methods and Results Single ventricle infants enrolled in a randomized trial of enalapril were genotyped for polymorphisms in 5 genes: angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 receptor, aldosterone synthase, and chymase. Alleles associated with RAAS upregulation were classified as risk alleles. Ventricular mass, volume, somatic growth, renal function using estimated glomerular filtration rate (eGFR), and response to enalapril were compared between patients with ≥2 homozygous risk genotypes (high-risk), and those with <2 homozygous risk genotypes (low-risk) at two time points - before the superior-cavopulmonary-connection (pre-SCPC) and at age 14 months. Of 230 trial subjects, 154 were genotyped: 38 were high-risk, 116 were low-risk. Ventricular mass and volume were elevated in both groups pre-SCPC. Ventricular mass and volume decreased and eGFR increased after SCPC in the low-risk (p<0.05) but not the high-risk group. These responses were independent of enalapril treatment. Weight and height z-scores were lower at baseline and height remained lower in the high-risk group at 14 months especially in those receiving enalapril (p<0.05). Conclusions RAAS-upregulation genotypes were associated with failure of reverse remodeling after SCPC surgery, less improvement in renal function, and impaired somatic growth, the latter especially in patients receiving enalapril. RAAS genotype may identify a high-risk subgroup of single ventricle patients who fail to fully benefit from volume unloading surgery. Follow-up is warranted to assess longterm impact. Clinical Trial Registration Clinical Trials.gov Identifier NCT00113087 PMID:21576655

  10. Skeletal muscle myoblasts possess a stretch-responsive local angiotensin signalling system.

    PubMed

    Johnston, Adam P W; Baker, Jeff; De Lisio, Michael; Parise, Gianni

    2011-06-01

    A paucity of information exists regarding the presence of local renin-angiotensin systems (RASs) in skeletal muscle and associated muscle stem cells. Skeletal muscle and muscle stem cells were isolated from C57BL/6 mice and examined for the presence of a local RAS using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), Western blotting and liquid chromatography-mass spectrometry (LC-MS). Furthermore, the effect of mechanical stimulation on RAS member gene expression was analysed. Whole skeletal muscle, primary myoblasts and C2C12 derived myoblasts and myotubes differentially expressed members of the RAS including angiotensinogen, angiotensin-converting enzyme (ACE), angiotensin II (Ang II) type 1 (AT(1)) and type 2 (AT(2)). Renin transcripts were never detected, however, mRNA for the 'renin-like' enzyme cathepsin D was observed and Ang I and Ang II were identified in cell culture supernatants from proliferating myoblasts. AT(1) appeared to co-localise with polymerised actin filaments in proliferating myoblasts and was primarily found in the nucleus of terminally differentiated myotubes. Furthermore, mechanical stretch of proliferating and differentiating C2C12 cells differentially induced mRNA expression of angiotensinogen, AT(1) and AT(2). Proliferating and differentiated muscle stem cells possess a local stress-responsive RAS in vitro. The precise function of a local RAS in myoblasts remains unknown. However, evidence presented here suggests that Ang II may be a regulator of skeletal muscle myoblasts.

  11. Prolonged fasting increases the response of the renin-angiotensin-aldosterone system, but not vasopressin levels, in postweaned northern elephant seal pups

    NASA Technical Reports Server (NTRS)

    Ortiz, R. M.; Wade, C. E.; Ortiz, C. L.

    2000-01-01

    The 8- to 12-week postweaning fast exhibited by northern elephant seal pups (Mirounga angustirostris) occurs without any apparent deleterious effects on fluid and electrolyte homeostasis. However, during the fast the role of vasopressin (AVP) has been shown to be inconclusive and the involvement of the renin-angiotensin-aldosterone system (RAAS) has yet to be examined. To examine the effects of prolonged fasting on these osmoregulatory hormones, 15 postweaned pups were serially blood-sampled during the first 49 days of their fast. Fasting did not induce significant changes in ionic or osmotic concentrations, suggesting electrolyte homeostasis. Total proteins were reduced by day 21 of fasting and remained depressed, suggesting a lack of dehydration. Aldosterone and plasma renin activity exhibited a correlated, linear increase over the first 49 days of the fast, suggesting an active RAAS. Aldosterone exhibited a parabolic trend over the fast with a peak at day 35, suggesting a shift in the sensitivity of the kidney to aldosterone later in the fast. AVP was elevated at day 49 only, but concentrations were relatively low. RAAS was modified during the postweaning fast in pups and appears to play a significant role in the regulation of electrolyte and, most likely, water homeostasis during this period. Copyright 2000 Academic Press.

  12. Incidence of and risk factors for severe acute kidney injury in children with heart failure treated with renin-angiotensin system inhibitors.

    PubMed

    Terano, Chikako; Ishikura, Kenji; Miura, Masaru; Hamada, Riku; Harada, Ryoko; Sakai, Tomoyuki; Hamasaki, Yuko; Hataya, Hiroshi; Ando, Takashi; Honda, Masataka

    2016-05-01

    No large cohort study has yet determined the incidence of acute kidney injury (AKI) in children with heart failure treated with renin-angiotensin system (RAS) inhibitors. We thus retrospectively analyzed the incidence and risk factors for severe AKI (stages 2-3 according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines) at our institutions from 2008 to 2011. Among 312 children (162 boys; median age, 7.3 months), 59 cases of AKI occurred in 45 children. The incidence of AKI was 14.3 cases per 100 person-years overall (follow-up 413.6 person-years), or 27.3, 16.8, and 4.5 cases per 100 person-years in children aged <1, 1-3, and ≥4 years, respectively. Among them, 23 (39.0 %) children had metabolic acidosis and 14 (23.7 %) had hyperkalemia. Younger age, myocardial disease, cyanotic congenital heart disease, use of spironolactone, and cardiac surgery were independent risk factors for AKI. Furthermore, 37.3 % of children suffered dehydration during AKI. AKI incidence is relatively high in children, particularly younger children, with heart failure treated using RAS inhibitors. Careful monitoring of renal function and serum electrolytes is essential. Proper management of fluid balance after infection and cardiac surgery may reduce the risk of AKI. Temporary discontinuation in RAS inhibitors should be considered during dehydration or surgery. • Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are the two main classes of renin-angiotensin system (RAS) inhibitors used to treat hypertension, heart failure, and chronic kidney disease. Acute kidney injury (AKI) and hyperkalemia are potentially life-threatening complications associated with the use of ACEIs and ARBs. Some reports have suggested that dehydration and cardiac surgery are risk factors for AKI in children. However, no large-scale cohort studies have determined the incidence of AKI, its risk factors, and its outcomes in children with heart failure treated

  13. Renin-angiotensin-aldosterone system inhibitors improve membrane stability and change gene-expression profiles in dystrophic skeletal muscles.

    PubMed

    Chadwick, Jessica A; Bhattacharya, Sayak; Lowe, Jeovanna; Weisleder, Noah; Rafael-Fortney, Jill A

    2017-02-01

    Angiotensin-converting enzyme inhibitors (ACEi) and mineralocorticoid receptor (MR) antagonists are FDA-approved drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) and are used to treat heart failure. Combined treatment with the ACEi lisinopril and the nonspecific MR antagonist spironolactone surprisingly improves skeletal muscle, in addition to heart function and pathology in a Duchenne muscular dystrophy (DMD) mouse model. We recently demonstrated that MR is present in all limb and respiratory muscles and functions as a steroid hormone receptor in differentiated normal human skeletal muscle fibers. The goals of the current study were to begin to define cellular and molecular mechanisms mediating the skeletal muscle efficacy of RAAS inhibitor treatment. We also compared molecular changes resulting from RAAS inhibition with those resulting from the current DMD standard-of-care glucocorticoid treatment. Direct assessment of muscle membrane integrity demonstrated improvement in dystrophic mice treated with lisinopril and spironolactone compared with untreated mice. Short-term treatments of dystrophic mice with specific and nonspecific MR antagonists combined with lisinopril led to overlapping gene-expression profiles with beneficial regulation of metabolic processes and decreased inflammatory gene expression. Glucocorticoids increased apoptotic, proteolytic, and chemokine gene expression that was not changed by RAAS inhibitors in dystrophic mice. Microarray data identified potential genes that may underlie RAAS inhibitor treatment efficacy and the side effects of glucocorticoids. Direct effects of RAAS inhibitors on membrane integrity also contribute to improved pathology of dystrophic muscles. Together, these data will inform clinical development of MR antagonists for treating skeletal muscles in DMD. Copyright © 2017 the American Physiological Society.

  14. Endogenous ouabain and the renin-angiotensin-aldosterone system: distinct effects on Na handling and blood pressure in human hypertension.

    PubMed

    Manunta, Paolo; Hamlyn, John M; Simonini, Marco; Messaggio, Elisabetta; Lanzani, Chiara; Bracale, Maria; Argiolas, Giuseppe; Casamassima, Nunzia; Brioni, Elena; Glorioso, Nicola; Bianchi, Giuseppe

    2011-02-01

    To evaluate whether the renin-angiotensin-aldosterone system (RAAS) and endogenous ouabain system differently affect renal Na handling and blood pressure. Three hundred and one patients in whom we compared blood pressure, and renal Na tubular reabsorption in the basal condition and 2 h (T120) after saline infusion. Following multivariate-adjusted linear and quartiles analysis, baseline mean blood pressure (MBP) was significantly higher (113.7 ± 1.33 mmHg) in the fourth versus the first endogenous ouabain quartile (103.8 ± 1.04 mmHg) and the trend across the quartiles was highly significant (β = 0.23, P = 3.53e-04). In contrast, an inverse relationship was present in the renin activity (PRA) quartiles with MBP highest in the first (112.5 ± 1.26) and lowest in the fourth PRA quartile (107.6 ± 1.48, P = 0.039). Following an acute saline load, changes in MBP and the slope of the pressure-natriuresis relationship were inversely related across the PRA quartiles. The fractional excretion of sodium (FENa) showed a negative linear trend going from the first to the third endogenous ouabain quartiles (2.35 ± 0.17 and 1.90 ± 0.14%, P = 0.05). Patients in the fourth endogenous ouabain quartile (>323 pmol/l) showed increased FENa T120 (2.78 ± 0.18%, P < 0.01) and increased Na tubular rejection fraction (P = 0.007) after Na load. After the saline load, there was a biphasic relationship between plasma endogenous ouabain and FENa favoring Na retention at low endogenous ouabain and Na excretion at high endogenous ouabain levels. The RAAS and endogenous ouabain system are two independent and complementary systems having an inverse (RAAS) or a direct (endogenous ouabain system) relationship with hemodynamic parameters.

  15. ACE insertion/deletion polymorphism (rs1799752) modifies the renoprotective effect of renin-angiotensin system blockade in patients with IgA nephropathy.

    PubMed

    Teranishi, Junya; Yamamoto, Ryohei; Nagasawa, Yasuyuki; Shoji, Tatsuya; Iwatani, Hirotsugu; Okada, Noriyuki; Moriyama, Toshiki; Yamauchi, Atsushi; Tsubakihara, Yoshiharu; Imai, Enyu; Rakugi, Hiromi; Isaka, Yoshitaka

    2015-09-01

    Little is known about genetic predictors that modify the renoprotective effect of renin-angiotensin system (RAS) blockade in IgA nephropathy (IgAN). The present multicenter retrospective observational study examined effect modification between RAS blockade and three RAS-related gene polymorphisms in 237 IgAN patients, including ACE I/D (rs1799752), AT1R A1166C (rs5186) and AGT T704C (rs699). During 9.9 ± 4.2 years of observation, 63 patients progressed to a 50% increase in serum creatinine level. Only ACE I/D predicted the outcome (ACE DD vs ID/II, hazard ratio 1.86 (95% confidence interval 1.03, 3.33)) and modified the renoprotective effect of RAS blockade (p for interaction between ACE DD and RAS blockade = 0.087). RAS blockade suppressed progression in ACE DD patients but not in ID/II patients (ACE ID/II with RAS blockade as a reference; ID/II without RAS blockade 1.45 (0.72, 2.92); DD without RAS blockade 3.06 (1.39, 6.73); DD with RAS blockade 1.51 (0.54, 4.19)), which was ascertained in a model with the outcome of slope of estimated glomerular filtration rate (p = 0.045 for interaction). ACE I/D predicted the IgAN progression and the renoprotective effect of RAS blockade in IgAN patients whereas neither AT1R A1166C nor AGT T704C did. © The Author(s) 2014.

  16. Role of Renin-Angiotensin System and Oxidative Stress on Vascular Inflammation in Insulin Resistence Model

    PubMed Central

    Renna, N. F.; Lembo, C.; Diez, E.; Miatello, R. M.

    2013-01-01

    (1) This study aims to demonstrate the causal involvement of renin angiotensin system (RAS) and oxidative stress (OS) on vascular inflammation in an experimental model of metabolic syndrome (MS) achieved by fructose administration to spontaneously hypertensive rats (FFHR) during 12 weeks. (2) Chronic treatment with candesartan (C) (10 mg/kg per day for the last 6 weeks) or 4OH-Tempol (T) (10−3 mmol/L in drinking water for the last 6 weeks) reversed the increment in metabolic variables and systolic blood pressure. In addition, chronic C treatment reverted cardiovascular remodeling but not T. (3) Furthermore, chronic treatment with C was able to completely reverse the expression of NF-κB and VCAM-1, but T only reduced the expression. C reduced the expression of proatherogenic cytokines as CINC2, CINC3, VEGF, Leptin, TNF-alpha, and MCP-1 and also significantly reduced MIP-3, beta-NGF, and INF-gamma in vascular tissue in this experimental model. T was not able to substantially modify the expression of these cytokines. (4) The data suggest the involvement of RAS in the expression of inflammatory proteins at different vascular levels, allowing the creation of a microenvironment suitable for the creation, perpetuation, growth, and destabilization of vascular injury. PMID:23365721

  17. Role of Renin-Angiotensin system and oxidative stress on vascular inflammation in insulin resistence model.

    PubMed

    Renna, N F; Lembo, C; Diez, E; Miatello, R M

    2013-01-01

    (1) This study aims to demonstrate the causal involvement of renin angiotensin system (RAS) and oxidative stress (OS) on vascular inflammation in an experimental model of metabolic syndrome (MS) achieved by fructose administration to spontaneously hypertensive rats (FFHR) during 12 weeks. (2) Chronic treatment with candesartan (C) (10 mg/kg per day for the last 6 weeks) or 4OH-Tempol (T) (10(-3) mmol/L in drinking water for the last 6 weeks) reversed the increment in metabolic variables and systolic blood pressure. In addition, chronic C treatment reverted cardiovascular remodeling but not T. (3) Furthermore, chronic treatment with C was able to completely reverse the expression of NF-κB and VCAM-1, but T only reduced the expression. C reduced the expression of proatherogenic cytokines as CINC2, CINC3, VEGF, Leptin, TNF-alpha, and MCP-1 and also significantly reduced MIP-3, beta-NGF, and INF-gamma in vascular tissue in this experimental model. T was not able to substantially modify the expression of these cytokines. (4) The data suggest the involvement of RAS in the expression of inflammatory proteins at different vascular levels, allowing the creation of a microenvironment suitable for the creation, perpetuation, growth, and destabilization of vascular injury.

  18. Renin knockout rat: control of adrenal aldosterone and corticosterone synthesis in vitro and adrenal gene expression

    PubMed Central

    Gehrand, Ashley; Bruder, Eric D.; Hoffman, Matthew J.; Engeland, William C.; Moreno, Carol

    2014-01-01

    The classic renin-angiotensin system is partly responsible for controlling aldosterone secretion from the adrenal cortex via the peptide angiotensin II (ANG II). In addition, there is a local adrenocortical renin-angiotensin system that may be involved in the control of aldosterone synthesis in the zona glomerulosa (ZG). To characterize the long-term control of adrenal steroidogenesis, we utilized adrenal glands from renin knockout (KO) rats and compared steroidogenesis in vitro and steroidogenic enzyme expression to wild-type (WT) controls (Dahl S rat). Adrenal capsules (ZG; aldosterone production) and subcapsules [zona reticularis/fasciculata (ZFR); corticosterone production] were separately dispersed and studied in vitro. Plasma renin activity and ANG II concentrations were extremely low in the KO rats. Basal and cAMP-stimulated aldosterone production was significantly reduced in renin KO ZG cells, whereas corticosterone production was not different between WT and KO ZFR cells. As expected, adrenal renin mRNA expression was lower in the renin KO compared with the WT rat. Real-time PCR and immunohistochemical analysis showed a significant decrease in P450aldo (Cyp11b2) mRNA and protein expression in the ZG from the renin KO rat. The reduction in aldosterone synthesis in the ZG of the renin KO adrenal seems to be accounted for by a specific decrease in P450aldo and may be due to the absence of chronic stimulation of the ZG by circulating ANG II or to a reduction in locally released ANG II within the adrenal gland. PMID:25394830

  19. Aldosterone and renin in cardiac patients referred for catheterization.

    PubMed

    Erne, Paul; Müller, Andrea; Rossi, Gian Paolo; Seifert, Burkhardt; Stehlin, Fabrice; Redondo, Maurice; Bauer, Peter T; Kobza, Richard; Resink, Therese J; Radovanovic, Dragana

    2017-06-01

    Little is known regarding alterations of the renin-angiotensin system in patients referred for cardiac catheterization. Here, we measured plasma levels of active renin and aldosterone in patients referred for cardiac catheterization in order to determine the prevalence of elevated renin, aldosterone, and the aldosterone-renin ratio.A chemiluminescence assay was used to measure plasma aldosterone concentration (PAC) and active renin levels in 833 consecutive patients, after an overnight fasting and without any medication for least 12 hours. We evaluated associations of the hormonal elevations in relation to hypertension, atrial fibrillation (AF), hypertensive cardiomyopathy, coronary artery disease (CAD), valvular disease, impaired left ventricular ejection fraction (LVEF < 35%), and pulmonary hypertension (arterial pulmonary mean pressure >25 mm Hg).Hyperaldosteronism occurred in around one-third of all examined patients, without significant differences between patients with or without the named cardiac diseases. In a comparison between patients with or without any given cardiac disease condition, renin was significantly elevated in patients with either hypertension (36.4% vs 15.9%), CAD (33.9% vs 22.1%), or impaired LVEF (47.3% vs 24.8%). The angiotensin-renin ratio was elevated in AF patients and in patients with hypertensive cardiomyopathy. Patients with AF and coexisting hypertension had elevated renin more frequently than AF patients without coexisting hypertension (35.3% vs 16.5%; P  =  .005). Patients with persistent/permanent AF more frequently had elevated renin than patients with paroxysmal AF (34.1% vs 15.8%; P  =  .007).This prospective study of consecutive cardiac disease patients referred for cardiac catheterization has revealed distinct cardiac disease condition-associated differences in the frequencies of elevations in plasma renin, PAC, and the aldosterone-renin ratio.

  20. Effects of peripherally and centrally applied ghrelin on the oxidative stress induced by renin angiotensin system in a rat model of renovascular hypertension.

    PubMed

    Boshra, Vivian; Abbas, Amr M

    2017-07-26

    Renovascular hypertension (RVH) is a result of renal artery stenosis, which is commonly due to astherosclerosis. In this study, we aimed to clarify the central and peripheral effects of ghrelin on the renin-angiotensin system (RAS) in a rat model of RVH. RVH was induced in rats by partial subdiaphragmatic aortic constriction. Experiment A was designed to assess the central effect of ghrelin via the intracerebroventricular (ICV) injection of ghrelin (5 μg/kg) or losartan (0.01 mg/kg) in RVH rats. Experiment B was designed to assess the peripheral effect of ghrelin via the subcutaneous (SC) injection of ghrelin (150 μg/kg) or losartan (10 mg/kg) for 7 consecutive days. Mean arterial blood pressure (MAP), heart rate, plasma renin activity (PRA), and oxidative stress markers were measured in all rats. In addition, angiotensin II receptor type 1 (AT1R) concentration was measured in the hypothalamus of rats in Experiment B. RVH significantly increased brain AT1R, PRA, as well as the brain and plasma oxidative stress. Either SC or ICV ghrelin or losartan caused a significant decrease in MAP with no change in the heart rate. Central ghrelin or losartan caused a significant decrease in brain AT1R with significant alleviation of the brain oxidative stress. Central ghrelin caused a significant decrease in PRA, whereas central losartan caused a significant increase in PRA. SC ghrelin significantly decreased PRA and plasma oxidative stress, whereas SC losartan significantly increased PRA and decreased plasma oxidative stress. The hypotensive effect of ghrelin is mediated through the amelioration of oxidative stress, which is induced by RAS centrally and peripherally.

  1. Effects of exercise training on circulating and skeletal muscle renin-angiotensin system in chronic heart failure rats.

    PubMed

    Gomes-Santos, Igor Lucas; Fernandes, Tiago; Couto, Gisele Kruger; Ferreira-Filho, Julio César Ayres; Salemi, Vera Maria Cury; Fernandes, Fernanda Barrinha; Casarini, Dulce Elena; Brum, Patricia Chakur; Rossoni, Luciana Venturini; de Oliveira, Edilamar Menezes; Negrao, Carlos Eduardo

    2014-01-01

    Accumulated evidence shows that the ACE-AngII-AT1 axis of the renin-angiotensin system (RAS) is markedly activated in chronic heart failure (CHF). Recent studies provide information that Angiotensin (Ang)-(1-7), a metabolite of AngII, counteracts the effects of AngII. However, this balance between AngII and Ang-(1-7) is still little understood in CHF. We investigated the effects of exercise training on circulating and skeletal muscle RAS in the ischemic model of CHF. Male Wistar rats underwent left coronary artery ligation or a Sham operation. They were divided into four groups: 1) Sedentary Sham (Sham-S), 2) exercise-trained Sham (Sham-Ex), sedentary CHF (CHF-S), and exercise-trained CHF (CHF-Ex). Angiotensin concentrations and ACE and ACE2 activity in the circulation and skeletal muscle (soleus and plantaris) were quantified. Skeletal muscle ACE and ACE2 protein expression, and AT1, AT2, and Mas receptor gene expression were also evaluated. CHF reduced ACE2 serum activity. Exercise training restored ACE2 and reduced ACE activity in CHF. Exercise training reduced plasma AngII concentration in both Sham and CHF rats and increased the Ang-(1-7)/AngII ratio in CHF rats. CHF and exercise training did not change skeletal muscle ACE and ACE2 activity and protein expression. CHF increased AngII levels in both soleus and plantaris muscle, and exercise training normalized them. Exercise training increased Ang-(1-7) in the plantaris muscle of CHF rats. The AT1 receptor was only increased in the soleus muscle of CHF rats, and exercise training normalized it. Exercise training increased the expression of the Mas receptor in the soleus muscle of both exercise-trained groups, and normalized it in plantaris muscle. Exercise training causes a shift in RAS towards the Ang-(1-7)-Mas axis in skeletal muscle, which can be influenced by skeletal muscle metabolic characteristics. The changes in RAS circulation do not necessarily reflect the changes occurring in the RAS of skeletal

  2. Mechanisms responsible for postmenopausal hypertension in a rat model: Roles of the renal sympathetic nervous system and the renin-angiotensin system.

    PubMed

    Maranon, Rodrigo O; Reckelhoff, Jane F

    2016-02-01

    Hypertension in postmenopausal women is less well controlled than in age-matched men. The aging female SHR is a model of postmenopausal hypertension that is mediated in part by activation of the renin-angiotensin system (RAS) and by the renal sympathetic nervous system. In this study, the hypothesis was tested that renal denervation would lower the blood pressure in old female SHR and would attenuate the antihypertensive effects of AT1 receptor antagonism. Retired breeder female SHR were subjected to right uninephrectomy (UNX) and left renal denervation (RD) or UNX and sham, and 2 weeks later, baseline mean arterial pressure (MAP; radiotelemetry) was measured for 4 days, and then rats were treated with angiotensin (AT1) receptor antagonist, losartan (40 mg/kg/day po) for 6 days. Renal denervation reduced MAP in old females compared to sham (172 ± 6 vs. 193 ± 6 mm Hg; P < 0.05). Losartan reduced MAP in both sham and RD rats similarly (numerically and by percentage) (142 ± 10 vs. 161 ± 6 mm Hg; P < 0.05 vs. RD, P < 0.05 vs. baseline). However, female SHR rats remained significantly hypertensive despite both pharmacological intervention and RD. The data suggest that both the renal sympathetic nervous system and the RAS have independent effects to control the blood pressure in old female SHR. Since the denervated rats treated with losartan remained hypertensive, the data also suggest that other mechanisms than the RAS and renal sympathetic nervous system contribute to the hypertension in old female SHR. The data also suggest that multiple mechanisms may mediate the elevated blood pressure in postmenopausal women. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  3. Resistant Hypertension On Treatment (ResHypOT): sequential nephron blockade compared to dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol in the treatment of resistant arterial hypertension - study protocol for a randomized controlled trial.

    PubMed

    Cestário, Elizabeth do Espirito Santo; Fernandes, Letícia Aparecida Barufi; Giollo-Júnior, Luiz Tadeu; Uyemura, Jéssica Rodrigues Roma; Matarucco, Camila Suemi Sato; Landim, Manoel Idelfonso Paz; Cosenso-Martin, Luciana Neves; Tácito, Lúcia Helena Bonalume; Moreno, Heitor; Vilela-Martin, José Fernando; Yugar-Toledo, Juan Carlos

    2018-02-12

    Resistant hypertension is characterized when the blood pressure (BP) remains above the recommended goal after taking three antihypertensive drugs with synergistic actions at their maximum recommended tolerated doses, preferably including a diuretic. Identifying the contribution of intravascular volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether acting on the control of intravascular volume or sodium balance, or acting on the effects of the renin-angiotensin-aldosterone system (RAAS) on the kidney. This is a randomized, open-label, clinical trial is designed to compare sequential nephron blockade and its contribution to the intravascular volume component with dual blockade of the RAAS plus bisoprolol and the importance of serum renin in maintaining BP levels. The trial has two arms: sequential nephron blockade versus dual blockade of the RAAS (with an angiotensin converting enzyme (ACE) inhibitor plus a beta-blocker) both added-on to a thiazide diuretic, a calcium-channel blocker and an angiotensin receptor-1 blocker (ARB). Sequential nephron blockade consists in a progressive increase in sodium depletion using a thiazide diuretic, an aldosterone-receptor blocker, furosemide and, finally, amiloride. On the other hand, the dual blockade of the RAAS consists of the progressive addition of an ACE inhibitor until the maximum dose and then the administration of a beta-blocker until the maximum dose. The primary outcomes will be reductions in the systolic BP, diastolic BP, mean BP and pulse pressure (PP) after 20 weeks of treatment. The secondary outcomes will evaluate treatment safety and tolerability, biochemical changes, evaluation of renal function and recognition of hypotension (ambulatory BP monitoring (ABPM)). The sample size was calculated assuming an alpha error of 5% to reject the null hypothesis with a statistical power of 80% giving a total of 40 individuals per group. In recent years, the cost of

  4. Acute Total and Chronic Partial Sleep Deprivation: Effects on Neurobehavioral Functions, Waking EEG and Renin-Angiotensin System

    NASA Technical Reports Server (NTRS)

    Dijk, Derk-Jan

    1999-01-01

    protocol of the Quantitative EEG and Waking Neurobehavioral Function project. This will allow us to investigate two additional specific aims: 1) Test the hypothesis that chronic partial sleep deprivation during a 17 day bed rest experiment results in deterioration of neurobehavioral function during waking and increases in EEG power density in the theta frequencies, especially in frontal areas of the brain, as well as the nonREM- REM cycle dependent modulation of heart-rate variability. 2) Test the hypothesis that acute total sleep deprivation modifies the circadian rhythm of the renin-angiotensin system, changes the acute responsiveness of this system to posture beyond what a microgravity environment alone does and affects the nonREM-REM cycle dependent modulation of heart-rate variability.

  5. Low LBNP tolerance in men is associated with attenuated activation of the renin-angiotensin system

    NASA Technical Reports Server (NTRS)

    Greenleaf, J. E.; Petersen, T. W.; Gabrielsen, A.; Pump, B.; Bie, P.; Christensen, N. J.; Warberg, J.; Videbaek, R.; Simonson, S. R.; Norsk, P.

    2000-01-01

    Plasma vasoactive hormone concentrations [epinephrine (p(Epi)), norepinephrine (p(NE)), ANG II (p(ANG II)), vasopressin (p(VP)), endothelin-1 (p(ET-1))] and plasma renin activity (p(RA)) were measured periodically and compared during lower body negative pressure (LBNP) to test the hypothesis that responsiveness of the renin-angiotensin system, the latter being one of the most powerful vasoconstrictors in the body, is of major importance for LBNP tolerance. Healthy men on a controlled diet (2,822 cal/day, 2 mmol. kg(-1). day(-1) Na(+)) were exposed to 30 min of LBNP from -15 to -50 mmHg. LBNP was uneventful for seven men [25 +/- 2 yr, high-tolerance (HiTol) group], but eight men (26 +/- 3 yr) reached presyncope after 11 +/- 1 min [P < 0.001, low-tolerance (LoTol) group]. Mean arterial pressure (MAP) did not change measurably, but central venous pressure and left atrial diameter decreased similarly in both groups (5-6 mmHg, by approximately 30%, P < 0.05). Control (0 mmHg LBNP) hormone concentrations were similar between groups, however, p(RA) differed between them (LoTol 0.6 +/- 0.1, HiTol 1.2 +/- 0.1 ng ANG I. ml(-1). h(-1), P < 0.05). LBNP increased (P < 0. 05) p(RA) and p(ANG II), respectively, more in the HiTol group (9.9 +/- 2.2 ng ANG I. ml(-1). h(-1) and 58 +/- 12 pg/ml) than in LoTol subjects (4.3 +/- 0.9 ng ANG I. ml(-1). h(-1) and 28 +/- 6 pg/ml). In contrast, the increase in p(VP) was higher (P < 0.05) in the LoTol than in the HiTol group. The increases (P < 0.05) for p(NE) were nonsignificant between groups, and p(ET-1) remained unchanged. Thus there may be a causal relationship between attenuated activation of p(RA) and p(ANG II) and presyncope, with p(VP) being a possible cofactor. Measurement of resting p(RA) may be of predictive value for those with lower hypotensive tolerance.

  6. Major barriers against renin-angiotensin-aldosterone system blocker use in chronic kidney disease stages 3-5 in clinical practice: a safety concern?

    PubMed

    Yildirim, Tolga; Arici, Mustafa; Piskinpasa, Serhan; Aybal-Kutlugun, Aysun; Yilmaz, Rahmi; Altun, Bulent; Erdem, Yunus; Turgan, Cetin

    2012-01-01

    Renin-angiotensin-aldosterone system (RAAS) blockers are underutilized in patients with chronic kidney disease (CKD). We aimed to determine barriers against the use of RAAS blockers in these patients. Patients with stage 3-5 CKD referred to Hacettepe University Hospital Nephrology Unit during a 1 year period were evaluated for RAAS blocker use. Two hundred and seventy-nine patients (166 male, 113 female) were analyzed. The mean age of the patients was 56.7 ± 15.2 years, mean serum creatinine was 2.45 ± 1.44 mg/dL, and mean glomerular filtration rate was 33.3 ± 15.1 mL/min. The mean follow-up time was 22.0 ± 21.9 months and the clinical visit number was 4.0 ± 3.5. Angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers were used by 68.8% of all patients and 67.7% of diabetic patients at the time of analysis. In 82.1% of patients, RAAS blockers had either been used earlier or were being used. Hyperkalemia was the principal reason for both not starting and also discontinuing these drugs in patients with CKD. In 37.4% of patients, reasons for not starting RAAS blockers were unclear. This study showed that hyperkalemia is the major barrier against the use of RAAS blockers in patients with CKD. There was, however, a subset of patients who did not receive RAAS blockers even without clear contraindications.

  7. A Continuum of Renin-Independent Aldosteronism in Normotension

    PubMed Central

    Baudrand, Rene; Guarda, Francisco J.; Fardella, Carlos; Hundemer, Gregory; Brown, Jenifer; Williams, Gordon; Vaidya, Anand

    2017-01-01

    Primary aldosteronism (PA) is a severe form of autonomous aldosteronism. Milder forms of autonomous and renin-independent aldosteronism may be common, even in normotension. We characterized aldosterone secretion in 210 normotensives who had suppressed plasma renin activity (PRA<1.0 ng/mL/h), completed an oral sodium suppression test, received an infusion of angiotensin II (AngII), and had measurements of blood pressure (BP) and renal plasma flow (RPF). Continuous associations between urinary aldosterone excretion rate (AER), renin, and potassium handling were investigated. Severe autonomous aldosterone secretion that was consistent with confirmed PA was defined based on accepted criteria of an AER >12 mcg/24h with urinary sodium excretion >200 mmol/24h. Across the population, there were strong and significant associations between higher AER and higher urinary potassium excretion, higher AngII-stimulated aldosterone, and lower PRA, suggesting a continuum of renin-independent aldosteronism and mineralocorticoid receptor activity. Autonomous aldosterone secretion that fulfilled confirmatory criteria for PA was detected in 29 participants (14%). Normotensives with evidence suggestive of confirmed PA had higher 24h urinary AER (20.2±12.2 vs. 6.2±2.9 mcg/24h, P<0.001) as expected, but also higher AngII-stimulated aldosterone (12.4±8.6 vs. 6.6±4.3 ng/dL, P<0.001) and lower 24h urinary sodium-to-potassium excretion (2.69±0.65 vs. 3.69±1.50 mmol/mmol, P=0.001); however, there were no differences in age, aldosterone-to-renin ratio, BP, or RPF between the two groups. These findings indicate a continuum of renin-independent aldosteronism and mineralocorticoid receptor activity in normotension that ranges from subtle to overtly dysregulated and autonomous. Longitudinal studies are needed to determine whether this spectrum of autonomous aldosterone secretion contributes to hypertension and cardiovascular disease. PMID:28289182

  8. Involvement of the renin-angiotensin system in the progression of severe hand-foot-and-mouth disease.

    PubMed

    Zhang, Chao; Chen, Shuaiyin; Zhou, Guangyuan; Jin, Yuefei; Zhang, Rongguang; Yang, Haiyan; Xi, Yuanlin; Ren, Jingchao; Duan, Guangcai

    2018-01-01

    Hand-foot-and-mouth disease (HFMD) is generally considered as a mild exanthematous disease to infants and young children worldwide. HFMD cases are usually mild and self-limiting but for few cases leads to complicated severe clinical outcomes, and even death. Previous studies have indicated that serum Ang II levels in patients with H7N9 infection were related to the severity of infection. However, the mechanisms underlying the pathogenesis of severe HFMD remain unclear. This study was undertaken to clarify the role of the renin-angiotensin system (RAS) in the progression of severe HFMD. In the present study, 162 children including HFMD patients and healthy controls were recruited. The data was analyzed by time-series fashion. Concentrations of angiotensin II (Ang II) and noradrenaline (NA) in serum of patients were measured with ELISA. We established a mouse model for enterovirus 71 (EV71) infection and determined concentrations of Ang II, NA in tissue lysates at 3, 5 and 7 days post infection (dpi). The concentrations of Ang II and NA in serum of the HFMD patients with mild or severe symptoms were significantly higher than that in healthy controls. Additionally, the concentrations of Ang II and NA in serum of severe cases were significantly higher than those mild cases and the increased concentrations of Ang II and NA showed the same time trend during the progression of HFMD in the severe cases. Furthermore, the concentrations of Ang II and NA in target organs of EV71-infected mice including brains, skeletal muscle, and lungs were increased with the progression of EV71 infection in mice. Histopathological alterations were observed in the brains, skeletal muscle and lungs of EV71-infected mice. Our study suggested that activation of the RAS is implicated in the pathogenesis of severe HFMD.

  9. Endoplasmic reticulum stress increases brain MAPK signaling, inflammation and renin-angiotensin system activity and sympathetic nerve activity in heart failure

    PubMed Central

    Wei, Shun-Guang; Yu, Yang; Weiss, Robert M.

    2016-01-01

    We previously reported that endoplasmic reticulum (ER) stress is induced in the subfornical organ (SFO) and the hypothalamic paraventricular nucleus (PVN) of heart failure (HF) rats and is reduced by inhibition of mitogen-activated protein kinase (MAPK) signaling. The present study further examined the relationship between brain MAPK signaling, ER stress, and sympathetic excitation in HF. Sham-operated (Sham) and HF rats received a 4-wk intracerebroventricular (ICV) infusion of vehicle (Veh) or the ER stress inhibitor tauroursodeoxycholic acid (TUDCA, 10 μg/day). Lower mRNA levels of the ER stress biomarkers GRP78, ATF6, ATF4, and XBP-1s in the SFO and PVN of TUDCA-treated HF rats validated the efficacy of the TUDCA dose. The elevated levels of phosphorylated p44/42 and p38 MAPK in SFO and PVN of Veh-treated HF rats, compared with Sham rats, were significantly reduced in TUDCA-treated HF rats as shown by Western blot and immunofluorescent staining. Plasma norepinephrine levels were higher in Veh-treated HF rats, compared with Veh-treated Sham rats, and were significantly lower in the TUDCA-treated HF rats. TUDCA-treated HF rats also had lower mRNA levels for angiotensin converting enzyme, angiotensin II type 1 receptor, tumor necrosis factor-α, interleukin-1β, cyclooxygenase-2, and NF-κB p65, and a higher mRNA level of IκB-α, in the SFO and PVN than Veh-treated HF rats. These data suggest that ER stress contributes to the augmented sympathetic activity in HF by inducing MAPK signaling, thereby promoting inflammation and renin-angiotensin system activity in key cardiovascular regulatory regions of the brain. PMID:27496879

  10. Aldosterone and renin in cardiac patients referred for catheterization

    PubMed Central

    Erne, Paul; Müller, Andrea; Rossi, Gian Paolo; Seifert, Burkhardt; Stehlin, Fabrice; Redondo, Maurice; Bauer, Peter T.; Kobza, Richard; Resink, Therese J.; Radovanovic, Dragana

    2017-01-01

    Abstract Little is known regarding alterations of the renin-angiotensin system in patients referred for cardiac catheterization. Here, we measured plasma levels of active renin and aldosterone in patients referred for cardiac catheterization in order to determine the prevalence of elevated renin, aldosterone, and the aldosterone-renin ratio. A chemiluminescence assay was used to measure plasma aldosterone concentration (PAC) and active renin levels in 833 consecutive patients, after an overnight fasting and without any medication for least 12 hours. We evaluated associations of the hormonal elevations in relation to hypertension, atrial fibrillation (AF), hypertensive cardiomyopathy, coronary artery disease (CAD), valvular disease, impaired left ventricular ejection fraction (LVEF < 35%), and pulmonary hypertension (arterial pulmonary mean pressure >25 mm Hg). Hyperaldosteronism occurred in around one-third of all examined patients, without significant differences between patients with or without the named cardiac diseases. In a comparison between patients with or without any given cardiac disease condition, renin was significantly elevated in patients with either hypertension (36.4% vs 15.9%), CAD (33.9% vs 22.1%), or impaired LVEF (47.3% vs 24.8%). The angiotensin-renin ratio was elevated in AF patients and in patients with hypertensive cardiomyopathy. Patients with AF and coexisting hypertension had elevated renin more frequently than AF patients without coexisting hypertension (35.3% vs 16.5%; P  =  .005). Patients with persistent/permanent AF more frequently had elevated renin than patients with paroxysmal AF (34.1% vs 15.8%; P  =  .007). This prospective study of consecutive cardiac disease patients referred for cardiac catheterization has revealed distinct cardiac disease condition-associated differences in the frequencies of elevations in plasma renin, PAC, and the aldosterone-renin ratio. PMID:28640140

  11. Hypovolemia in syncope and orthostatic intolerance role of the renin-angiotensin system

    NASA Technical Reports Server (NTRS)

    Jacob, G.; Robertson, D.; Mosqueda-Garcia, R.; Ertl, A. C.; Robertson, R. M.; Biaggioni, I.

    1997-01-01

    PURPOSE: Orthostatic intolerance is the cause of significant disability in otherwise normal patients. Orthostatic tachycardia is usually the dominant hemodynamic abnormality, but symptoms may include dizziness, visual changes, discomfort in the head or neck, poor concentration, fatigue, palpitations, tremulousness, anxiety and, in some cases, syncope. It is the most common disorder of blood pressure regulation after essential hypertension. There is a predilection for younger rather than older adults and for women more than men. Its cause is unknown; partial sympathetic denervation or hypovolemia has been proposed. METHODS AND MATERIALS: We tested the hypothesis that reduced plasma renin activity, perhaps from defects in sympathetic innervation of the kidney, could underlie a hypovolemia, giving rise to these clinical symptoms. Sixteen patients (14 female, 2 male) ranging in age from 16 to 44 years were studied. Patients were enrolled in the study if they had orthostatic intolerance, together with a raised upright plasma norepinephrine (> or = 600 pg/mL). Patients underwent a battery of autonomic tests and biochemical determinations. RESULTS: There was a strong positive correlation between the blood volume and plasma renin activity (r = 0.84, P = 0.001). The tachycardic response to upright posture correlated with the severity of the hypovolemia. There was also a correlation between the plasma renin activity measured in these patients and their concomitant plasma aldosterone level. CONCLUSIONS: Hypovolemia occurs commonly in orthostatic intolerance. It is accompanied by an inappropriately low level of plasma renin activity. The degree of abnormality of blood volume correlates closely with the degree of abnormality in plasma renin activity. Taken together, these observations suggest that reduced plasma renin activity may be an important pathophysiologic component of the syndrome of orthostatic intolerance.

  12. Effect of dual blockade of the renin-angiotensin system on the progression of type 2 diabetic nephropathy: a randomized trial.

    PubMed

    Fernandez Juarez, Gema; Luño, José; Barrio, Vicente; de Vinuesa, Soledad García; Praga, Manuel; Goicoechea, Marian; Cachofeiro, Victoria; Nieto, Javier; Fernández Vega, Francisco; Tato, Ana; Gutierrez, Eduardo

    2013-02-01

    Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers has been shown to lessen the rate of decrease in glomerular filtration rate in patients with diabetic nephropathy. A multicenter open-label randomized controlled trial to compare the efficacy of combining the angiotensin-converting enzyme inhibitor lisinopril and the angiotensin II receptor blocker irbesartan with that of each drug in monotherapy (at both high and equipotent doses) in slowing the progression of type 2 diabetic nephropathy. 133 patients with type 2 diabetic nephropathy (age, 66 ± 8 years; 76% men) from 17 centers in Spain. Patients were randomly assigned (1:1:2) to lisinopril (n = 35), irbesartan (n = 28), or the combination of both (n = 70). The primary composite outcome was a >50% increase in baseline serum creatinine level, end-stage renal disease, or death. Baseline values for mean estimated glomerular filtration rate and blood pressure were 49 ± 21 mL/min/1.73 m(2) and 153 ± 19/81 ± 11 mm Hg. Mean geometric baseline proteinuria was protein excretion of 1.32 (95% CI, 1.10-1.62) g/g creatinine. After a median follow-up of 32 months, 21 (30%) patients in the combination group, 10 (29%) in the lisinopril group, and 8 (29%) in the irbesartan group reached the primary outcome. HRs were 0.96 (95% CI, 0.44-2.05; P = 0.9) and 0.90 (95% CI, 0.39-2.02; P = 0.8) for the combination versus the lisinopril and irbesartan groups, respectively. There were no significant differences in proteinuria reduction or blood pressure control between groups. The number of adverse events, including hyperkalemia, was similar in all 3 groups. The study was not double blind. The sample size studied was small. We were unable to show a benefit of the combination of lisinopril and irbesartan compared to either agent alone at optimal high doses on the risk of progression of type 2 diabetic nephropathy. Copyright © 2013 National Kidney Foundation, Inc

  13. The secretory phospholipase A2 group IIA: a missing link between inflammation, activated renin-angiotensin system, and atherogenesis?

    PubMed

    Divchev, Dimitar; Schieffer, Bernhard

    2008-01-01

    Inflammation, lipid peroxidation and chronic activation of the renin-angiotensin system (RAS) are hallmarks of the development of atherosclerosis. Recent studies have suggested the involvement of the pro-inflammatory secretory phospholipase A(2) (sPLA(2))-IIA in atherogenesis. This enzyme is produced by different cell types through stimulation by pro-inflammatory cytokines. It is detectable in the intima and in media smooth muscle cells, not only in atherosclerotic lesions but also in the very early stages of atherogenesis. sPLA(2)-IIA can hydrolyse the phospholipid monolayers of low density lipoproteins (LDL). Such modified LDL show increased affinity to proteoglycans. The modified particles have a greater tendency to aggregate and an enhanced ability to insert cholesterol into cells. This modification may promote macrophage LDL uptake leading to the formation of foam cells. Furthermore, sPLA(2)-IIA is not only a mediator for localized inflammation but may be also used as an independent predictor of adverse outcomes in patients with stable coronary artery disease or acute coronary syndromes. An interaction between activated RAS and phospholipases has been indicated by observations showing that inhibitors of sPLA(2) decrease angiotensin (Ang) II-induced macrophage lipid peroxidation. Meanwhile, various interactions between Ang II and oxLDL have been demonstrated suggesting a central role of sPLA(2)-IIA in these processes and offering a possible target for treatment. The role of sPLA(2)-IIA in the perpetuation of atherosclerosis appears to be the missing link between inflammation, activated RAS and lipid peroxidation.

  14. Erythropoietin during hypoglycaemia in type 1 diabetes: relation to basal renin-angiotensin system activity and cognitive function.

    PubMed

    Kristensen, Peter Lommer; Høi-Hansen, Thomas; Olsen, Niels Vidiendal; Pedersen-Bjergaard, Ulrik; Thorsteinsson, Birger

    2009-07-01

    Preservation of cognitive function during hypoglycaemic episodes is crucial for patients with insulin-treated diabetes to avoid severe hypoglycaemic events. Erythropoietin has neuroprotective potential. However, the role of erythropoietin during hypoglycaemia is unclear. The aim of the study was to explore plasma erythropoietin response to hypoglycaemia and the relationship to basal renin-angiotensin system (RAS) activity and cognitive function. We performed a single-blinded, controlled, cross-over study with induced hypoglycaemia or maintained glycaemic level. Nine patients with type 1 diabetes with high and nine with low activity in RAS were studied. Hypoglycaemia was induced using a standardized insulin-infusion. Overall, erythropoietin concentrations increased during hypoglycaemia. In the high RAS group erythropoietin rose 29% (p=0.032) whereas no significant response was observed in the low RAS group (7% increment; p=0.43). Independently, both hypoglycaemia and high RAS activity were associated with higher levels of erythropoietin (p=0.02 and 0.04, respectively). Low plasma erythropoietin at baseline was associated with poorer cognitive performance during hypoglycaemia. Hypoglycaemia triggers a rise in plasma erythropoietin in patients with type 1 diabetes. The response is influenced by basal RAS activity. Erythropoietin may carry a neuroprotective potential during hypoglycaemia.

  15. Advances in understanding the renin-angiotensin-aldosterone system (RAAS) in blood pressure control and recent pivotal trials of RAAS blockade in heart failure and diabetic nephropathy.

    PubMed

    Ghazi, Lama; Drawz, Paul

    2017-01-01

    The renin-angiotensin-aldosterone system (RAAS) plays a fundamental role in the physiology of blood pressure control and the pathophysiology of hypertension (HTN) with effects on vascular tone, sodium retention, oxidative stress, fibrosis, sympathetic tone, and inflammation. Fortunately, RAAS blocking agents have been available to treat HTN since the 1970s and newer medications are being developed. In this review, we will (1) examine new anti-hypertensive medications affecting the RAAS, (2) evaluate recent studies that help provide a better understanding of which patients may be more likely to benefit from RAAS blockade, and (3) review three recent pivotal randomized trials that involve newer RAAS blocking agents and inform clinical practice.

  16. A Novel Single-Strand RNAi Therapeutic Agent Targeting the (Pro)renin Receptor Suppresses Ocular Inflammation.

    PubMed

    Kanda, Atsuhiro; Ishizuka, Erdal Tan; Shibata, Atsushi; Matsumoto, Takahiro; Toyofuku, Hidekazu; Noda, Kousuke; Namba, Kenichi; Ishida, Susumu

    2017-06-16

    The receptor-associated prorenin system (RAPS) refers to the pathogenic mechanism whereby prorenin binding to the (pro)renin receptor [(P)RR] dually activates the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling. Here we revealed significant upregulation of prorenin and soluble (P)RR levels in the vitreous fluid of patients with uveitis compared to non-inflammatory controls, together with a positive correlation between these RAPS components and monocyte chemotactic protein-1 among several upregulated cytokines. Moreover, we developed a novel single-strand RNAi agent, proline-modified short hairpin RNA directed against human and mouse (P)RR [(P)RR-PshRNA], and we determined its safety and efficacy in vitro and in vivo. Application of (P)RR-PshRNA in mice caused significant amelioration of acute (uveitic) and chronic (diabetic) models of ocular inflammation with no apparent adverse effects. Our findings demonstrate the significant implication of RAPS in the pathogenesis of human uveitis and the potential usefulness of (P)RR-PshRNA as a therapeutic agent to reduce ocular inflammation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Plasma renin activity to plasma aldosterone concentration ratio correlates with night-time and pulse pressures in essential hypertensive patients treated with angiotensin-converting enzyme inhibitors/AT1 blockers.

    PubMed

    Spannella, Francesco; Giulietti, Federico; Balietti, Paolo; Borioni, Elisabetta; Lombardi, Francesca E; Ricci, Maddalena; Cocci, Guido; Landi, Laura; Sarzani, Riccardo

    2017-11-01

    Angiotensin-converting enzyme inhibitors (ACE-I) and AT1 blockers (ARB) are commonly used antihypertensive drugs, but several factors may affect their effectiveness. We evaluated the associations between ambulatory blood pressure (BP) monitoring (ABPM) parameters and plasma renin activity (PRA)-to-plasma aldosterone concentration (PAC) ratio (RAR) to test renin-angiotensin-aldosterone system inhibition in essential hypertensive patients treated with ACE-I or ARB for at least 12 months. We evaluated 194 consecutive patients referred to our Hypertension Centre. ABPM, PRA and PAC tests were performed without any changes in drug therapy. RAR, PRA and PAC tertiles were considered for the analyses. Mean age: 57.4 ± 12.0 years; male prevalence: 63.9%. No differences between RAR tertiles regarding the use of ACE-I or ARB (P = 0.385), as well as the other antihypertensive drug classes, were found. A reduction of all ABPM values considered (24-h BP, daytime BP and night-time BP and 24-h pulse pressure (PP), daytime PP and night-time PP) and a better BP control were observed at increasing RAR tertiles, with an odds ratio = 0.12 to be not controlled during night-time period for patients in the third tertile compared with patients in the first tertile (P < 0.001). This association remained significant even after adjusting for 24-h BP control. All the associations were also confirmed for PRA tertiles, but not for PAC tertiles. Higher RAR values indicate effective renin-angiotensin-aldosterone system inhibition and lower night-time and pulse pressures in real-life clinical practice. It could be a useful biomarker in the management of essential hypertensive patients treated with ACE-I or ARB.

  18. Association of Circulating Renin and Aldosterone With Osteocalcin and Bone Mineral Density in African Ancestry Families.

    PubMed

    Kuipers, Allison L; Kammerer, Candace M; Pratt, J Howard; Bunker, Clareann H; Wheeler, Victor W; Patrick, Alan L; Zmuda, Joseph M

    2016-05-01

    Hypertension is associated with accelerated bone loss, and the renin-angiotensin-aldosterone system is a key regulator of blood pressure. Although components of this system are expressed in human bone cells, studies in humans are sparse. Thus, we studied the association of circulating renin and aldosterone with osteocalcin and bone mineral density. We recruited 373 African ancestry family members without regard to health status from 6 probands (mean family size: 62 and relative pairs: 1687). Participants underwent a clinical examination, dual-energy x-ray absorptiometry, and quantitative computed tomographic scans. Renin activity, aldosterone concentration, and osteocalcin were measured in fasting blood samples. Aldosterone/renin ratio was calculated as aldosterone concentration/renin activity. All models were analyzed using pedigree-based variance components methods. Full models included adjustment for age, sex, body composition, comorbidities, lifestyle factors, blood pressure, and antihypertensive medication. Higher renin activity was significantly associated with lower total osteocalcin and with higher trabecular bone mineral density (both P<0.01). There were also significant genetic correlations between renin activity and whole-body bone mineral density. There were no associations with aldosterone concentration in any model and results for aldosterone/renin ratio were similar to those for renin activity. This is the first study to report a significant association between renin activity and a marker of bone turnover and bone mineral density in generally healthy individuals. Also, there is evidence for significant genetic pleiotropy and, thus, there may be a shared biological mechanism underlying both the renin-angiotensin-aldosterone system and bone metabolism that is independent of hypertension. © 2016 American Heart Association, Inc.

  19. ASSOCIATION OF CIRCULATING RENIN AND ALDOSTERONE WITH OSTEOCALCIN AND BONE MINERAL DENSITY IN AFRICAN ANCESTRY FAMILIES

    PubMed Central

    Kuipers, Allison L; Kammerer, Candace M; Howard Pratt, J; Bunker, Clareann H; Wheeler, Victor W; Patrick, Alan L; Zmuda, Joseph M

    2016-01-01

    Hypertension is associated with accelerated bone loss and the renin-angiotensin-aldosterone system is a key regulator of blood pressure. Although components of this system are expressed in human bone cells, studies in humans are sparse. Thus, we studied the association of circulating renin and aldosterone with osteocalcin and bone mineral density. We recruited 373 African ancestry family members without regard to health status from 6 probands (mean family size: 62; relative pairs: 1687). Participants underwent a clinical exam, dual energy x-ray absorptiometry, and quantitative computed tomography scans. Renin activity, aldosterone concentration, and osteocalcin were measured in fasting blood samples. Aldosterone to renin ratio was calculated as aldosterone concentration/renin activity. All models were analyzed using pedigree-based variance components methods. Full models included adjustment for age, sex, body composition, co-morbidities, lifestyle factors, blood pressure, and antihypertensive medication. Higher renin activity was significantly associated with lower total osteocalcin and with higher trabecular bone mineral density (both p<0.01). There were also significant genetic correlations between renin activity and whole body bone mineral density. There were no associations with aldosterone concentration in any model and results for aldosterone to renin ratio were similar to those for renin activity. This is the first study to report a significant association between renin activity and a marker of bone turnover and bone mineral density in generally healthy individuals. Also, there is evidence for significant genetic pleiotropy and, thus, there may be a shared biologic mechanism underlying both the renin-angiotensin-aldosterone system and bone metabolism that is independent of hypertension. PMID:26975710

  20. A fluorogenic near-infrared imaging agent for quantifying plasma and local tissue renin activity in vivo and ex vivo

    PubMed Central

    Zhang, Jun; Preda, Dorin V.; Vasquez, Kristine O.; Morin, Jeff; Delaney, Jeannine; Bao, Bagna; Percival, M. David; Xu, Daigen; McKay, Dan; Klimas, Michael; Bednar, Bohumil; Sur, Cyrille; Gao, David Z.; Madden, Karen; Yared, Wael; Rajopadhye, Milind

    2012-01-01

    The renin-angiotensin system (RAS) is well studied for its regulation of blood pressure and fluid homeostasis, as well as for increased activity associated with a variety of diseases and conditions, including cardiovascular disease, diabetes, and kidney disease. The enzyme renin cleaves angiotensinogen to form angiotensin I (ANG I), which is further cleaved by angiotensin-converting enzyme to produce ANG II. Although ANG II is the main effector molecule of the RAS, renin is the rate-limiting enzyme, thus playing a pivotal role in regulating RAS activity in hypertension and organ injury processes. Our objective was to develop a near-infrared fluorescent (NIRF) renin-imaging agent for noninvasive in vivo detection of renin activity as a measure of tissue RAS and in vitro plasma renin activity. We synthesized a renin-activatable agent, ReninSense 680 FAST (ReninSense), using a NIRF-quenched substrate derived from angiotensinogen that is cleaved specifically by purified mouse and rat renin enzymes to generate a fluorescent signal. This agent was assessed in vitro, in vivo, and ex vivo to detect and quantify increases in plasma and kidney renin activity in sodium-sensitive inbred C57BL/6 mice maintained on a low dietary sodium and diuretic regimen. Noninvasive in vivo fluorescence molecular tomographic imaging of the ReninSense signal in the kidney detected increased renin activity in the kidneys of hyperreninemic C57BL/6 mice. The agent also effectively detected renin activity in ex vivo kidneys, kidney tissue sections, and plasma samples. This approach could provide a new tool for assessing disorders linked to altered tissue and plasma renin activity and to monitor the efficacy of therapeutic treatments. PMID:22674025

  1. Central sympathoexcitatory actions of angiotensin II: role of type 1 angiotensin II receptors.

    PubMed

    DiBona, G F

    1999-01-01

    The role of the renin-angiotensin system in the control of sympathetic nerve activity is reviewed. Two general mechanisms are considered, one that involves the effects of circulating angiotensin II (AngII) on the central nervous system and a second that involves the central nervous system effects of AngII that originates within the central nervous system. The role of type 1 AngII receptors in discrete brain sites that mediate the sympathoexcitatory actions of AngII of either circulating or central nervous system origin is examined. AngII of circulating origin has ready access to the subfornical organ and area postrema, where it can bind to type 1 AngII receptors on neurons whose connections to the nucleus tractus solitarius and rostral ventrolateral medulla result in sympathoexcitation. In the rostral ventrolateral medulla, angiotensin peptides of central nervous system origin, likely involving angiotensin species in addition to AngII and binding to receptors other than type 1 or 2 AngII receptors, tonically support sympathetic nerve activity.

  2. High fat diet exacerbates neuroinflammation in an animal model of multiple sclerosis by activation of the Renin Angiotensin system.

    PubMed

    Timmermans, Silke; Bogie, Jeroen F J; Vanmierlo, Tim; Lütjohann, Dieter; Stinissen, Piet; Hellings, Niels; Hendriks, Jerome J A

    2014-03-01

    Epidemiological studies suggest a positive correlation between the incidence and severity of multiple sclerosis (MS) and the intake of fatty acids. It remains to be clarified whether high fat diet (HFD) indeed can exacerbate the disease pathology associated with MS and what the underlying mechanisms are. In this study, we determined the influence of HFD on the severity and pathology of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Mice were fed either normal diet (ND) or HFD and subsequently induced with EAE. Immunohistochemical staining and real-time PCR were used to determine immune cell infiltration and inflammatory mediators in the central nervous system (CNS). Our data show that HFD increases immune cell infiltration and inflammatory mediator production in the CNS and thereby aggravates EAE. Moreover, our data demonstrate that activation of the renin angiotensin system (RAS) is associated with the HFD-mediated effects on EAE severity. These results show that HFD exacerbates an autoreactive immune response within the CNS. This indicates that diets containing excess fat have a significant influence on neuroinflammation in EAE, which may have important implications for the treatment and prevention of neuroinflammatory disorders.

  3. Renin-angiotensin system inhibition ameliorates CCl4-induced liver fibrosis in mice through the inactivation of nuclear transcription factor kappa B.

    PubMed

    Saber, Sameh; Mahmoud, Amr A A; Helal, Noha S; El-Ahwany, Eman; Abdelghany, Rasha H

    2018-06-01

    Therapeutic interventions for liver fibrosis are still limited due to the complicated molecular pathogenesis. Renin-angiotensin system (RAS) seems to contribute to the development of hepatic fibrosis. Therefore, we aimed to examine the effect of RAS inhibition on CCl 4 -induced liver fibrosis. Mice were treated with silymarin (30 mg·kg -1 ), perindopril (1 mg·kg -1 ), fosinopril (2 mg·kg -1 ), or losartan (10 mg·kg -1 ). The administration of RAS inhibitors improved liver histology and decreased protein expression of alpha smooth muscle actin (α-SMA) and hepatic content of hydroxyproline. These effects found to be mediated via inactivation of nuclear transcription factor kappa B (NFκB) pathway by the inhibition of NFκB p65 phosphorylation at the Ser536 residue and phosphorylation-induced degradation of nuclear factor kappa-B inhibitor alpha (NFκBia) subsequently inhibited NFκB-induced TNF-α and TGF-β1, leading to lower levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and vascular endothelial growth factor (VEGF). We concluded that the tissue affinity of the angiotensin converting enzyme inhibitors (ACEIs) has no impact on its antifibrotic activity and that interfering the RAS either through the inhibition of ACE or the blockade of AT1R has the same therapeutic benefit. These results suggest RAS inhibitors as promising candidates for further clinical trials in the management of hepatic fibrosis.

  4. Inhibition of the renin-angiotensin system improves physiological outcomes in mice with mild or severe cancer cachexia.

    PubMed

    Murphy, Kate T; Chee, Annabel; Trieu, Jennifer; Naim, Timur; Lynch, Gordon S

    2013-09-01

    Cancer cachexia describes the progressive skeletal muscle wasting and weakness associated with many cancers. Cachexia reduces mobility and quality of life and accounts for 20-30% of all cancer-related deaths. Activation of the renin-angiotensin system causes skeletal muscle wasting and weakness. We tested the hypothesis that treatment with the angiotensin converting enzyme (ACE) inhibitor, perindopril, would enhance whole body and skeletal muscle function in cachectic mice bearing Colon-26 (C-26) tumors. CD2F1 mice received a subcutaneous injection of phosphate buffered saline or C-26 tumor cells inducing either a mild or severe cachexia. The following day, one cohort of C-26 mice began receiving perindopril in their drinking water (4 mg kg(-1) day(-1) ) for 21 days. In mild and severe cachexia, perindopril increased measures of whole body function (grip strength and rotarod) and reduced fatigue in isolated contracting diaphragm muscle strips (p < 0.05). In severely cachectic mice, perindopril reduced tumor growth, improved locomotor activity and reduced fatigue of tibialis anterior muscles in situ (p < 0.05), which was associated with increased oxidative enzyme capacity (succinate deyhydrogenase, p < 0.05). Perindopril attenuated the increase in MuRF-1 and IL-6 mRNA expression and enhanced Akt phosphorylation in severely cachectic mice but neither body nor muscle mass was increased. These findings support the therapeutic potential of ACE inhibition for enhancing whole body function and reducing fatigue of respiratory muscles in early and late stage cancer cachexia and should be confirmed in future clinical trials. Since ACE inhibition alone did not enhance body or muscle mass, co-treatment with an anabolic agent may be required to address these aspects of cancer cachexia. Copyright © 2013 UICC.

  5. Gonadectomy prevents the increase in blood pressure and glomerular injury in angiotensin-converting enzyme 2 knockout diabetic male mice. Effects on renin-angiotensin system.

    PubMed

    Clotet, Sergi; Soler, María José; Rebull, Marta; Gimeno, Javier; Gurley, Susan B; Pascual, Julio; Riera, Marta

    2016-09-01

    Angiotensin-converting enzyme 2 (ACE2) deletion worsens kidney injury, and its amplification ameliorates diabetic nephropathy. Male sex increases the incidence, prevalence, and progression of chronic kidney disease in our environment. Here, we studied the effect of ACE2 deficiency and gonadectomy (GDX) on diabetic nephropathy and its relationship with fibrosis, protein kinase B (Akt) activation, and the expression of several components of the renin-angiotensin system (RAS).Mice were injected with streptozotocin to induce diabetes and followed for 19 weeks. Physiological and renal parameters were studied in wild-type and ACE2 knockout (ACE2KO) male mice with and without GDX. Diabetic ACE2KO showed increased blood pressure (BP), glomerular injury, and renal fibrosis compared with diabetic wild-type. Gonadectomized diabetic ACE2KO presented a decrease in BP. In the absence of ACE2, GDX attenuated albuminuria and renal lesions, such as mesangial matrix expansion and podocyte loss. Both, α-smooth muscle actin accumulation and collagen deposition were significantly decreased in renal cortex of gonadectomized diabetic ACE2KO but not diabetic wild-type mice. GDX also reduced circulating ACE activity in ACE2KO mice. Loss of ACE2 modified the effect of GDX on cortical gene expression of RAS in diabetic mice. Akt phosphorylation in renal cortex was increased by diabetes and loss of ACE2 and decreased by GDX in control and diabetic ACE2KO but not in wild-type mice. Our results suggest that GDX may exert a protective effect within the kidney under pathological conditions of diabetes and ACE2 deficiency. This renoprotection may be ascribed to different mechanisms such as decrease in BP, modulation of RAS, and downregulation of Akt-related pathways.

  6. Activation of cardiac renin-angiotensin system and plasminogen activator inhibitor-1 gene expressions in oral contraceptive-induced cardiometabolic disorder.

    PubMed

    Olatunji, Lawrence A; Usman, Taofeek O; Seok, Young-Mi; Kim, In-Kyeom

    2017-02-01

    Clinical studies have shown that combined oral contraceptive (COC) use is associated with cardiometabolic disturbances. Elevated renin-angiotensin system (RAS) and plasminogen activator inhibitor-1 (PAI-1) have also been implicated in the development of cardiometabolic events. To determine the effect of COC treatment on cardiac RAS and PAI-1 gene expressions, and whether the effect is circulating aldosterone or corticosterone dependent. Female rats were treated (p.o.) with olive oil (vehicle) or COC (1.0 µg ethinylestradiol and 10.0 µg norgestrel) daily for six weeks. COC treatment led to increases in blood pressure, HOMA-IR, Ace1 mRNA, Atr1 mRNA, Pai1 mRNA, cardiac PAI-1, plasma PAI-1, C-reactive protein, uric acid, insulin and corticosterone. COC treatment also led to dyslipidemia, decreased glucose tolerance and plasma 17β-estradiol. These results demonstrates that hypertension and insulin resistance induced by COC is associated with increased cardiac RAS and PAI-1 gene expression, which is likely to be through corticosterone-dependent but not aldosterone-dependent mechanism.

  7. Hemodynamic effects of renin-angiotensin-aldosterone inhibitor and β-blocker combination therapy vs. β-blocker monotherapy for portal hypertension in cirrhosis: A meta-analysis

    PubMed Central

    Wang, Jianrong; Lu, Wenxia; Li, Jingjing; Zhang, Rong; Zhou, Yuqing; Yin, Qin; Zheng, Yuanyuan; Wang, Fan; Xia, Yujing; Chen, Kan; Li, Sainan; Liu, Tong; Lu, Jie; Zhou, Yingqun; Guo, Chuan-Yong

    2017-01-01

    β-blockers are commonly used for the treatment of acute variceal bleeding in cirrhosis. Renin-angiotensin-aldosterone antagonists (angiotensin I-converting enzyme inhibitors, angiotensin receptor blockers and aldosterone antagonists) are potential therapies for portal hypertension. Several studies have compared the renin-angiotensin-aldosterone system (RAAS) inhibitor and β-blocker combination therapy vs. β-blocker monotherapy, with inconsistent results. The aim of the present study was to assess the efficacy of the RAAS inhibitor and β-blocker combination therapy vs. β-blocker monotherapy for hepatic vein pressure gradient (HVPG) reduction in cirrhosis. Studies were obtained using PubMed, Embase, Medline and Cochrane library databases up to July 2015, and the weighted mean difference (WMD) in HVPG reduction was used as a measure of treatment efficacy. In total, three studies (91 patients) were included. When compared to the β-blocker monotherapy, the RAAS inhibitor and β-blocker combination therapy resulted in a significant HVPG reduction [WMD 1.70; 95% confidence interval (CI): 0.52–2.88]. However, there was no significant difference in the heart rate reduction between the monotherapy and combination therapy groups (WMD −0.11; 95% CI: −3.51–3.29). In addition, no significant difference in the hemodynamic response was observed between the two groups (WMD 1.46; 95% CI: 0.93–2.30). In conclusion, the RAAS inhibitor and β-blocker combination therapy reduces portal hypertension significantly and to a greater extent than β-blocker monotherapy. Both therapies reduced the heart rate to similar levels; however, the RAAS inhibitor and β-blocker combination therapy reduced the mean arterial pressure to a greater extent. Due to the limited number of studies included, the data available do not allow a satisfactory comparison of adverse events. Moreover, further larger-scale trials are required in order to strengthen the results of the present study. PMID

  8. Advances in understanding the renin-angiotensin-aldosterone system (RAAS) in blood pressure control and recent pivotal trials of RAAS blockade in heart failure and diabetic nephropathy

    PubMed Central

    Ghazi, Lama; Drawz, Paul

    2017-01-01

    The renin-angiotensin-aldosterone system (RAAS) plays a fundamental role in the physiology of blood pressure control and the pathophysiology of hypertension (HTN) with effects on vascular tone, sodium retention, oxidative stress, fibrosis, sympathetic tone, and inflammation. Fortunately, RAAS blocking agents have been available to treat HTN since the 1970s and newer medications are being developed. In this review, we will (1) examine new anti-hypertensive medications affecting the RAAS, (2) evaluate recent studies that help provide a better understanding of which patients may be more likely to benefit from RAAS blockade, and (3) review three recent pivotal randomized trials that involve newer RAAS blocking agents and inform clinical practice. PMID:28413612

  9. The Divergent Cardiovascular Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Blockers in Adult Patients With Type 2 Diabetes Mellitus.

    PubMed

    Strauss, Martin H; Hall, Alistair S

    2018-04-01

    The renin angiotensin aldosterone system (RAAS) plays a central role in the pathophysiology of hypertension and vascular disease. Angiotensin-converting enzyme inhibitors (ACEi's) suppress angiotensin II (ANG II) concentrations, whereas angiotensin II type 1 (AT 1 ) receptor blockers (ARBs) block the binding of ANG II to AT 1 receptors. ACEi's and ARBs are both effective antihypertensive agents and produce similar risk reductions for stroke, a blood pressure-dependent phenomenon. ACEi's also reduce the risk for myocardial infarction (MI) and all-cause mortality in high-risk hypertensive patients as well as in people with diabetes, vascular disease and congestive heart failure. ARBs, in contrast, do not reduce the risk for MI or death in randomized clinical trials when assessed vs. placebo. Systematic reviews of ARBs that include meta-analyses or metaregression analyses confirm that ARBs lack the cardiovascular-protective effects of ACEi's. Practice guidelines, especially those for high-risk patients, such as those with diabetes mellitus, should reflect the evidence that ACEi's and ARBs have divergent cardiovascular effects: ACEi's reduce mortality, whereas ARBs do not. ACEi's should remain the preferred RAAS inhibitor for patients at high risk. Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.

  10. Exacerbation of acute kidney injury by bone marrow stromal cells from rats with persistent renin-angiotensin system activation.

    PubMed

    Kankuri, Esko; Mervaala, Elina E; Storvik, Markus; Ahola, Aija M J; Levijoki, Jouko; Müller, Dominik N; Finckenberg, Piet; Mervaala, Eero M

    2015-06-01

    Hypertension and persistent activation of the renin-angiotensin system (RAS) are predisposing factors for the development of acute kidney injury (AKI). Although bone-marrow-derived stromal cells (BMSCs) have shown therapeutic promise in treatment of AKI, the impact of pathological RAS on BMSC functionality has remained unresolved. RAS and its local components in the bone marrow are involved in several key steps of cell maturation processes. This may also render the BMSC population vulnerable to alterations even in the early phases of RAS pathology. We isolated transgenic BMSCs (TG-BMSCs) from young end-organ-disease-free rats with increased RAS activation [human angiotensinogen/renin double transgenic rats (dTGRs)] that eventually develop hypertension and die of end-organ damage and kidney failure at 8 weeks of age. Control cells (SD-BMSCs) were isolated from wild-type Sprague-Dawley rats. Cell phenotype, mitochondrial reactive oxygen species (ROS) production and respiration were assessed, and gene expression profiling was carried out using microarrays. Cells' therapeutic efficacy was evaluated in a rat model of acute ischaemia/reperfusion-induced AKI. Serum urea and creatinine were measured at 24 h and 48 h. Acute tubular damage was scored and immunohistochemistry was used for evaluation for markers of inflammation [monocyte chemoattractant protein (MCP-1), ED-1], and kidney injury [kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL)]. TG-BMSCs showed distinct mitochondrial morphology, decreased cell respiration and increased production of ROS. Gene expression profiling revealed a pronounced pro-inflammatory phenotype. In contrast with the therapeutic effect of SD-BMSCs, administration of TG-BMSCs in the AKI model resulted in exacerbation of kidney injury and high mortality. Our results demonstrate that early persistent RAS activation can dramatically compromise therapeutic potential of BMSCs by causing a shift into a pro

  11. The influence of a tilt training programme on the renin-angiotensin-aldosterone system activity in patients with vasovagal syncope.

    PubMed

    Gajek, Jacek; Zyśko, Dorota; Krzemińska, Sylwia; Mazurek, Walentyna

    2009-08-01

    We assessed the influence of short-term and long-term tilt training on the activity of the renin-angiotensin-aldosterone system (RAAS) in vasovagal patients. Thirty-nine patients (28 F, 11 M) aged 39.7 +/- 11.2 years with a history of vasovagal syncope and a positive head-up tilt test (HUT) were studied. Blood samples for plasma renin activity (PRA) and aldosterone (ALDO) concentration were drawn at the baseline, immediately after HUT and 10 min after HUT, during the diagnostic, the negative short-term (2-5 days) follow-up HUT and long-term (1-3 months) follow-up HUT. Tilt training was started after diagnostic HUT. In diagnostic HUT, PRA increased significantly immediately after HUT comparing to the baseline, during recovery the values did not change. ALDO concentration increased after HUT comparing to baseline and further increased during recovery. After short-term tilt training, PRA and ALDO concentrations did not significantly change compared to their corresponding values in diagnostic HUT. After long-term tilt training, PRA did not significantly change compared to the values in the diagnostic and short-term follow-up HUT. ALDO concentration also did not change significantly at the baseline and immediately after HUT, and 10 min after HUT ALDO concentration was significantly lower than after diagnostic HUT. Tilt training changes the response of RAAS to the prolonged orthostasis in vasovagal patients. The coupling between PRA and ALDO after diagnostic HUT has been found to be altered and the physiological relationship was restored after long-term tilt training. The beneficial effect of tilt training depends partially on changed RAAS activation.

  12. Role of renin-angiotensin-aldosterone system gene polymorphisms and hypertension-induced end-stage renal disease in autosomal dominant polycystic kidney disease.

    PubMed

    Ramanathan, Gnanasambandan; Elumalai, Ramprasad; Periyasamy, Soundararajan; Lakkakula, Bhaskar

    2014-07-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disease of the kidneys and is marked by progressive cyst growth and decline in kidney function, resulting in end-stage renal disease (ESRD). Hypertension is thought to be a significant modifying factor in the progression of renal failure in ADPKD. A number of genetic variations involved in renin-angiotensin-aldosterone system (RAAS) pathway genes have clinical or physiological impacts on pathogenesis of hypertension-induced ESRD in ADPKD. Information on RAAS pathway gene polymorphisms and their association with ESRD and ADPKD, published till March 2013, was collected using MEDLINE search. The present review deals with RAAS gene polymorphisms focused on hypertension-induced ESRD in ADPKD in different populations. The results were inconclusive and limited by heterogeneity in the study designs and the population stratification. In lieu of applying next generation sequencing technologies to study complex diseases, it is also possible to apply the same to unravel the complexity of ESRD in ADPKD.

  13. [Role of rennin-angiotensin system in cholinergic agonist carbachol-induced cardiovascular responses in ovine fetus].

    PubMed

    Geng, Chun-Song; Wan, Zhen; Feng, Ya-Hong; Fan, Yi-Sun

    2012-06-25

    To investigate the mechanisms underlying the cholinergic agonist carbachol-induced cardiovascular responses, changes of renin-angiotensin system were examined in fetal hormonal systems. In the ovine fetal model under stressless condition, the cardiovascular function was recorded. Blood samples were collected before (during baseline period) and after the intravenous administration of carbachol. Simultaneously, the levels of angiotensin I (Ang I), angiotensin II (Ang II) and vasopressin in the fetal plasma were detected by immunoradiological method. Also, blood gas, plasma osmolality and electrolyte concentrations were analyzed in blood samples. Results showed that in chronically prepared ovine fetus, intravenous infusion of carbachol led to a significant decrease of heart rate (P < 0.05), and a transient decrease followed by an increase of blood pressure (P < 0.05) within 30 min. After the intravenous infusion of carbachol, blood concentrations of Ang I and Ang II in near-term ovine fetus were both significantly increased (P < 0.05); however, blood concentration of vasopressin, values of blood gas, electrolytes and plasma osmolality in near-term ovine fetus were not significantly changed (P > 0.05). Blood levels of Ang I and Ang II in the atropine (M receptor antagonist) + carbachol intravenous administration group was lower than those in the carbachol group without atropine administration (P < 0.05). In conclusion, this study indicates that the near-term changes of cardiovascular system induced by intravenous administration of carbachol in ovine fetus, such as blood pressure and heart rate, are associated with the changes of hormones of circulatory renin-angiotensin system.

  14. Angiotensin II mediated signal transduction. Important role of tyrosine kinases.

    PubMed

    Haendeler, J; Berk, B C

    2000-11-24

    It has been 100 years since the discovery of renin by Bergman and Tigerstedt. Since then, numerous studies have advanced our understanding of the renin-angiotensin system. A remarkable aspect was the discovery that angiotensin II (AngII) is the central product of the renin-angiotensin system and that this octapeptide induces multiple physiological responses in different cell types. In addition to its well known vasoconstrictive effects, growing evidence supports the notion that AngII may play a central role not only in hypertension, but also in cardiovascular and renal diseases. Binding of AngII to the seven-transmembrane angiotensin II type 1 receptor is responsible for nearly all of the physiological actions of AngII. Recent studies underscore the new concept that activation of intracellular second messengers by AngII requires tyrosine phosphorylation. An increasing number of tyrosine kinases have been shown to be activated by AngII, including the Src kinase family, the focal adhesion kinase family, the Janus kinases and receptor tyrosine kinases. These actions of AngII contribute to the pathophysiology of cardiac hypertrophy and remodeling, vascular thickening, heart failure and atherosclerosis. In this review, we discuss the important role of tyrosine kinases in AngII-mediated signal transduction. Understanding the importance of tyrosine phosphorylation in AngII-stimulated signaling events may contribute to new therapies for cardiovascular and renal diseases.

  15. Combination Direct Renin Inhibition with Angiotensin Type 1 Receptor Blockade improves Aldosterone but does not improve Kidney Injury in the Transgenic Ren2 rat

    PubMed Central

    Whaley-Connell, Adam; Habibi, Javad; Nistala, Ravi; Hayden, Melvin R; Pulakat, Lakshmi; Sinak, Catherine; Locher, Bonnie; Ferrario, Carlos M; Sowers, James R

    2012-01-01

    Enhanced renin-angiotensin-aldosterone system (RAAS) activation contributes to proteinuria and chronic kidney disease by increasing glomerular and tubulointerstitial oxidative stress, promotion of fibrosis. Renin activation is the rate limiting step in angiotensin (Ang II) and aldosterone generation, and recent work suggests direct renin inhibition improves proteinuria comparable to that seen with Ang type 1 receptor (AT1R) blockade. This is important as, even with contemporary use of AT1R blockade, the burden of kidney disease remains high. Thereby, we sought to determine if combination direct renin inhibition with AT1R blockade in vivo, via greater attenuation of kidney oxidative stress, would attenuate glomerular and proximal tubule injury to a greater extent than either intervention alone. We utilized the transgenic Ren2 rat with increased tissue RAS activity and higher serum levels of aldosterone, which manifests hypertension and proteinuria. Ren2 rats were treated with renin inhibition (aliskiren), AT1R blockade (valsartan), the combination (aliskiren+valsartan), or vehicle for 21 days. Compared to Sprague-Dawley controls, Ren2 rats displayed increased systolic pressure (SBP), circulating aldosterone, proteinuria and greater urine levels of the proximal tubule protein excretory marker beta-N-acetylglucosaminidase (β-NAG). These functional and biochemical alterations were accompanied by increases in kidney tissue NADPH oxidase subunit Rac1 and 3-nitrotyrosine (3-NT) content as well as fibronectin and collagen type III. These findings occurred in conjunction with reductions in the podocyte-specific protein podocin as well as the proximal tubule-specific megalin. Further, in transgenic animals there was increased tubulointerstitial fibrosis on light microscopy as well as ultrastructural findings of glomerular podocyte foot-process effacement and reduced tubular apical endosomal/lysosomal activity. Combination therapy led to greater reductions in SBP and serum

  16. Genetic polymorphisms of the renin-angiotensin system and obesity-related metabolic changes in response to low-energy diets in obese women.

    PubMed

    Hamada, Taku; Kotani, Kazuhiko; Nagai, Narumi; Tsuzaki, Kokoro; Sano, Yoshiko; Matsuoka, Yukiyo; Fujibayashi, Mami; Kiyohara, Natsuki; Tanaka, Seitaro; Yoshimura, Makiko; Egawa, Kahori; Kitagawa, Yoshinori; Kiso, Yoshinobu; Moritani, Toshio; Sakane, Naoki

    2011-01-01

    Genetic polymorphisms of the renin-angiotensin system have been implicated in cardiovascular and metabolic diseases. The purpose of this study was to investigate whether the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene and 3123C/A polymorphism of the angiotensin II type 2 receptor (AT(2)R) gene affect blood pressure and other obesity-related metabolic changes in response to low-energy diets using meal replacement shakes for weight loss. Clinical, metabolic, and biochemical profiles were measured before and after a 2-mo intervention in 32 obese women (age 49.9 ± 8.4 [SD] y; BMI 28.4 ± 3.3 kg/m²) restricted to 1200 kcal/d (5021 kJ/d). The polymorphisms were determined with an intercalater-mediated FRET probe assay system. Although weight loss and nutrient intake levels did not differ among the genotypes, the reduction in body fat after weight loss was significantly less in the ACE deletion/deletion (D/D) genotype than insertion/insertion (I/I) plus I/D genotype (-2.25 ± 1.40% versus -0.80 ± 1.57%, P < 0.05). The AT₂R A/A group had significantly less improved levels of systolic blood pressure (-7.23 ± 8.50 versus 2.50 ± 12.6 mmHg, P < 0.05), low-density lipoprotein-cholesterol (-0.36 ± 0.29 versus -0.09 ± 0.25 mmol/L, P < 0.05), carbohydrate (-54.4 ± 27.2 versus -31.8 ± 16.3 mg/min, P < 0.05) and fat oxidation (8.31 ± 11.86 versus 0.05 ± 9.99 mg/min, P < 0.05) than the C/C plus C/A genotypes. The present findings suggest that the homozygous form of the ACE gene may hinder the improvement of body fat and that the homozygous form of the AT₂R gene may make improving systolic blood pressure and some obesity-related metabolic parameters through a dietary intervention difficult among obese women. Copyright © 2011 Elsevier Inc. All rights reserved.

  17. STUDIES ON THE MECHANISM OF EXPERIMENTAL PROTEINURIA INDUCED BY RENIN

    PubMed Central

    Deodhar, Sharad D.; Cuppage, Francis E.; Gableman, E.

    1964-01-01

    Renin-induced proteinuria in the rat was investigated, with special emphasis on the relationship between the enzymatic activity and the proteinuric effect of renin. The dependence of the proteinuric effect on the enzymatic activity was shown by using (a) renin preparations of widely varying purity and (b) chemically modified "active" and "inactive" renin derivatives. Angiotensin II, the pressor product of the enzymatic action of renin, also produced significant proteinuria. Adrenalectomy abolished the proteinuria induced by renin. Proteinuria, however, occurred as a result of pretreatment with DOCA, or aldosterone, or without treatment, 7 to 8 weeks after adrenalectomy. Electron microscopic studies of the kidney at the time of maximal proteinuria showed focal flattening and fusion of epithelial foot processes, as well as swelling and vesicle formation in endothelial and epithelial cells of the glomeruli. Studies with intravenously injected saccharated iron oxide showed increased permeability of the glomerular capillary basement membrane to these particles. These changes were transient and were not seen 24 hours after renin injection. Adrenalectomy prevented these changes. It is concluded that renin, acting through angiotensin, causes glomerular capillary damage with increased permeability of these structures to protein and resultant proteinuria. The adrenal glands participate in a permissive role in this phenomenon. PMID:14212126

  18. Effect of the direct Renin inhibitor aliskiren, the Angiotensin receptor blocker losartan, or both on left ventricular mass in patients with hypertension and left ventricular hypertrophy.

    PubMed

    Solomon, Scott D; Appelbaum, Evan; Manning, Warren J; Verma, Anil; Berglund, Tommy; Lukashevich, Valentina; Cherif Papst, Cheraz; Smith, Beverly A; Dahlöf, Björn

    2009-02-03

    Left ventricular (LV) hypertrophy, a marker of cardiac end-organ damage, is associated with an increased risk of cardiovascular morbidity and mortality. Inhibitors of the renin-angiotensin-aldosterone system may reduce LV mass to a greater extent than other antihypertensive agents. We compared the effect of aliskiren, the first orally active direct renin inhibitor, the angiotensin-receptor blocker losartan, and their combination on the reduction of LV mass in hypertensive patients. We randomized 465 patients with hypertension, increased ventricular wall thickness, and body mass index >25 kg/m(2) to receive aliskiren 300 mg, losartan 100 mg, or their combination daily for 9 months. Patients were treated to standard blood pressure targets with add-on therapy, excluding other inhibitors of the renin-angiotensin-aldosterone system and beta-blockers. Patients underwent cardiovascular magnetic resonance imaging for assessment of LV mass at baseline and at study completion. The primary objective was to compare change in LV mass index from baseline to follow-up in the combination and losartan arms; the secondary objective was to determine whether aliskiren was noninferior to losartan in reducing LV mass index from baseline to follow-up. Systolic and diastolic blood pressures were reduced similarly in all treatment groups (6.5+/-14.9/3.8+/-10.1 mm Hg in the aliskiren group; 5.5+/-15.6/3.7+/-10.7 mm Hg in the losartan group; 6.6+/-16.6/4.6+/-10.5 mm Hg in the combination arm; P<0.0001 within groups, P=0.81 between groups). LV mass index was reduced significantly from baseline in all treatment groups (4.9-, 4.8-, and 5.8 g/m(2) reductions in the aliskiren, losartan, and combination arms, respectively; P<0.0001 for all treatment groups). The reduction in LV mass index in the combination group was not significantly different from that with losartan alone (P=0.52). Aliskiren was as effective as losartan in reducing LV mass index (P<0.0001 for noninferiority). Safety and

  19. Long-term Effects of Renin-Angiotensin System–Blocking Therapy and a Low Blood Pressure Goal on Progression of Hypertensive Chronic Kidney Disease in African Americans

    PubMed Central

    Appel, Lawrence J.; Wright, Jackson T.; Greene, Tom; Kusek, John W.; Lewis, Julia B.; Wang, Xuelei; Lipkowitz, Michael S.; Norris, Keith C.; Bakris, George L.; Rahman, Mahboob; Contreras, Gabriel; Rostand, Stephen G.; Kopple, Joel D.; Gabbai, Francis B.; Schulman, Gerald I.; Gassman, Jennifer J.; Charleston, Jeanne; Agodoa, Lawrence Y.

    2013-01-01

    Background Antihypertensive drugs that block the renin-angiotensin system (angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers) are recommended for patients with chronic kidney disease (CKD). A low blood pressure (BP) goal (BP, <130/80 mm Hg) is also recommended. The objective of this study was to determine the long-term effects of currently recommended BP therapy in 1094 African Americans with hypertensive CKD. Methods Multicenter cohort study following a randomized trial. Participants were 1094 African Americans with hypertensive renal disease (glomerular filtration rate, 20–65 mL/min/1.73 m2). Following a 3×2-factorial trial (1995–2001) that tested 3 drugs used as initial antihypertensive therapy (ACEIs, calcium channel blockers, and β-blockers) and 2 levels of BP control (usual and low), we conducted a cohort study (2002–2007) in which participants were treated with ACEIs to a BP lower than 130/80 mm Hg. The outcome measures were a composite of doubling of the serum creatinine level, end-stage renal disease, or death. Results During each year of the cohort study, the annual use of an ACEI or an angiotensin receptor blocker ranged from 83.7% to 89.0% (vs 38.5% to 49.8% during the trial). The mean BP in the cohort study was 133/78 mm Hg (vs 136/82 mm Hg in the trial). Overall, 567 participants experienced the primary outcome; the 10-year cumulative incidence rate was 53.9%. Of 576 participants with at least 7 years of follow-up, 33.5% experienced a slow decline in kidney function (mean annual decline in the estimated glomerular filtration rate, <1 mL/min/1.73 m2). Conclusion Despite the benefits of renin-angiotensin system–blocking therapy on CKD progression, most African Americans with hypertensive CKD who are treated with currently recommended BP therapy continue to progress during the long term. PMID:18443258

  20. [(Pro) renin receptor in the pathogenesis of proliferative diabetic retinopathy].

    PubMed

    Kanda, Atsuhiro

    2014-11-01

    The renin-angiotensin system (RAS), originally regarded as an important controller of systemic blood pressure (circulatory RAS), plays a pivotal role in pathological vascular conditions including inflammation and angiogenesis (tissue RAS). (Pro) renin receptor [(P) RR] is known to bind with prorenin causing the dual activation of tissue renin-angiotensin system (RAS) together with RAS-independent intracellular signaling pathways and contributes to the molecular pathogenesis of end-organ damage. In this review, we investigated localization and expression of (P)RR in fibrovascular tissues and vitreous fluids from patients with proliferative diabetic retinopathy and evaluated the molecular mechanisms in vitro in order to confirm the conclusions regarding (P) RR from animal studies. (P)RR immunoreactivity was detected in vascular endothelial cells, co-localized with prorenin, phosphorylated extracellular signal-regulated kinase and vascular endothelial growth factor (VEGF). Protein levels of soluble (P) RR in the vitreous fluids were higher in proliferative diabetic retinopathy (PDR) eyes than in non-diabetic control eyes, and were significantly correlated with vitreous VEGF levels and the vascular density of fibrovascular tissues. We herein report the first evidence that shows the close association of (P) RR with angiogenic activity in human PDR. The present data suggest the validity of (P) RR as a molecular target for the treatment of PDR.

  1. Effects of renal denervation on cardiac oxidative stress and local activity of the sympathetic nervous system and renin-angiotensin system in acute myocardial infracted dogs.

    PubMed

    Feng, Qiaoli; Lu, Chengzhi; Wang, Li; Song, Lijun; Li, Chao; Uppada, Ravi Chandra

    2017-02-17

    This study sought to evaluate the therapeutic effects of renal denervation (RDN) on acute myocardial infarction (MI) in canines and explore its possible mechanisms of action. Eighteen healthy mongrel dogs were randomly assigned to either the control group, the MI group or the MI + RDN group. To assess cardiac function, left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD) and fraction shortening (FS) were recorded. Additionally, haemodynamic parameters such as left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP) and heart rate (HR) were measured. Cardiac oxidative stress levels were evaluated based on the expression of p47 phox mRNA, malondialdehyde (MDA), anti-superoxide anion free radical (ASAFR) and activity of superoxide dismutase (SOD). To measure the local activity of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS), the levels of tyrosine hydroxylase (TH), angiotensin II (AngII), angiotensin-converting enzyme 2 (ACE2), angiotensin (1-7) [Ang(1-7)] and Mas receptor (MasR) in myocardial tissues were recorded. The expression of TH in renal tissue and serum creatinine were used to assess the effectiveness of the RDN procedure and renal function, respectively. We found that MI deteriorated heart function and activated cardiac oxidative stress and the local neurohumoral system, while RDN partially reversed these changes. Compared with the control group, parameters including LVEDD, LVESD, LVEDP and the levels of ASAFR, MDA, p47 phox ,ACE2, Ang(1-7), MasR, AngII and TH-positive nerves were increased (all P < 0.05) in myocardial infracted dogs; meanwhile, LVEF, FS, LVSP and SOD expression were decreased (all P < 0.05). However, after RDN therapy, these changes were significantly improved (P < 0.05), except that there were no significant differences observed in FS or LVSP between the two groups (P = 0

  2. [Cardiovascular risk study in patients with renin-angiotensin system blockade by means of the proteone of circulating extracellular vesicles].

    PubMed

    de la Cuesta, F; Baldan-Martin, M; Mourino-Alvarez, L; Sastre-Oliva, T; Alvarez-Llamas, G; Gonzalez-Calero, L; Ruiz-Hurtado, G; Segura, J; Vivanco, F; Ruilope, L M; Barderas, M G

    2016-01-01

    Extracellular vesicles (EVs) are released to the bloodstream by certain cell types due to transport, activation and cell death processes. Blood count of EVs from platelet and endothelial origin has been proved to be a cardiovascular risk biomarker. Thus, EVs proteome might reflect the underlying cellular processes in hypertensive patients with albuminuria. Protein content of circulating EVs was analyzed by liquid chromatography coupled to mass spectrometry. EVs were isolated by an ultracentrifugation protocol optimized in order to avoid contamination by blood plasma proteins. Purity of the isolated fraction was verified by electronic and confocal microscopy, and by flow cytometry. We hereby show a method to isolate circulating EVs from hypertensive patients with/without albuminuria with high yield and purity. Besides, we provide a reference proteome of the EVs of these patients, composed of 2,463 proteins, and prove that the proteins carried by these vesicles are associated with crucial processes involved in the inherent cardiovascular risk. The proteome of circulating EVs is an interesting source of indicators in the evaluation of cardiovascular risk in hypertensive patients with renin-angiotensin system blockage. Copyright © 2015 SEHLELHA. Published by Elsevier España, S.L.U. All rights reserved.

  3. Fructose-rich diet induces gender-specific changes in expression of the renin-angiotensin system in rat heart and upregulates the ACE/AT1R axis in the male rat aorta.

    PubMed

    Bundalo, Maja M; Zivkovic, Maja D; Romic, Snjezana Dj; Tepavcevic, Snezana N; Koricanac, Goran B; Djuric, Tamara M; Stankovic, Aleksandra D

    2016-01-01

    The cardiovascular renin-angiotensin system (RAS) could be affected by gender and dietary regime. We hypothesized that male rats will be more susceptible to activation of RAS in the heart and aorta, as a response to a fructose-rich diet (FRD). Both male and female Wistar rats were given a 10% (w/v) fructose solution for 9 weeks. We measured the biochemical parameters, blood pressure (BP) and heart rate. We used Western blot and real-time polymerase chain reaction (PCR) to quantify protein and gene expression. In the male rats, the FRD elevated BP and expression of cardiac angiotensin-converting enzyme (ACE), while the expression of angiotensin-converting enzyme 2 (ACE2) and angiotensin II Type 2 receptor (AT2R) were significantly decreased. In female rats, there were no changes in cardiac RAS expression due to FRD. Furthermore, the ACE/AT1R axis was overexpressed in the FRD male rats' aortae, while only AT1R was upregulated in the FRD female rats' aortae. ACE2 expression remained unchanged in the aortae of both genders receiving the FRD. The FRD induced gender-specific changes in the expression of the RAS in the heart and aortae of male rats. Further investigations are required in order to get a comprehensive understanding of the underlying mechanisms of gender-specific fructose-induced cardiovascular pathologies. © The Author(s) 2016.

  4. Combination of direct renin inhibition with angiotensin type 1 receptor blockade improves aldosterone but does not improve kidney injury in the transgenic Ren2 rat.

    PubMed

    Whaley-Connell, Adam; Habibi, Javad; Nistala, Ravi; Hayden, Melvin R; Pulakat, Lakshmi; Sinak, Catherine; Locher, Bonnie; Ferrario, Carlos M; Sowers, James R

    2012-06-10

    Enhanced renin-angiotensin-aldosterone system (RAAS) activation contributes to proteinuria and chronic kidney disease by increasing glomerular and tubulointerstitial oxidative stress, promotion of fibrosis. Renin activation is the rate limiting step in angiotensin (Ang II) and aldosterone generation, and recent work suggests direct renin inhibition improves proteinuria comparable to that seen with Ang type 1 receptor (AT(1)R) blockade. This is important as, even with contemporary use of AT(1)R blockade, the burden of kidney disease remains high. Thereby, we sought to determine if combination of direct renin inhibition with AT(1)R blockade in vivo, via greater attenuation of kidney oxidative stress, would attenuate glomerular and proximal tubule injury to a greater extent than either intervention alone. We utilized the transgenic Ren2 rat with increased tissue RAS activity and higher serum levels of aldosterone, which manifests hypertension and proteinuria. Ren2 rats were treated with renin inhibition (aliskiren), AT(1)R blockade (valsartan), the combination (aliskiren+valsartan), or vehicle for 21days. Compared to Sprague-Dawley controls, Ren2 rats displayed increased systolic pressure (SBP), circulating aldosterone, proteinuria and greater urine levels of the proximal tubule protein excretory marker beta-N-acetylglucosaminidase (β-NAG). These functional and biochemical alterations were accompanied by increases in kidney tissue NADPH oxidase subunit Rac1 and 3-nitrotyrosine (3-NT) content as well as fibronectin and collagen type III. These findings occurred in conjunction with reductions in the podocyte-specific protein podocin as well as the proximal tubule-specific megalin. Further, in transgenic animals there was increased tubulointerstitial fibrosis on light microscopy as well as ultrastructural findings of glomerular podocyte foot-process effacement and reduced tubular apical endosomal/lysosomal activity. Combination therapy led to greater reductions in SBP

  5. The effect of renin-angiotensin system blockade on renal protection in chronic kidney disease patients with hyperkalemia.

    PubMed

    Lee, Ju-Hyun; Kwon, Young Eun; Park, Jung Tak; Lee, Mi Jung; Oh, Hyung Jung; Han, Seung Hyeok; Kang, Shin-Wook; Choi, Kyu Hun; Yoo, Tae-Hyun

    2014-12-01

    The aim of this study was to determine the effects of renin-angiotensin system (RAS) blockade maintenance on renal protection in chronic kidney disease (CKD) patients with hyperkalemia occurring during treatment with RAS blockade. CKD III or IV patients, who were prescribed with RAS blockers and also had hyperkalemia, were included. The study population was divided into two groups based on maintenance or withdrawal of RAS blocker. Renal outcomes (doubling of creatinine or end-stage renal disease) and incidence of hyperkalemia were compared between the two groups. Out of 258 subjects who developed hyperkalemia during treatment with RAS blockers, 150 (58.1%) patients continued on RAS blockades, while RAS blockades were discontinued for more than 3 months in the remaining 108 patients. Renal event-free survival was significantly higher in the maintenance group compared with the withdrawal group. Cox proportional hazard ratio for renal outcomes was 1.35 (95% CI: 1.08-1.92, p=0.04) in the withdrawal group compared with the maintenance group. However, the incidence of hyperkalemia and hyperkalemia-related hospitalization or mortality did not differ between the two groups. This study demonstrated that the maintenance of RAS blockade is beneficial for the preservation of renal function and relatively tolerable in patients with CKD and hyperkalemia occurring during treatment with RAS blockade. © The Author(s) 2014.

  6. Mitochondrial reactive oxygen species (ROS) as signaling molecules of intracellular pathways triggered by the cardiac renin-angiotensin II-aldosterone system (RAAS)

    PubMed Central

    De Giusti, V. C.; Caldiz, C. I.; Ennis, I. L.; Pérez, N. G.; Cingolani, H. E.; Aiello, E. A.

    2013-01-01

    Mitochondria represent major sources of basal reactive oxygen species (ROS) production of the cardiomyocyte. The role of ROS as signaling molecules that mediate different intracellular pathways has gained increasing interest among physiologists in the last years. In our lab, we have been studying the participation of mitochondrial ROS in the intracellular pathways triggered by the renin-angiotensin II-aldosterone system (RAAS) in the myocardium during the past few years. We have demonstrated that acute activation of cardiac RAAS induces mitochondrial ATP-dependent potassium channel (mitoKATP) opening with the consequent enhanced production of mitochondrial ROS. These oxidant molecules, in turn, activate membrane transporters, as sodium/hydrogen exchanger (NHE-1) and sodium/bicarbonate cotransporter (NBC) via the stimulation of the ROS-sensitive MAPK cascade. The stimulation of such effectors leads to an increase in cardiac contractility. In addition, it is feasible to suggest that a sustained enhanced production of mitochondrial ROS induced by chronic cardiac RAAS, and hence, chronic NHE-1 and NBC stimulation, would also result in the development of cardiac hypertrophy. PMID:23755021

  7. Mitochondrial reactive oxygen species (ROS) as signaling molecules of intracellular pathways triggered by the cardiac renin-angiotensin II-aldosterone system (RAAS).

    PubMed

    De Giusti, V C; Caldiz, C I; Ennis, I L; Pérez, N G; Cingolani, H E; Aiello, E A

    2013-01-01

    Mitochondria represent major sources of basal reactive oxygen species (ROS) production of the cardiomyocyte. The role of ROS as signaling molecules that mediate different intracellular pathways has gained increasing interest among physiologists in the last years. In our lab, we have been studying the participation of mitochondrial ROS in the intracellular pathways triggered by the renin-angiotensin II-aldosterone system (RAAS) in the myocardium during the past few years. We have demonstrated that acute activation of cardiac RAAS induces mitochondrial ATP-dependent potassium channel (mitoKATP) opening with the consequent enhanced production of mitochondrial ROS. These oxidant molecules, in turn, activate membrane transporters, as sodium/hydrogen exchanger (NHE-1) and sodium/bicarbonate cotransporter (NBC) via the stimulation of the ROS-sensitive MAPK cascade. The stimulation of such effectors leads to an increase in cardiac contractility. In addition, it is feasible to suggest that a sustained enhanced production of mitochondrial ROS induced by chronic cardiac RAAS, and hence, chronic NHE-1 and NBC stimulation, would also result in the development of cardiac hypertrophy.

  8. Correlations of plasma renin activity and aldosterone concentration with ambulatory blood pressure responses to nebivolol and valsartan, alone and in combination, in hypertension.

    PubMed

    Giles, Thomas D; Bakris, George; Oparil, Suzanne; Weber, Michael A; Li, Huiling; Mallick, Madhuja; Bharucha, David B; Chen, ChunLin; Ferguson, William G

    2015-11-01

    After demonstration of the antihypertensive efficacy of the combination of the beta-blocker nebivolol and the angiotensin receptor blocker valsartan in an 8-week, randomized, placebo-controlled trial (N = 4161), we now report the effects of this treatment on the renin-angiotensin-aldosterone system in a substudy (n = 805). Plasma renin activity increased with valsartan (54%-73%) and decreased with nebivolol (51%-65%) and the combination treatment (17%-39%). Plasma aldosterone decreased with individual treatments (valsartan, 11%-22%; nebivolol, 20%-26%), with the largest reduction (35%) observed with maximum combination dose (20 mg nebivolol/320 mg valsartan). Baseline ln(plasma renin activity) correlated with the 8-week reductions in 24-hour systolic and diastolic BP following treatments with the combination (all doses combined, P = .003 and P < .001) and nebivolol (both, P < .001), but not with valsartan. Baseline ln(aldosterone) correlated with 24-hour systolic and diastolic BP reductions following combination treatment only (P < .001 and P = .005). The implications of the renin-angiotensin-aldosterone system effects of this beta blocker-angiotensin receptor blocker combination should be explored further. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Molecular recognition and regulation of human angiotensin-I converting enzyme (ACE) activity by natural inhibitory peptides

    PubMed Central

    Masuyer, Geoffrey; Schwager, Sylva L. U.; Sturrock, Edward D.; Isaac, R. Elwyn; Acharya, K. Ravi

    2012-01-01

    Angiotensin-I converting enzyme (ACE), a two-domain dipeptidylcarboxypeptidase, is a key regulator of blood pressure as a result of its critical role in the renin-angiotensin-aldosterone and kallikrein-kinin systems. Hence it is an important drug target in the treatment of cardiovascular diseases. ACE is primarily known for its ability to cleave angiotensin I (Ang I) to the vasoactive octapeptide angiotensin II (Ang II), but is also able to cleave a number of other substrates including the vasodilator bradykinin and N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), a physiological modulator of hematopoiesis. For the first time we provide a detailed biochemical and structural basis for the domain selectivity of the natural peptide inhibitors of ACE, bradykinin potentiating peptide b and Ang II. Moreover, Ang II showed selective competitive inhibition of the carboxy-terminal domain of human somatic ACE providing evidence for a regulatory role in the human renin-angiotensin system (RAS). PMID:23056909

  10. Bovine ovarian cells have (pro)renin receptors and prorenin induces resumption of meiosis in vitro.

    PubMed

    Dau, Andressa Minussi Pereira; da Silva, Eduardo Pradebon; da Rosa, Paulo Roberto Antunes; Bastiani, Felipe Tusi; Gutierrez, Karina; Ilha, Gustavo Freitas; Comim, Fabio Vasconcellos; Gonçalves, Paulo Bayard Dias

    2016-07-01

    The discovery of a receptor that binds prorenin and renin in human endothelial and mesangial cells highlights the possible effect of renin-independent prorenin in the resumption of meiosis in oocytes that was postulated in the 1980s.This study aimed to identify the (pro)renin receptor in the ovary and to assess the effect of prorenin on meiotic resumption. The (pro)renin receptor protein was detected in bovine cumulus-oocyte complexes, theca cells, granulosa cells, and in the corpus luteum. Abundant (pro)renin receptor messenger ribonucleic acid (mRNA) was detected in the oocytes and cumulus cells, while prorenin mRNA was identified in the cumulus cells only. Prorenin at concentrations of 10(-10), 10(-9), and 10(-8)M incubated with oocytes co-cultured with follicular hemisections for 15h caused the resumption of oocyte meiosis. Aliskiren, which inhibits free renin and receptor-bound renin/prorenin, at concentrations of 10(-7), 10(-5), and 10(-3)M blocked this effect (P<0.05). To determine the involvement of angiotensin II in prorenin-induced meiosis resumption, cumulus-oocyte complexes and follicular hemisections were treated with prorenin and with angiotensin II or saralasin (angiotensin II antagonist). Prorenin induced the resumption of meiosis independently of angiotensin II. Furthermore, cumulus-oocyte complexes cultured with forskolin (200μM) and treated with prorenin and aliskiren did not exhibit a prorenin-induced resumption of meiosis (P<0.05). Only the oocytes' cyclic adenosine monophosphate levels seemed to be regulated by prorenin and/or forskolin treatment after incubation for 6h. To the best of our knowledge, this is the first study to identify the (pro)renin receptor in ovarian cells and to demonstrate the independent role of prorenin in the resumption of oocyte meiosis in cattle. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Effect of dietary sodium intake on central angiotensinergic pathways.

    PubMed

    DiBona, Gerald F; Jones, Susan Y

    2002-06-28

    The role of central angiotensinergic pathways in the cardiovascular regulation has been examined using the microinjection of angiotensin peptides and angiotensin receptor antagonists. However, in such studies, neither the overall nor the local level of activity of the renin-angiotensin system is generally known. Herein, physiological changes in the endogenous level of activity of the renin-angiotensin system were produced by alterations in the dietary sodium intake. Microinjection of the angiotensin II AT1 receptor antagonists losartan or candesartan into the rostral ventrolateral medulla produced the bradycardic, depressor and renal sympathoinhibitory responses which were greater in low sodium diet rats with stimulated activity of the renin-angiotensin system than in high sodium diet rats with suppressed activity of the renin-angiotensin system activity. The renal sympathoexcitatory responses to activation of the paraventricular nucleus by microinjection of bicuculline, known to be dependent on the excitatory synaptic inputs to the rostral ventrolateral medulla mediated by AT1 receptors, were greater in low sodium diet rats than in high sodium rats. These observations support the view that physiologically regulated angiotensin peptides of the brain origin exert a local paracrine or autocrine action on sites that influence the renal sympathetic nerve activity.

  12. Interactions of NADPH oxidase, renin-angiotensin-aldosterone system and reactive oxygen species in mequindox-mediated aldosterone secretion in Wistar rats.

    PubMed

    Huang, Xian-Ju; Wang, Xu; Ihsan, Awais; Liu, Qin; Xue, Xi-Juan; Su, Shi-Jia; Yang, Chun-Hui; Zhou, Wen; Yuan, Zong-Hui

    2010-10-05

    High doses of mequindox (MEQ) are associated with oxidative stress and pathological toxicity in the kidney. In this study, we demonstrated long term effects of MEQ on intra- or extra-adrenal renin-angiotensin-aldosterone system (RAAS) in vivo. RAAS plays a major role in aldosterone secretion. High doses of MEQ in the diet for 180 days in male rats led to inhibition of intra- and extra-adrenal RAAS, concident with down-regulation of Na(+)/K(+)-ATPase (NAKA) and mineralocorticoid receptor (MR), the downstream of aldosterone action. Significant changes of malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) in kidney were also observed in the high doses (110, 275mg/kg) groups. The mRNA levels of most subunits of NADPH oxidase were significantly upregulated at low doses (25-110mg/kg) but the upregulation was diminished at higher doses in both kidney and adrenal gland, indicating a complicated and contradictory effect of MEQ on NADPH. These results highlight the complex interactions of drug metabolism, RAAS, NADPH oxidase and oxidative stress in response to MEQ-induced tissue toxicity and aldosterone secretion. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  13. New angiotensin II type 1 receptor blocker, azilsartan, attenuates cardiac remodeling after myocardial infarction.

    PubMed

    Nakamura, Yuichi; Suzuki, Satoshi; Saitoh, Shu-ichi; Takeishi, Yasuchika

    2013-01-01

    After an acute myocardial infarction (MI), neurohumoral systems including renin-angiotensin-aldosterone system (RAAS) are activated which in turn aggravate cardiac remodeling. Angiotensin receptor blockers (ARBs) are useful drugs for suppression of RAAS. The purpose of this study was to evaluate a new ARB, azilsartan, for suppressing cardiac remodeling and progression to heart failure after MI. We created MI by left anterior descending coronary artery ligation in male mice, and these mice were orally administered saline (0.2 mL) in the control group (Group C), 0.1 mg/kg/d of azilsartan in the low dose group (Group L), and 1.0 mg/kg/d in the high dose group (Group H) everyday. Blood pressure was decreased in Group H, but not in Group L, compared to Group C. At 2 weeks after MI creation, infarct size and fibrotic change at the site remote to the myocardial infarcted area were attenuated in Group L and Group H compared to Group C. Echocardiography revealed that cardiac remodeling was suppressed in Group L and Group H compared to Group C. Increases of mRNA expression levels related to fibrotic change were attenuated in Group L and Group H compared to Group C. The new ARB, azilsartan, had a cardiac remodeling suppression effect after MI, and this effect was observed without blood pressure lowering.

  14. The renin-angiotensin-aldosterone system blockade in patients with advanced diabetic kidney disease.

    PubMed

    Bermejo, Sheila; García, Carles Oriol; Rodríguez, Eva; Barrios, Clara; Otero, Sol; Mojal, Sergi; Pascual, Julio; Soler, María José

    Diabetic kidney disease is the leading cause of end-stage chronic kidney disease. The renin-angiotensin-aldosterone system (RAAS) blockade has been shown to slow the progression of diabetic kidney disease. Our objectives were: to study the percentage of patients with diabetic kidney disease treated with RAAS blockade, to determine its renal function, safety profile and assess whether its administration is associated with increased progression of CKD after 3 years of follow-up. Retrospective study. 197 diabetic kidney disease patients were included and divided into three groups according to the treatment: patients who had never received RAAS blockade (non-RAAS blockade), patients who at some point had received RAAS blockade (inconstant-RAAS blockade) and patients who received RAAS blockade (constant-RAAS blockade). Clinical characteristics and analytical variables such as renal function, electrolytes, glycosylated haemoglobin and glomerular filtration rate according to chronic kidney disease -EPI and MDRD formulas were assessed. We also studied their clinical course (baseline, 1 and 3 years follow-up) in terms of treatment group, survival, risk factors and renal prognosis. Non-RAAS blockade patients had worse renal function and older age (p<0.05) at baseline compared to RAAS blockade patients. Patients who received RAAS blockade were not found to have greater toxicity or chronic kidney disease progression and no differences in renal prognosis were identified. Mortality was higher in non-RAAS blockade patients, older patients and patients with worse renal function (p<0.05). In the multivariate analysis, older age and worse renal function were risk factors for mortality. Treatment with RAAS blockade is more common in diabetic kidney disease patients with eGFR≥30ml/min/1.73m 2 . In our study, there were no differences in the evolution of renal function between the three groups. Older age and worse renal function were associated with higher mortality in patients who

  15. The Role of Vasodilator Receptors of Renin-angiotensin System on Nitric Oxide Formation and Kidney Circulation after Angiotensin II Infusion in Renal Ischemia/Reperfusion Rats.

    PubMed

    Maleki, Maryam; Hasanshahi, Jalal; Moslemi, Fatemeh

    2018-01-01

    Nitric oxide (NO) as a vasodilator factor has renoprotective effect against renal ischemia. The balance between angiotensin II (Ang II) and NO can affect kidney homeostasis. The aim of this study was to determine NO alteration in response to renin-Ang system vasodilator receptors antagonists (PD123319; Ang II type 2 receptor antagonist and A779; Mas receptor antagonist) in renal ischemia/reperfusion injury (IRI) in rats. Sixty-three Wistar male and female rats were used. Animals from each gender were divided into four groups received saline, Ang II, PD123319 + Ang II, and A779 + Ang II after renal IRI. Renal IRI induced with an adjustable hook. Blood pressure and renal blood flow (RBF) measured continuously. The nitrite levels were measured in serum, kidney, and urine samples. In female rats, the serum and kidney nitrite levels increased significantly by Ang II ( P < 0.05) and decreased significantly ( P < 0.05) when PD123319 was accompanied with Ang II. Such observation was not seen in male. Ang II decreased RBF significantly in all groups ( P < 0.05), while PD + Ang II group showed significant decrease in RBF in comparison with the other groups in female rats ( P < 0.05). Males show more sensibility to Ang II infusion; in fact, it is suggested that there is gender dimorphism in the Ang II and NO production associated with vasodilator receptors.

  16. Evolving concepts on regulation and function of renin in distal nephron

    PubMed Central

    Prieto, Minolfa C.; Gonzalez, Alexis A.

    2012-01-01

    Sustained stimulation of the intrarenal/intratubular renin–angiotensin system in a setting of elevated arterial pressure elicits renal vasoconstriction, increased sodium reabsorption, proliferation, fibrosis, and eventual renal injury. Activation of luminal AT1 receptors in proximal and distal nephron segments by local Ang II formation stimulates various transport systems. Augmented angiotensinogen (AGT) production by proximal tubule cells increases AGT secretion contributing to increased proximal Ang II levels and leading to spillover of AGT into the distal nephron segments, as reflected by increased urinary AGT excretion. The increased distal delivery of AGT provides substrate for renin, which is expressed in principal cells of the collecting tubule and collecting ducts, and is also stimulated by AT1 receptor activation. Renin and prorenin are secreted into the tubular lumen and act on the AGT delivered from the proximal tubule to form more Ang I. The catalytic actions of renin and or prorenin may be enhanced by binding to prorenin receptors on the intercalated cells or soluble prorenin receptor secreted into the tubular fluid. There is also increased luminal angiotensin converting enzyme in collecting ducts facilitating Ang II formation leading to stimulation of sodium reabsorption via sodium channel and sodium/chloride co-transporter. Thus, increased collecting duct renin contributes to Ang II-dependent hypertension by augmenting distal nephron intra-tubular Ang II formation leading to sustained stimulation of sodium reabsorption and progression of hypertension. PMID:22990760

  17. Cardiovascular and Renal Outcomes of Renin-Angiotensin System Blockade in Adult Patients with Diabetes Mellitus: A Systematic Review with Network Meta-Analyses.

    PubMed

    Catalá-López, Ferrán; Macías Saint-Gerons, Diego; González-Bermejo, Diana; Rosano, Giuseppe M; Davis, Barry R; Ridao, Manuel; Zaragoza, Abel; Montero-Corominas, Dolores; Tobías, Aurelio; de la Fuente-Honrubia, César; Tabarés-Seisdedos, Rafael; Hutton, Brian

    2016-03-01

    Medications aimed at inhibiting the renin-angiotensin system (RAS) have been used extensively for preventing cardiovascular and renal complications in patients with diabetes, but data that compare their clinical effectiveness are limited. We aimed to compare the effects of classes of RAS blockers on cardiovascular and renal outcomes in adults with diabetes. Eligible trials were identified by electronic searches in PubMed/MEDLINE and the Cochrane Database of Systematic Reviews (1 January 2004 to 17 July 2014). Interventions of interest were angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and direct renin (DR) inhibitors. The primary endpoints were cardiovascular mortality, myocardial infarction, and stroke-singly and as a composite endpoint, major cardiovascular outcome-and end-stage renal disease [ESRD], doubling of serum creatinine, and all-cause mortality-singly and as a composite endpoint, progression of renal disease. Secondary endpoints were angina pectoris and hospitalization for heart failure. In all, 71 trials (103,120 participants), with a total of 14 different regimens, were pooled using network meta-analyses. When compared with ACE inhibitor, no other RAS blocker used in monotherapy and/or combination was associated with a significant reduction in major cardiovascular outcomes: ARB (odds ratio [OR] 1.02; 95% credible interval [CrI] 0.90-1.18), ACE inhibitor plus ARB (0.97; 95% CrI 0.79-1.19), DR inhibitor plus ACE inhibitor (1.32; 95% CrI 0.96-1.81), and DR inhibitor plus ARB (1.00; 95% CrI 0.73-1.38). For the risk of progression of renal disease, no significant differences were detected between ACE inhibitor and each of the remaining therapies: ARB (OR 1.10; 95% CrI 0.90-1.40), ACE inhibitor plus ARB (0.97; 95% CrI 0.72-1.29), DR inhibitor plus ACE inhibitor (0.99; 95% CrI 0.65-1.57), and DR inhibitor plus ARB (1.18; 95% CrI 0.78-1.84). No significant differences were showed between ACE inhibitors and ARBs with

  18. The role of angiotensin receptor-neprilysin inhibitors in cardiovascular disease-existing evidence, knowledge gaps, and future directions.

    PubMed

    Ambrosy, Andrew P; Mentz, Robert J; Fiuzat, Mona; Cleland, John G F; Greene, Stephen J; O'Connor, Christopher M; Teerlink, John R; Zannad, Faiez; Solomon, Scott D

    2018-02-21

    Although traditional renin-angiotensin system antagonists including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have revolutionized the treatment of cardiovascular disease (CVD), the pivotal PARADIGM-HF trial demonstrated that sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), was superior to an angiotensin-converting enzyme inhibitor in reducing cardiovascular morbidity and mortality in patients with heart failure and reduced ejection fraction. However, despite international regulatory approval and strong recommendations in the guidelines, uptake of sacubitril/valsartan has been disappointing. Sacubitril/valsartan is now the focus of a large programme of clinical trials testing the hypothesis that ARNIs may supplant conventional renin-angiotensin system inhibitors across the spectrum of CVD, including hypertension, secondary prevention after myocardial infarction, and heart failure with preserved ejection fraction. This review summarizes the existing evidence, knowledge gaps, and future directions of ARNIs in CVD based on discussions between clinical trialists, industry representatives, and regulatory authorities at the 2016 Global CardioVascular Clinical Trialists Forum in Washington, D.C. © 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.

  19. Correlation between renin-angiotensin system gene polymorphisms and essential hypertension in the Chinese Yi ethnic group.

    PubMed

    Yang, Yu-Ling; Mo, Yan-Ping; He, Yong-Shu; Yang, Fang; Xu, Yan; Li, Cheng-Cheng; Wang, Jiao; Reng, Hao-Ming; Long, Li

    2015-12-01

    The renin-angiotensin system (RAS) has been considered to play an important role in the regulation of blood pressure. This study aimed to investigate the correlation between RAS gene polymorphisms and essential hypertension (EH) in the Chinese Yi ethnic group. A total of 244 EH subjects and 185 normotensive individuals from the Chinese Yi ethnic group were genotyped for AGT M235T (rs699), AT1R A1166C (rs5186), ACE I/D (rs4340) and ACE G2350A (rs4343) polymorphisms by the polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. Significant differences in the allele and genotype frequency of ACE G2350A were observed between the EH cases and controls (p=0.001, 0.002). After being grouped by gender, significant differences in the allele and genotype frequency of ACE G2350A and AT1R A1166C were observed between females of the EH cases and controls (ACE G2350A: p=0.000, 0.002; AT1R A1166C: p=0.008, 0.011). After excluding the influence of multifactorial interactions, the ACE G2350A polymorphism is significantly associated with the pathogenesis of EH in the Chinese Yi ethnic group (odds ratio (OR)=1.656, 95% confidence interval (CI) 1.807-2.524, p=0.019). The RAS-related ACE G2350A polymorphism is associated with the pathogenesis of EH in the Chinese Yi ethnic group. © The Author(s) 2015.

  20. Role of (Pro)Renin Receptor in Albumin Overload-Induced Nephropathy in Rats.

    PubMed

    Fang, Hui; Deng, Mokan; Zhang, Linlin; Lu, Aihua; Su, Jiahui; Xu, Chuanming; Zhou, Li; Wang, Lei; Ou, Jing-Song; Wang, Weidong; Yang, Tianxin

    2018-05-30

    Proteinuria is not only a common feature of chronic kidney diseases (CKD) but also an independent risk factor promoting CKD progression to end-stage renal failure. However, the underlying molecular mechanisms for protein overload-induced renal injury remain elusive. The present study examined the role of (pro)renin receptor (PRR) in pathogenesis of albumin overload (AO)-induced nephropathy and activation of intrarenal renin-angiotensin system (RAS) in rats. Wistar rats underwent unilateral nephrectomy and were treated for 7 weeks with vehicle, bovine serum albumin (5 g/kg/d via a single i.p. injection) alone or in conjunction with a PRR decoy inhibitor PRO20 (500 μg/kg/d via 3 s.c. injections). The AO rat model exhibited severe proteinuria, tubular necrosis, and interstitial fibrosis, oxidative stress, inflammation, accompanied by elevated urinary N-acetyl-beta-D-glucosaminidase activity and urinary β2-microglobulin secretion, all of which were significantly attenuated by PRO20. Urinary and renal levels of renin, angiotensinogen (AGT), and Ang II were elevated by AO and suppressed by PRO20, contrasting to largely unaltered plasma levels of the RAS parameters. The AO model also showed increased renal expression of full-length PRR and soluble PRR (sPRR) and urinary excretion of sPRR. Taken together, we conclude that PRR antagonism with PRO20 alleviates AO-induced nephropathy via inhibition of intrarenal RAS.

  1. Antiproteinuric effects of renin-angiotensin inhibitors in lung cancer patients receiving bevacizumab.

    PubMed

    Nihei, Satoru; Sato, Junya; Harada, Toshiyuki; Kuyama, Shoichi; Suzuki, Toshiro; Waga, Nobutsugu; Saito, Yoshitaka; Kisara, Shigeki; Yokota, Atsuko; Okada, Kouji; Tsuchiya, Masami; Terui, Kazufumi; Tadokoro, Yumiko; Chiba, Takeshi; Kudo, Kenzo; Oizumi, Satoshi; Inoue, Akira; Morikawa, Naoto

    2018-06-01

    The objective of this study was to investigate the effect of renin-angiotensin system inhibitors (RASIs) on bevacizumab (BV)-induced proteinuria in non-small cell lung cancer (NSCLC) patients. We retrospectively reviewed the medical records of NSCLC patients receiving BV between 2008 and 2014 at 11 hospitals. The patients were categorized into three groups according to their antihypertensive drug use: RASI user, non-RASI user, and non-user groups. The primary outcome was a proteinuria event of any grade during the first 6 cycles of BV treatment. A total of 211 patients were included, 89 of whom received antihypertensive drugs. Of these 89 patients, 49 were in the RASI user group, and 40 were in the non-RASI user group. The non-user group comprised 122 patients. The occurrence of proteinuria in the RASI user group was significantly lower than that in the non-RASI user group (P = 0.037) but was not significantly lower than that in the non-user group (P = 0.287). Patients using RASIs had a lower rate of proteinuria than those who did not use RASIs according to multivariate analysis (odds ratio 0.32; 95% confidence interval 0.12-0.86; P = 0.024). Our study suggests that RASI administration reduces the risk of proteinuria in patients receiving BV.

  2. THE INFLUENCE OF BODY-MASS INDEX AND RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM ACTIVITY ON THE RELATIONSHIP BETWEEN 25-HYDROXYVITAMIN D AND ADIPONECTIN IN CAUCASIAN MEN

    PubMed Central

    Vaidya, Anand; Forman, John P.; Underwood, Patricia C.; Hopkins, Paul N.; Williams, Gordon H.; Pojoga, Luminita H.; Williams, Jonathan S.

    2011-01-01

    Objective Prior studies have suggested that circulating adiponectin concentrations are associated positively with vitamin D and negatively with body-mass index (BMI), but have not accounted for the influence of the renin-angiotensin-aldosterone system (RAAS) in this relationship. This is particularly relevant because increased RAAS activity is associated with obesity and is known to lower adiponectin levels. We evaluated the association between adiponectin and 25-hydroxyvitamin D (25[OH]D) after controlling RAAS activity with dietary sodium equilibration, and also evaluated whether this relationship was influenced by BMI. Design Cross-sectional study of 115 hypertensive Caucasian men from the HyperPATH Consortium. Methods To manipulate RAAS activity, all subjects underwent one week of high sodium (HS) diet to suppress RAAS, and one week of low sodium (LS) diet to stimulate RAAS. Linear regression was used to evaluate the association between adiponectin and 25(OH)D, and the effect of BMI on this relationship, in each dietary condition. Results Adiponectin was higher on HS, where circulating RAAS activity was low, when compared to LS (HS=2.9 versus LS=2.4 µg/mL, p<0.0001). 25(OH)D levels were positively associated with adiponectin, and BMI was a statistically significant effect modifier of the relationship between 25(OH)D and adiponectin on both diets (p-interaction < 0.01 between BMI and 25[OH]D). Conclusions Higher 25(OH)D concentrations were independently associated with higher adiponectin levels, particularly when BMI was high. Dietary sodium balance and circulating RAAS activity did not appear to affect this relationship. Future studies should explore whether vitamin D supplementation increases adiponectin levels in obesity. PMID:21402748

  3. Combined use of drugs inhibiting the renin-angiotensin system: prescribing patterns and risk of acute kidney injury in German nursing home residents.

    PubMed

    Dörks, Michael; Herget-Rosenthal, Stefan; Hoffmann, Falk; Jobski, Kathrin

    2018-01-01

    In 2012, the European Medicines Agency reviewed the safety of dual renin-angiotensin system (RAS) blockade because of potentially increased risks for inter alia acute kidney injury (AKI). Since residents of nursing homes are particularly vulnerable to adverse drug outcomes, the aims of our study were to describe RAS-inhibiting drug use in German nursing home residents and examine the risk of AKI associated with dual RAS blockade. Based on claims data, a nested case-control study within a cohort of RAS-inhibiting drug users was conducted. Using conditional logistic regression, confounder-adjusted odds ratios (aORs) and 95% confidence intervals (CI) were obtained for the risk of AKI associated with dual RAS blockade. Subgroup analyses were performed in patients with diabetes or chronic kidney disease and both comorbidities. Of all 127,227 nursing home residents, the study cohort included 64,567 (50.7%) who were treated with at least one RAS-inhibiting drug. More than three quarters of the study population were female (77.1%). Mean age was 86.0 ± 6.8 years. Most residents were treated with angiotensin-converting enzyme inhibitors (77.8%), followed by angiotensin II receptor blockers (21.6%) and aliskiren (0.2%). Annual prevalence of dual RAS blockade declined from 9.6 (95% CI 7.8-11.8) in 2010 to 4.7 (95% CI 4.0-5.4) per 1,000 users in 2014. In the overall cohort, AKI was not significantly associated with dual RAS blockade (aOR 1.99; 0.77-5.17). However, significantly increased aORs were observed when considering patients with diabetes (3.47; 1.27-9.47), chronic kidney disease (4.74; 1.24-18.13) or both (11.17; 2.65-47.15). Prescribing of drugs inhibiting the RAS is common in German nursing homes. Though the prevalence of dual RAS blockade declined, our study showed an increased risk of AKI in patients with diabetes and/or chronic kidney disease. Therefore, cautious use is warranted in these vulnerable patients.

  4. ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage.

    PubMed

    Sato, Teruki; Sato, Chitose; Kadowaki, Ayumi; Watanabe, Hiroyuki; Ho, Lena; Ishida, Junji; Yamaguchi, Tomokazu; Kimura, Akinori; Fukamizu, Akiyoshi; Penninger, Josef M; Reversade, Bruno; Ito, Hiroshi; Imai, Yumiko; Kuba, Keiji

    2017-06-01

    Elabela/Toddler/Apela (ELA) has been identified as a novel endogenous peptide ligand for APJ/Apelin receptor/Aplnr. ELA plays a crucial role in early cardiac development of zebrafish as well as in maintenance of self-renewal of human embryonic stem cells. Apelin was the first identified APJ ligand, and exerts positive inotropic heart effects and regulates the renin-angiotensin system. The aim of this study was to investigate the biological effects of ELA in the cardiovascular system. Continuous infusion of ELA peptide significantly suppressed pressure overload-induced cardiac hypertrophy, fibrosis and impaired contractility in mice. ELA treatment reduced mRNA expression levels of genes associated with heart failure and fibrosis. The cardioprotective effects of ELA were diminished in APJ knockout mice, indicating that APJ is the key receptor for ELA in the adult heart. Mechanistically, ELA downregulated angiotensin-converting enzyme (ACE) expression in the stressed hearts, whereas it showed little effects on angiotensin-converting enzyme 2 (ACE2) expression, which are distinct from the effects of Apelin. FoxM1 transcription factor, which induces ACE expression in the stressed hearts, was downregulated by ELA but not by Apelin. ELA antagonized angiotensin II-induced hypertension, cardiac hypertrophy, and fibrosis in mice. The ELA-APJ axis protects from pressure overload-induced heart failure possibly via suppression of ACE expression and pathogenic angiotensin II signalling. The different effects of ELA and Apelin on the expression of ACE and ACE2 implicate fine-tuned mechanisms for a ligand-induced APJ activation and downstream signalling. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions please email: journals.permissions@oup.com.

  5. Renin and aldosterone measurements in the management of arterial hypertension.

    PubMed

    Viola, A; Monticone, S; Burrello, J; Buffolo, F; Lucchiari, M; Rabbia, F; Williams, T A; Veglio, F; Mengozzi, G; Mulatero, P

    2015-06-01

    Renin-angiotensin-aldosterone system (RAAS) is recognized as the main regulatory system of hemodynamics in man, and its derangements have a key role in the development and maintenance of arterial hypertension. Classification of the hypertensive states according to different patterns of renin and aldosterone levels ("RAAS profiling") allows the diagnosis of specific forms of secondary hypertension and may identify distinct hemodynamic subsets in essential hypertension. In this review, we summarize the application of RAAS profiling for the diagnostic assessment of hypertensive patients and discuss how the pathophysiological framework provided by RAAS profiling may guide therapeutic decision-making, especially in the context of uncontrolled hypertension not responding to multi-therapy. © Georg Thieme Verlag KG Stuttgart · New York.

  6. Angiotensins as therapeutic targets beyond heart disease.

    PubMed

    Passos-Silva, Danielle Gomes; Brandan, Enrique; Santos, Robson Augusto Souza

    2015-05-01

    The renin-angiotensin system (RAS) plays a pivotal role in cardiovascular and hydro-electrolyte homeostasis. Blockade of the RAS as a therapeutic strategy for treating hypertension and related cardiovascular diseases is well established. However, actions of the RAS go far beyond the targets initially described. In this regard, the recent identification of novel components of the RAS, including angiotensin-(1-7) [Ang-(1-7)], Ang-(1-9), and alamandine, have opened new possibilities for interfering with the development and manifestations of cardiovascular and non-cardiovascular diseases. In this article, we briefly review novel targets for angiotensins and its therapeutic implications in diverse areas, including cancer, inflammation, and glaucoma. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Vitamin D in the Pathophysiology of Hypertension, Kidney Disease, and Diabetes: Examining the Relationship Between Vitamin D and the Renin-Angiotensin System in Human Diseases

    PubMed Central

    Vaidya, Anand; Williams, Jonathan S.

    2011-01-01

    Objective Vitamin D has been implicated in the pathophysiology of extra-skeletal conditions such as hypertension, kidney disease, and diabetes, via its ability to negatively regulate the renin-angiotensin system (RAS). This article reviews the evidence supporting a link between vitamin D and the RAS in these conditions, with specific emphasis on translational observations and their limitations. Methods Literature review of animal and human studies evaluating the role of vitamin D in hypertension, kidney disease, and diabetes. Results Excess activity of the RAS has been implicated in the pathogenesis of hypertension, chronic kidney disease, decreased insulin secretion, and insulin resistance. Animal studies provide strong support for 1,25(OH)2D mediated down-regulation of renin expression and RAS activity via its interaction with the vitamin D receptor. Furthermore, the activity of vitamin D metabolites in animals is associated with reductions in blood pressure, proteinuria and renal injury, and with improved β–cell function. Many observational, and a few interventional, studies in humans have supported these findings; however, there is a lack of well designed prospective human interventional studies to definitively assess clinical outcomes. Conclusion Animal studies implicate vitamin D receptor agonist therapy to lower RAS activity as a potential method to reduce the risk of hypertension, kidney disease, and diabetes. There is a need for more well designed prospective interventional studies to validate this hypothesis in human clinical outcomes. PMID:22075270

  8. Bilateral Renal Denervation Ameliorates Isoproterenol-Induced Heart Failure through Downregulation of the Brain Renin-Angiotensin System and Inflammation in Rat

    PubMed Central

    Li, Jian-Dong; Cheng, Ai-Yuan; Huo, Yan-Li; Fan, Jie; Zhang, Yu-Ping; Fang, Zhi-Qin; Sun, Hong-Sheng; Peng, Wei; Zhang, Jin-Shun

    2016-01-01

    Heart failure (HF) is characterized by cardiac dysfunction along with autonomic unbalance that is associated with increased renin-angiotensin system (RAS) activity and elevated levels of proinflammatory cytokines (PICs). Renal denervation (RD) has been shown to improve cardiac function in HF, but the protective mechanisms remain unclear. The present study tested the hypothesis that RD ameliorates isoproterenol- (ISO-) induced HF through regulation of brain RAS and PICs. Chronic ISO infusion resulted in remarked decrease in blood pressure (BP) and increase in heart rate and cardiac dysfunction, which was accompanied by increased BP variability and decreased baroreflex sensitivity and HR variability. Most of these adverse effects of ISO on cardiac and autonomic function were reversed by RD. Furthermore, ISO upregulated mRNA and protein expressions of several components of the RAS and PICs in the lamina terminalis and hypothalamic paraventricular nucleus, two forebrain nuclei involved in cardiovascular regulations. RD significantly inhibited the upregulation of these genes. Either intracerebroventricular AT1-R antagonist, irbesartan, or TNF-α inhibitor, etanercept, mimicked the beneficial actions of RD in the ISO-induced HF. The results suggest that the RD restores autonomic balance and ameliorates ISO-induced HF and that the downregulated RAS and PICs in the brain contribute to these beneficial effects of RD. PMID:27746855

  9. Pharmacological significance of the interplay between angiotensin receptors: MAS receptors as putative final mediators of the effects elicited by angiotensin AT1 receptors antagonists.

    PubMed

    Pernomian, Larissa; Pernomian, Laena; Gomes, Mayara S; da Silva, Carlos H T P

    2015-12-15

    The interplay between angiotensin AT1 receptors and MAS receptors relies on several inward regulatory mechanisms from renin-angiotensin system (RAS) including the functional crosstalk between angiotensin II and angiotensin-(1-7), the competitive AT1 antagonism exhibited by angiotensin-(1-7), the antagonist feature assigned to AT1/MAS heterodimerization on AT1 signaling and the AT1-mediated downregulation of angiotensin-converting enzyme 2 (ACE2). Recently, such interplay has acquired an important significance to RAS Pharmacology since a few studies have supporting strong evidences that MAS receptors mediate the effects elicited by AT1 antagonists. The present Perspective provides an overview of the regulatory mechanisms involving AT1 and MAS receptors, their significance to RAS Pharmacology and the future directions on the interplay between angiotensin receptors. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Renin-angiotensin II-aldosterone system blockers and time to renal replacement therapy in children with CKD.

    PubMed

    Abraham, Alison G; Betoko, Aisha; Fadrowski, Jeffrey J; Pierce, Christopher; Furth, Susan L; Warady, Bradley A; Muñoz, Alvaro

    2017-04-01

    Clinical care decisions to treat chronic kidney disease (CKD) in a growing child must often be made without the benefit of evidence from clinical trials. We used observational data from the Chronic Kidney Disease in Children cohort to estimate the effectiveness of renin-angiotensin II-aldosterone system blockade (RAAS) to delay renal replacement therapy (RRT) in children with CKD. A total of 851 participants (median age: 11 years, median glomerular filtration rate [GFR]: 52 ml/min/1.73 m 2 , median urine protein to creatinine ratio: 0.35 mg/mg) were included. RAAS use was reported at annual study visits. Both Cox proportional hazards models with time-varying RAAS exposure and Cox marginal structural models (MSM) were used to evaluate the effect of RAAS use on time to RRT. Analyses were adjusted or weighted to control for age, male sex, glomerular diagnosis, GFR, nephrotic range proteinuria, anemia, elevated blood pressure, acidosis, elevated phosphate and elevated potassium. There were 217 RRT events over a 4.1-year median follow-up. At baseline, 472 children (55 %) were prevalent RAAS users, who were more likely to be older, have a glomerular etiology, have higher urine protein, be anemic, have elevated serum phosphate and potassium, take more medications, but less likely to have elevated blood pressure, compared with non-users. RAAS use was found to reduce the risk of RRT by 21 % (hazard ratio: 0.79) to 37 % (hazard ratio: 0.63) from standard regression adjustment and MSM models, respectively. These results support inferences from adult studies of a substantial benefit of RAAS use in pediatric CKD patients.

  11. Angiotensin II-producing enzyme III from acidified serum of nephrectomized dogs.

    PubMed

    Haas, E; Lewis, L; Koshy, T J; Varde, A U; Renerts, L; Bagai, R C

    1989-09-01

    A highly active angiotensin-producing enzyme (enzyme III) was obtained from the serum of bilaterally nephrectomized dogs by acid treatment and ammonium sulfate fractionation. An inactive precursor (proenzyme III) was converted to enzyme III during prolonged storage (or by treatment with acid or with cathepsin G or by incubation at 38 degrees C as described in the following paper). Enzyme III reacted maximally at pH 7.7 and it produced up to 400 ng of angiotensin II/mL serum/h (i.e., amounts 4000 times higher than that generated by the endogenous renin present in serum after bilateral nephrectomy). Enzyme III produced angiotensin II at identical rates when either dog angiotensinogen or angiotensin I was used as substrate, but the rate was 710 times higher with synthetic tetradecapeptide renin substrate. Enzyme III is not identical to renin, cathepsin G, tonin, enzyme I, enzyme II, the calcium-dependent angiotensin I-converting enzyme, or the calcium-independent carboxy peptidase, which acts by sequential cleavage of angiotensin I. Enzyme III was inhibited by alpha-1-antitrypsin, diisopropyl fluorophosphate, and lima bean trypsin inhibitor (hence it is a serine proteinase). It was not inhibited by Captopril, Teprotide, or Enalapril. It had been reported previously that cathepsin G released from neutrophil granulocytes, by producing high local concentrations of angiotensin II, may provide a mobile means for modulating blood flow in tissue microvasculature during the inflammatory response. The present study offers a new, additional pathway, by enzyme III, for a similar rapid formation of angiotensin II from serum protein substrate or angiotensin I.

  12. New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) I: Endogenous Angiotensin Converting Enzyme (ACE) Inhibition

    PubMed Central

    Fagyas, Miklós; Úri, Katalin; Siket, Ivetta M.; Daragó, Andrea; Boczán, Judit; Bányai, Emese; Édes, István; Papp, Zoltán; Tóth, Attila

    2014-01-01

    Angiotensin-converting enzyme (ACE) inhibitors represent the fifth most often prescribed drugs. ACE inhibitors decrease 5-year mortality by approximately one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors, which endogenous inhibitory effects are much less characterized than that for the clinically administered ACE inhibitors. Here we aimed to investigate this endogenous ACE inhibition in human sera. It was hypothesized that ACE activity is masked by an endogenous inhibitor, which dissociates from the ACE when its concentration decreases upon dilution. ACE activity was measured by FAPGG hydrolysis first. The specific (dilution corrected) enzyme activities significantly increased by dilution of human serum samples (23.2±0.7 U/L at 4-fold dilution, 51.4±0.3 U/L at 32-fold dilution, n = 3, p = 0.001), suggesting the presence of an endogenous inhibitor. In accordance, specific enzyme activities did not changed by dilution when purified renal ACE was used, where no endogenous inhibitor was present (655±145 U/L, 605±42 U/L, n = 3, p = 0.715, respectively). FAPGG conversion strongly correlated with angiotensin I conversion suggesting that this feature is not related to the artificial substrate. Serum samples were ultra-filtered to separate ACE (MW: 180 kDa) and the hypothesized inhibitor. Filtering through 50 kDa filters was without effect, while filtering through 100 kDa filters eliminated the inhibiting factor (ACE activity after <100 kDa filtering: 56.4±2.4 U/L, n = 4, control: 26.4±0.7 U/L, n = 4, p<0.001). Lineweaver-Burk plot indicated non-competitive inhibition of ACE by this endogenous factor. The endogenous inhibitor had higher potency on the C-terminal active site than N-terminal active site of ACE. Finally, this endogenous ACE inhibition was also present in mouse, donkey, goat, bovine sera besides men (increasing of specific ACE activity

  13. Associations of Renin-Angiotensin-Aldosterone System Genes With Blood Pressure Changes and Hypertension Incidence.

    PubMed

    He, William J; Li, Changwei; Rao, Dabeeru C; Hixson, James E; Huang, Jianfeng; Cao, Jie; Rice, Treva K; Shimmin, Lawrence C; Gu, Dongfeng; Kelly, Tanika N

    2015-11-01

    The renin-angiotensin-aldosterone system (RAAS) plays an important role in blood pressure (BP) regulation. The current study uses single-marker and gene-based analyses to examine the association between RAAS genes and longitudinal BP phenotypes in a Han Chinese population. A total of 1,768 participants from the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) follow-up study were included in the current study. Twenty-seven BP measurements were taken using random-zero sphygmomanometers at baseline and 2 follow-up visits. Mixed-effect models were used to assess the additive associations of 106 single-nucleotide polymorphisms (SNPs) in 10 RAAS genes with longitudinal BP changes and hypertension incidence. Gene-based analyses were conducted using the truncated product method. Attempts were made to replicate significant findings among Asian participants of the Multi-ethnic Study of Atherosclerosis (MESA). False discovery rate procedures were used to adjust for multiple testing. During an average of 7.2 years of follow-up, average systolic and diastolic BP increased, and 32.1% (512) of participants free from hypertension at baseline developed hypertension. NR3C2 SNPs rs7694064 and rs6856803 were significantly associated with longitudinal changes in systolic BP (P interaction = 6.9×10(-5) and 8.2×10(-4), respectively). Through gene-based analysis, NR3C2 was found to be significantly associated with longitudinal systolic BP change (P value of 1.00×10(-7)), even after removal of significant markers rs7694064 and rs6856803 from the analysis. The association between NR3C2 and longitudinal systolic BP change was replicated in Asian MESA participants (P value of 1.00×10(-4)). These findings indicate that NR3C2 may play an important role in BP progression and development of hypertension. © American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. Anti-stress and nootropic activity of drugs affecting the renin-angiotensin system in rats based on indirect biochemical evidence.

    PubMed

    Anil Kumar, K V; Nagwar, Shrasti; Thyloor, Rama; Satyanarayana, Sreemantula

    2015-12-01

    Various stress hormones are responsible for bringing out stress-related changes and are implicated in learning and memory processes. The extensive clinical experience of angiotensin receptor blockers (ARBs) and direct renin inhibitor as antihypertensive agents provides anecdotal evidence of improvements in cognition. The neurochemical basis underlying the anti-stress and nootropic effects are unclear. This study was aimed to determine the effects of aliskiren, valsartan and their combination on the neuromediators of the central nervous system (CNS) and periphery as well as on cognitive function. Groups of rats were subjected to a forced swim stress for one hour after daily treatment with aliskiren, valsartan and their combination. The 24 h urinary excretion of vanillylmandellic acid (VMA), 5-hydroxyindoleacetic acid (5-HIAA), 6-β-hydroxycortisol (6-β-OH) cortisol and homovanillic acid (HVA) was determined in all groups under normal and stressed conditions. Nootropic activity was studied using cook's pole climbing apparatus and acetylcholinesterase (AChE) inhibitory activity by Ellman's method. Administration of aliskiren (10 mg/kg), valsartan (20 mg/kg) and their combination at a dose of 5 and 10 mg/kg respectively reduced the urinary metabolite levels. Further, all drugs showed significant improvement in scopolamine-impaired performance and produced inhibition of the AChE enzyme. The present study provides scientific support for the anti-stress and nootropic activities of aliskiren, valsartan and their combination. © The Author(s) 2014.

  15. Possible Mechanisms of Local Tissue Renin-Angiotensin System Activation in the Cardiorenal Metabolic Syndrome and Type 2 Diabetes Mellitus

    PubMed Central

    Hayden, Melvin R.; Sowers, Kurt M.; Pulakat, Lakshmi; Joginpally, Tejaswini; Krueger, Bennett; Whaley-Connell, Adam; Sowers, James R.

    2011-01-01

    The role of local tissue renin-angiotensin system (tRAS) activation in the cardiorenal metabolic syndrome (CRS) and type 2 diabetes mellitus (T2DM) is not well understood. To this point, we posit that early redox stress-mediated injury to tissues and organs via accumulation of excessive reactive oxygen species (ROS) and associated wound healing responses might serve as a paradigm to better understand how tRAS is involved. There are at least five common categories responsible for generating ROS that may result in a positive feedback ROS-tRAS axis. These mechanisms include metabolic substrate excess, hormonal excess, hypoxia-ischemia/reperfusion, trauma, and inflammation. Because ROS are toxic to proteins, lipids, and nucleic acids they may be the primary instigator, serving as the injury nidus to initiate the wound healing process. Insulin resistance is central to the development of the CRS and T2DM, and there are now thought to be four major organ systems important in their development. In states of overnutrition and tRAS activation, adipose tissue, skeletal muscle (SkM), islet tissues, and liver (the quadrumvirate) are individually and synergistically related to the development of insulin resistance, CRS, and T2DM. The obesity epidemic is thought to be the driving force behind the CRS and T2DM, which results in the impairment of multiple end-organs, including the cardiovascular system, pancreas, kidney, retina, liver, adipose tissue, SkM, and nervous system. A better understanding of the complex mechanisms leading to local tRAS activation and increases in tissue ROS may lead to new therapies emphasizing global risk reduction of ROS resulting in decreased morbidity and mortality. PMID:22096455

  16. Cognitive performance, symptoms and counter-regulation during hypoglycaemia in patients with type 1 diabetes and high or low renin-angiotensin system activity.

    PubMed

    Høi-Hansen, Thomas; Pedersen-Bjergaard, Ulrik; Andersen, Rikke Due; Kristensen, Peter Lommer; Thomsen, Carsten; Kjaer, Troels; Høgenhaven, Hans; Smed, Annelise; Holst, Jens Juul; Dela, Flemming; Boomsma, Frans; Thorsteinsson, Birger

    2009-12-01

    High basal renin-angiotensin system (RAS) activity is associated with increased risk of severe hypoglycaemia in type 1 diabetes. We tested whether this might be explained by more pronounced cognitive dysfunction during hypoglycaemia in patients with high RAS activity than in patients with low RAS activity. Nine patients with type 1 diabetes and high and nine with low RAS activity were subjected to hypoglycaemia and euglycaemia in a cross-over study using an intravenous insulin infusion protocol. Cognitive function, electroencephalography, auditory evoked potentials and hypoglycaemic symptoms were recorded. At a hypoglycaemic nadir of 2.2 (SD 0.3) mmol/L the high RAS group displayed significant deterioration in cognitive performance during hypoglycaemia in the three most complex reaction time tasks. In the low RAS group, hypoglycaemia led to cognitive dysfunction in only one reaction time task. The high RAS group reported lower symptom scores during hypoglycaemia than the low RAS group, suggesting poorer hypoglycaemia awareness. High RAS activity is associated with increased cognitive dysfunction and blunted symptoms during mild hypoglycaemia compared to low RAS activity. This may explain why high RAS activity is a risk factor for severe hypoglycaemia in type 1 diabetes.

  17. Losartan suppresses the kainate-induced changes of angiotensin AT1 receptor expression in a model of comorbid hypertension and epilepsy.

    PubMed

    Atanasova, Dimitrinka; Tchekalarova, Jana; Ivanova, Natasha; Nenchovska, Zlatina; Pavlova, Ekaterina; Atanassova, Nina; Lazarov, Nikolai

    2018-01-15

    Experimental and clinical studies have demonstrated that components of renin-angiotensin system are elevated in the hippocampus in epileptogenic conditions. In the present work, we explored the changes in the expression of angiotensin II receptor, type 1 (AT 1 receptor) in limbic structures, as well as the effect of the AT1 receptor antagonist losartan in a model of comorbid hypertension and epilepsy. The expression of AT 1 receptors was compared between spontaneously hypertensive rats (SHRs) and Wistar rats by using immunohistochemistry in the kainate (KA) model of temporal lobe epilepsy (TLE). The effect of losartan was studied on AT 1 receptor expression in epileptic rats that were treated for a period of 4weeks after status epilepticus. The naive and epileptic SHRs were characterized by stronger protein expression of AT 1 receptor than normotensive Wistar rats in the CA1, CA3a, CA3b, CA3c field and the hilus of the dentate gyrus of the dorsal hippocampus but fewer cells were immunostained in the piriform cortex. Increased AT 1 immunostaining was observed in the basolateral amygdala of epileptic SHRs but not of epileptic Wistar rats. Losartan exerted stronger and structure-dependent suppression of AT 1 receptor expression in SHRs compared to Wistar rats. Our results confirm the important role of AT 1 receptor in epilepsy and suggest that the AT 1 receptor antagonists could be used as a therapeutic strategy for treatment of comorbid hypertension and epilepsy. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Connexin 40 is dispensable for vascular renin cell recruitment but is indispensable for vascular baroreceptor control of renin secretion.

    PubMed

    Machura, Katharina; Neubauer, Bjoern; Müller, Hanna; Tauber, Philipp; Kurtz, Armin; Kurtz, Lisa

    2015-08-01

    requirement for intramural vascular localization of RSCs nor for reversible metaplastic transformation of SMCs into RSCs. Therefore, the ectopic localization of RSCs in Cx40(-/-) kidneys is more likely due to a disturbed intercellular communication rather than being the result of chronic overactivation of the renin-angiotensin-aldosterone system or hypertension. Moreover, our findings suggest that Cx40 is a requirement for the pressure control of renin secretion irrespective of the localization of RSCs.

  19. The Renin-Angiotensin Pathway in PTSD: ACE inhibitor and ARB medications are associated with fewer traumatic stress symptoms

    PubMed Central

    Khoury, Nayla; Marvar, Paul J.; Gillespie, Charles F.; Wingo, Aliza; Schwartz, Ann; Bradley, Bekh; Kramer, Michael; Ressler, Kerry J

    2014-01-01

    Objective PTSD is a debilitating stress-related illness associated with trauma exposure. The peripheral and central mechanisms mediating stress response in PTSD are incompletely understood. Recent data suggest that the renin-angiotensin pathway, essential to cardiovascular regulation, is also involved in mediating stress and anxiety. In this study, the authors examined the relationship between active treatment with blood pressure medication, including angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs), and PTSD symptom severity within a highly traumatized civilian medical population. Method Cross-sectional, observational data was analyzed from a larger study, recruiting patients from Grady Memorial Hospital's outpatient population from 2006 to November 2010. Multi-variable linear regression models were fit to statistically evaluate the independent association of being prescribed an ACE-I or ARB with PTSD symptoms, using a sub-set of patients for whom medical information was available (n=505). PTSD diagnosis was assessed using the modified PTSD Symptom Scale (PSS) based on DSM-IV criteria with PTSD symptoms based on PSS and Clinician Administered PTSD Scale (CAPS). Results A significant association was determined between presence of ACE-I / ARB medication and decreased PTSD symptoms (mean PSS score 11.4 vs 14.9 for individuals prescribed vs not prescribed ACE-I/ARBs, respectively (p = 0.014)). After adjustment for covariates, ACE-I/ARB treatment remained significantly associated with decreased PTSD symptoms (p = 0.044). Notably, other blood pressure medications, including beta-blockers, calcium channel blockers, and diuretics, were not significantly associated with reduced PTSD symptoms. Conclusions These data provide the first clinical evidence supporting a role for the reninangiotensin system in the regulation of stress response in patients diagnosed with PTSD. Further studies should examine whether available medications

  20. Fibroblast growth factor 23 and the antiproteinuric response to dietary sodium restriction during renin-angiotensin-aldosterone system blockade.

    PubMed

    Humalda, Jelmer K; Lambers Heerspink, Hiddo J; Kwakernaak, Arjan J; Slagman, Maartje C J; Waanders, Femke; Vervloet, Marc G; Ter Wee, Pieter M; Navis, Gerjan; de Borst, Martin H

    2015-02-01

    Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patients. Previous studies linked high fibroblast growth factor 23 (FGF-23) levels with volume overload; others linked higher serum phosphate levels with impaired RAAS-blockade efficacy. We hypothesized that FGF-23 reduces the capacity of dietary sodium restriction to potentiate RAAS blockade, impairing the antiproteinuric effect. Post hoc analysis of cohort data from a randomized crossover trial with two 6-week study periods comparing proteinuria after a regular-sodium diet with proteinuria after a low-sodium diet, both during background angiotensin-converting enzyme inhibition. 47 nondiabetic patients with CKD with residual proteinuria (median protein excretion, 1.9 [IQR, 0.8-3.1] g/d; mean age, 50±13 [SD] years; creatinine clearance, 69 [IQR, 50-110] mL/min). Plasma carboxy-terminal FGF-23 levels. Difference in residual proteinuria at the end of the regular-sodium versus low-sodium study period. Residual proteinuria during the low-sodium diet period adjusted for proteinuria during the regular-sodium diet period. Higher baseline FGF-23 level was associated with reduced antiproteinuric response to dietary sodium restriction (standardized β=-0.46; P=0.001; model R(2)=0.71). For every 100-RU/mL increase in FGF-23 level, the antiproteinuric response to dietary sodium restriction was reduced by 10.6%. Higher baseline FGF-23 level was a determinant of more residual proteinuria during the low-sodium diet (standardized β=0.27; P=0.003) in linear regression analysis adjusted for baseline proteinuria (model R(2)=0.71). There was no interaction with creatinine clearance (P interaction=0.5). Baseline FGF-23 level did not predict changes in systolic or diastolic blood pressure upon intensified

  1. Vasopressin and angiotensin II in reflex regulation of ACTH, glucocorticoids, and renin: effect of water deprivation

    NASA Technical Reports Server (NTRS)

    Brooks, V. L.; Keil, L. C.

    1992-01-01

    Angiotensin II (ANG II) and vasopressin participate in baroreflex regulation of adrenocorticotropic hormone (ACTH), glucocorticoid, and renin secretion. The purpose of this study was to determine whether this participation is enhanced in water-deprived dogs, with chronically elevated plasma ANG II and vasopressin levels, compared with water-replete dogs. The baroreflex was assessed by infusing increasing doses of nitroprusside (0.3, 0.6, 1.5, and 3.0 micrograms.kg-1.min-1) in both groups of animals. To quantitate the participation of ANG II and vasopressin, the dogs were untreated or pretreated with the competitive ANG II antagonist saralasin, a V1-vasopressin antagonist, or combined V1/V2-vasopressin antagonist, either alone or in combination. The findings were as follows. 1) Larger reflex increases in ANG II, vasopressin, and glucocorticoids, but not ACTH, were produced in water-deprived dogs compared with water-replete dogs. 2) ANG II blockade blunted the glucocorticoid and ACTH responses to hypotension in water-deprived dogs, but not water-replete dogs. In contrast, vasopressin blockade reduced the ACTH response only in water-replete dogs. 3) Vasopressin or combined vasopressin and ANG II blockade reduced the plasma level of glucocorticoids related either to the fall in arterial pressure or to the increase in plasma ACTH concentration in water-replete dogs, and this effect was enhanced in water-deprived dogs. 4) In both water-deprived and water-replete animals, saralasin and/or a V1-antagonist increased the renin response to hypotension, but a combined V1/V2-antagonist did not. These results reemphasize the importance of endogenous ANG II and vasopressin in the regulation of ACTH, glucocorticoid, and renin secretion.(ABSTRACT TRUNCATED AT 250 WORDS).

  2. Angiotensin-(1-7) regulates Angiotensin II-induced VCAM-1 expression on vascular endothelial cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhang, Feng; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London; Ren, Jingyi

    Highlights: Black-Right-Pointing-Pointer We for the first time found that Ang-(1-7) inhibits Ang II-induced VCAM-1 expression. Black-Right-Pointing-Pointer The inhibitory effect of Ang-(1-7) on VCAM-1 is mediated by MAS receptor. Black-Right-Pointing-Pointer The effect of Ang-(1-7) is due to the suppression of NF-kappaB translocation. -- Abstract: Angiotensin II (Ang II) and Angiotensin-(1-7) (Ang-(1-7)) are key effector peptides in the renin-angiotensin system. Increased circulatory Ang II level is associated with the development of hypertension and atherosclerosis, whereas Ang-(1-7) is a counter-regulatory mediator of Ang II which appears to be protective against cardiovascular disease. However, whether Ang-(1-7) regulates the action of Ang II on vascularmore » endothelial cells (EC) remains unclear. We investigated the effects of Ang II and Ang-(1-7) in the context of atherogenesis, specifically endothelial cell VCAM-1 expression that is implicated in early plaque formation. The results show that Ang II increased VCAM-1 mRNA expression and protein displayed on EC surface, while Ang-(1-7) alone exerted no effects. However, Ang-(1-7) significantly suppressed Ang II-induced VCAM-1 expression. Ang-(1-7) also inhibited the Ang II-induced VCAM-1 promoter activity driven by transcription factor NF-KappaB. Furthermore, immunofluorescence assay and ELISA showed that Ang II facilitated the nuclear translocation of NF-kappaB in ECs, and this was attenuated by the presence of Ang-(1-7). The inhibitory effects of Ang-(1-7) on Ang II-induced VCAM-1 promoter activity and NF-kappaB nuclear translocation were all reversed by the competitive antagonist of Ang-(1-7) at the Mas receptor. Our results suggest that Ang-(1-7) mediates its affects on ECs through the Mas receptor, and negatively regulates Ang II-induced VCAM-1 expression by attenuating nuclear translocation of NF-kappaB.« less

  3. Aldosterone, Renin, and Diabetes Mellitus in African Americans: The Jackson Heart Study.

    PubMed

    Joseph, Joshua J; Echouffo-Tcheugui, Justin B; Kalyani, Rita R; Yeh, Hsin-Chieh; Bertoni, Alain G; Effoe, Valery S; Casanova, Ramon; Sims, Mario; Correa, Adolfo; Wu, Wen-Chih; Wand, Gary S; Golden, Sherita H

    2016-04-01

    Previous research has suggested that activation of the renin-angiotensin-aldosterone system may promote insulin resistance and β-cell dysfunction, but the association with incident diabetes in African Americans is unknown. We examined the association of aldosterone and renin with insulin resistance, β-cell function, and incident diabetes in a large African American cohort. The Jackson Heart Study is a prospective study of the development and progression of cardiovascular disease in African Americans. Participants were recruited from the tricounty area of metropolitan Jackson, Mississippi. A total of 5301 African American adults, aged 21–94 years, were assessed at baseline and through 12 years of follow-up. Data on aldosterone, renin, and risk factors were collected at baseline (2000–2004). Diabetes (fasting glucose ≥ 126 mg/dL, physician diagnosis, use of diabetes drugs, or glycated hemoglobin ≥ 6.5%) was assessed at baseline and through 12 years of follow-up. Participants were excluded for missing data on baseline covariates or diabetes follow-up. Cox regression was used to estimate hazard ratios (HR) for incident diabetes using sequential modeling adjusting for age, sex, education, occupation, systolic blood pressure, current smoking, physical activity, dietary intake, and body mass index. Aldosterone, renin, and diabetes risk factors were measured. Outcomes included the homeostatic model assessment of insulin resistance (HOMA-IR) and incident diabetes. Among 3234 participants over a median of 8.0 years of follow-up, there were 554 cases of incident diabetes. Every 1% increase in log-transformed aldosterone was associated with a 0.18% higher log-transformed HOMA-IR in cross-sectional analyses of nondiabetic participants (P < .001). Log-transformed aldosterone and renin levels in the fifth vs first quintile were associated with a 78% (HR 1.78, 95% confidence interval 1.35–2.34) and 35% (HR 1.35, 95% confidence interval 1.06–1.72) increase in diabetes

  4. The aldo-keto reductase AKR1B7 coexpresses with renin without influencing renin production and secretion.

    PubMed

    Machura, Katharina; Iankilevitch, Elina; Neubauer, Björn; Theuring, Franz; Kurtz, Armin

    2013-03-01

    On the basis of evidence that within the adult kidney, the aldo-keto reductase AKR1B7 (aldo-keto reductase family 1, member 7, also known as mouse vas deferens protein, MVDP) is selectively expressed in renin-producing cells, we aimed to define a possible role of AKR1B7 for the regulation and function of renin cells in the kidney. We could confirm colocalization and corecruitment of renin and of AKR1B7 in wild-type kidneys. Renin cells in AKR1B7-deficient kidneys showed normal morphology, numbers, and intrarenal distribution. Plasma renin concentration (PRC) and renin mRNA levels of AKR1B7-deficient mice were normal at standard chow and were lowered by a high-salt diet directly comparable to wild-type mice. Treatment with a low-salt diet in combination with an angiotensin-converting enzyme inhibitor strongly increased PRC and renin mRNA in a similar fashion both in AKR1B7-deficient and wild-type mice. Under this condition, we also observed a strong retrograde recruitment of renin-expressing cell along the preglomerular vessels, however, without a difference between AKR1B7-deficient and wild-type mice. The isolated perfused mouse kidney model was used to study the acute regulation of renin secretion by ANG II and by perfusion pressure. Regarding these parameters, no differences were observed between AKR1B7-deficient and wild-type kidneys. In summary, our data suggest that AKR1B7 is not of major relevance for the regulation of renin production and secretion in spite of its striking coregulation with renin expression.

  5. Deterioration of kidney function by the (pro)renin receptor blocker handle region peptide in aliskiren-treated diabetic transgenic (mRen2)27 rats.

    PubMed

    te Riet, Luuk; van den Heuvel, Mieke; Peutz-Kootstra, Carine J; van Esch, Joep H M; van Veghel, Richard; Garrelds, Ingrid M; Musterd-Bhaggoe, Usha; Bouhuizen, Angelique M; Leijten, Frank P J; Danser, A H Jan; Batenburg, Wendy W

    2014-05-15

    Dual renin-angiotensin system (RAS) blockade in diabetic nephropathy is no longer feasible because of the profit/side effect imbalance. (Pro)renin receptor [(P)RR] blockade with handle region peptide (HRP) has been reported to exert beneficial effects in various diabetic models in a RAS-independent manner. To what degree (P)RR blockade adds benefits on top of RAS blockade is still unknown. In the present study, we treated diabetic TGR(mREN2)27 rats, a well-established nephropathy model with high prorenin levels [allowing continuous (P)RR stimulation in vivo], with HRP on top of renin inhibition with aliskiren. Aliskiren alone lowered blood pressure and exerted renoprotective effects, as evidenced by reduced glomerulosclerosis, diuresis, proteinuria, albuminuria, and urinary aldosterone levels as well as diminished renal (P)RR and ANG II type 1 receptor expression. It also suppressed plasma and tissue RAS activity and suppressed cardiac atrial natriuretic peptide and brain natriuretic peptide expression. HRP, when given on top of aliskiren, did not alter the effects of renin inhibition on blood pressure, RAS activity, or aldosterone. However, it counteracted the beneficial effects of aliskiren in the kidney, induced hyperkalemia, and increased plasma plasminogen activator-inhibitor 1, renal cyclooxygenase-2, and cardiac collagen content. All these effects have been linked to (P)RR stimulation, suggesting that HRP might, in fact, act as a partial agonist. Therefore, the use of HRP on top of RAS blockade in diabetic nephropathy is not advisable. Copyright © 2014 the American Physiological Society.

  6. Associations of aldosterone and renin concentrations with inflammation-the Study of Health in Pomerania and the German Conn's Registry.

    PubMed

    Grotevendt, A; Wallaschofski, H; Reincke, M; Adolf, C; Quinkler, M; Nauck, M; Hoffmann, W; Rettig, R; Hannemann, A

    2017-08-01

    Chronic inflammation is an age-independent and body mass index-independent contributor to the development of multi-morbidity. Alterations of the renin-angiotensin-aldosterone system are observed within the context of proinflammatory states. We assessed circulating aldosterone, renin, and inflammatory biomarker concentrations in healthy, normotensive subjects and patients with primary aldosteronism. We included 1177 normotensive individuals from the population-based Study of Health in Pomerania (first follow-up, Study of Health in Pomerania-1) and 103 primary aldosteronism patients from the German Conn's Registry. A 1:1 matching for sex, age, body mass index, smoking status, diabetes mellitus, and the estimated glomerular filtration rate was performed to determine whether primary aldosteronism patients exhibit higher inflammatory biomarker concentrations than normotensive controls. The associations of plasma aldosterone concentration or plasma renin concentration with circulating fibrinogen concentrations, white blood cell count, and high sensitive C-reactive protein concentrations in the normotensive sample were determined with multivariable linear and logistic regression analyses. 1:1 matched primary aldosteronism patients demonstrated significantly (p < 0.01) higher plasma aldosterone concentration (198 vs. 47 ng/l), lower plasma renin concentration (3.1 vs. 7.7 ng/l) and higher high sensitive C-reactive protein concentrations (1.5 vs. 1.0 mg/l) than normotensive controls. Within the normotensive cohort, plasma renin concentration but not plasma aldosterone concentration was positively associated with fibrinogen concentrations and white blood cell count. Further, a J-shaped association between plasma renin concentration and high sensitive C-reactive protein concentrations was detected. High plasma aldosterone concentration in a primary aldosteronism cohort and high plasma renin concentration in normotensive subjects are associated with increased

  7. New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) III: Endogenous Inhibition of Angiotensin Converting Enzyme (ACE) Provides Protection against Cardiovascular Diseases

    PubMed Central

    Fagyas, Miklós; Úri, Katalin; Siket, Ivetta M.; Daragó, Andrea; Boczán, Judit; Bányai, Emese; Édes, István; Papp, Zoltán; Tóth, Attila

    2014-01-01

    ACE inhibitor drugs decrease mortality by up to one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors. Here we investigated the clinical significance of this potential endogenous ACE inhibition. ACE concentration and activity was measured in patient's serum samples (n = 151). ACE concentration was found to be in a wide range (47–288 ng/mL). ACE activity decreased with the increasing concentration of the serum albumin (HSA): ACE activity was 56±1 U/L in the presence of 2.4±0.3 mg/mL HSA, compared to 39±1 U/L in the presence of 12±1 mg/mL HSA (values are mean±SEM). Effects of the differences in ACE concentration were suppressed in human sera: patients with ACE DD genotype exhibited a 64% higher serum ACE concentration (range, 74–288 ng/mL, median, 155.2 ng/mL, n = 52) compared to patients with II genotype (range, 47–194 ng/mL, median, 94.5 ng/mL, n = 28) while the difference in ACE activities was only 32% (range, 27.3–59.8 U/L, median, 43.11 U/L, and range 15.6–55.4 U/L, median, 32.74 U/L, respectively) in the presence of 12±1 mg/mL HSA. No correlations were found between serum ACE concentration (or genotype) and cardiovascular diseases, in accordance with the proposed suppressed physiological ACE activities by HSA (concentration in the sera of these patients: 48.5±0.5 mg/mL) or other endogenous inhibitors. Main implications are that (1) physiological ACE activity can be stabilized at a low level by endogenous ACE inhibitors, such as HSA; (2) angiotensin II elimination may have a significant role in angiotensin II related pathologies. PMID:24690767

  8. Iron Overload Accelerates the Progression of Diabetic Retinopathy in Association with Increased Retinal Renin Expression.

    PubMed

    Chaudhary, Kapil; Promsote, Wanwisa; Ananth, Sudha; Veeranan-Karmegam, Rajalakshmi; Tawfik, Amany; Arjunan, Pachiappan; Martin, Pamela; Smith, Sylvia B; Thangaraju, Muthusamy; Kisselev, Oleg; Ganapathy, Vadivel; Gnana-Prakasam, Jaya P

    2018-02-14

    Diabetic retinopathy (DR) is a leading cause of blindness among working-age adults. Increased iron accumulation is associated with several degenerative diseases. However, there are no reports on the status of retinal iron or its implications in the pathogenesis of DR. In the present study, we found that retinas of type-1 and type-2 mouse models of diabetes have increased iron accumulation compared to non-diabetic retinas. We found similar iron accumulation in postmortem retinal samples from human diabetic patients. Further, we induced diabetes in HFE knockout (KO) mice model of genetic iron overload to understand the role of iron in the pathogenesis of DR. We found increased neuronal cell death, vascular alterations and loss of retinal barrier integrity in diabetic HFE KO mice compared to diabetic wildtype mice. Diabetic HFE KO mouse retinas also exhibited increased expression of inflammation and oxidative stress markers. Severity in the pathogenesis of DR in HFE KO mice was accompanied by increase in retinal renin expression mediated by G-protein-coupled succinate receptor GPR91. In light of previous reports implicating retinal renin-angiotensin system in DR pathogenesis, our results reveal a novel relationship between diabetes, iron and renin-angiotensin system, thereby unraveling new therapeutic targets for the treatment of DR.

  9. Renin-angiotensin system blockade alone or combined with ETA receptor blockade: effects on the course of chronic kidney disease in 5/6 nephrectomized Ren-2 transgenic hypertensive rats.

    PubMed

    Sedláková, Lenka; Čertíková Chábová, Věra; Doleželová, Šárka; Škaroupková, Petra; Kopkan, Libor; Husková, Zuzana; Červenková, Lenka; Kikerlová, Soňa; Vaněčková, Ivana; Sadowski, Janusz; Kompanowska-Jezierska, Elzbieta; Kujal, Petr; Kramer, Herbert J; Červenka, Luděk

    2017-01-01

    Early addition of endothelin (ET) type A (ET A ) receptor blockade to complex renin-angiotensin system (RAS) blockade has previously been shown to provide better renoprotection against progression of chronic kidney disease (CKD) in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX). In this study, we examined if additional protection is provided when ET A blockade is applied in rats with already developed CKD. For complex RAS inhibition, an angiotensin-converting enzyme inhibitor along with angiotensin II type 1 receptor blocker was used. Alternatively, ET A receptor blocker was added to the RAS blockade. The treatments were initiated 6 weeks after 5/6 NX and the follow-up period was 50 weeks. When applied in established CKD, addition of ET A receptor blockade to the complex RAS blockade brought no further improvement of the survival rate (30% in both groups); surprisingly, aggravated albuminuria (588 ± 47 vs. 245 ± 38 mg/24 h, p < 0.05) did not reduce renal glomerular injury index (1.25 ± 0.29 vs. 1.44 ± 0.26), did not prevent the decrease in creatinine clearance (203 ± 21 vs. 253 ± 17 µl/min/100 g body weight), and did not attenuate cardiac hypertrophy to a greater extent than observed in 5/6 NX TGR treated with complex RAS blockade alone. When applied in the advanced phase of CKD, addition of ET A receptor blockade to the complex RAS blockade brings no further beneficial renoprotective effects on the CKD progression in 5/6 NX TGR, in addition to those seen with RAS blockade alone.

  10. Review: Intracardiac intracellular angiotensin system in diabetes

    PubMed Central

    Kumar, Rajesh; Yong, Qian Chen; Thomas, Candice M.

    2012-01-01

    The renin-angiotensin system (RAS) has mainly been categorized as a circulating and a local tissue RAS. A new component of the local system, known as the intracellular RAS, has recently been described. The intracellular RAS is defined as synthesis and action of ANG II intracellularly. This RAS appears to differ from the circulating and the local RAS, in terms of components and the mechanism of action. These differences may alter treatment strategies that target the RAS in several pathological conditions. Recent work from our laboratory has demonstrated significant upregulation of the cardiac, intracellular RAS in diabetes, which is associated with cardiac dysfunction. Here, we have reviewed evidence supporting an intracellular RAS in different cell types, ANG II's actions in cardiac cells, and its mechanism of action, focusing on the intracellular cardiac RAS in diabetes. We have discussed the significance of an intracellular RAS in cardiac pathophysiology and implications for potential therapies. PMID:22170614

  11. The contributions of renin and vasopressin to the adaptation of the Australian spinifex hopping mouse (Notomys alexis) to free water deprivation.

    PubMed

    Weaver, D; Walker, L; Alcorn, D; Skinner, S

    1994-05-01

    Xeric-adaptation was studied during 28 days of total water deprivation (TWD) in Notomys alexis. Beyond 7 days, the initial reductions in body weight and increases in haematocrit, plasma renin and juxtaglomerular (JG) cell morphological activity returned to normal. Mus musculus showed similar changes at 7 days but could not be maintained thereafter. TWD decreased the blood pressure of Notomys but endogenous angiotensin and vasopressin did not support pressure to a greater extent than controls, as revealed by selective antagonists. The normal morphology of the JG apparatus in Notomys was similar to other rodents. Fluid volume and blood pressure maintenance during TWD in Notomys do not depend upon enhanced activities of the renin-angiotensin and antidiuretic hormonal systems.

  12. Recent insights and therapeutic perspectives of angiotensin-(1-9) in the cardiovascular system.

    PubMed

    Ocaranza, Maria Paz; Michea, Luis; Chiong, Mario; Lagos, Carlos F; Lavandero, Sergio; Jalil, Jorge E

    2014-11-01

    Chronic RAS (renin-angiotensin system) activation by both AngII (angiotensin II) and aldosterone leads to hypertension and perpetuates a cascade of pro-hypertrophic, pro-inflammatory, pro-thrombotic and atherogenic effects associated with cardiovascular damage. In 2000, a new pathway consisting of ACE2 (angiotensin-converting enzyme2), Ang-(1-9) [angiotensin-(1-9)], Ang-(1-7) [angiotensin-(1-7)] and the Mas receptor was discovered. Activation of this novel pathway stimulates vasodilation, anti-hypertrophy and anti-hyperplasia. For some time, studies have focused mainly on ACE2, Ang-(1-7) and the Mas receptor, and their biological properties that counterbalance the ACE/AngII/AT1R (angiotensin type 1 receptor) axis. No previous information about Ang-(1-9) suggested that this peptide had biological properties. However, recent data suggest that Ang-(1-9) protects the heart and blood vessels (and possibly the kidney) from adverse cardiovascular remodelling in patients with hypertension and/or heart failure. These beneficial effects are not modified by the Mas receptor antagonist A779 [an Ang-(1-7) receptor blocker], but they are abolished by the AT2R (angiotensin type 2 receptor) antagonist PD123319. Current information suggests that the beneficial effects of Ang-(1-9) are mediated via the AT2R. In the present review, we summarize the biological effects of the novel vasoactive peptide Ang-(1-9), providing new evidence of its cardiovascular-protective activity. We also discuss the potential mechanism by which this peptide prevents and ameliorates the cardiovascular damage induced by RAS activation.

  13. Elevated renin levels in patients with liver cirrhosis and hepatocellular carcinoma.

    PubMed

    Lotfy, Mahmoud; El-Kenawy, Ayman El-Meghawry; Abdel-Aziz, Mohamed M; El-Kady, Ibrahim; Talaat, Ayman

    2010-01-01

    Liver fibrosis is the common consequence of chronic liver injury of any etiology, disrupting the normal architecture,and causing hepatocellular dysfunction and portal hypertension. Since the renin-angiotensin system (RAS) may be involved in chronic liver diseases, in the present study we assayed renin levels using ELISA in groups of Egyptian patients with liver cirrhosis (N=32) and hepatocellular carcinoma (HCC) (N=67), for comparison with twenty five healthy controls. The results showed significant differences between the control and liver cirrhosis patients (P<0.001) and also the controls and HCC patients (P<0.001), without significant variation between the patient groups. Furthermore, in HCC patients, it was found that the renin levels negatively correlated with serum albumin and prothrombin time (P=0.003 for each) and positively with α-fetoprotein (P=0.04). Thus, it is concluded that renin levels are elevated in patients with liver cirrhosis and HCC and suitable medical intervention should be placed for management of such alteration. Moreover, further studies are warranted to explore its prognostic significance.

  14. (Pro)renin receptor: Involvement in diabetic retinopathy and development of molecular targeted therapy.

    PubMed

    Kanda, Atsuhiro; Ishida, Susumu

    2018-03-25

    The renin-angiotensin system (RAS), a crucial regulator of systemic blood pressure (circulatory RAS), plays distinct roles in pathological angiogenesis and inflammation in various organs (tissue RAS), such as diabetic microvascular complications. Using ocular clinical samples and animal disease models, we elucidated molecular mechanisms in which tissue RAS excites the expression of vascular endothelial growth factor (VEGF)-A responsible for retinal inflammation and angiogenesis, the two major pathological events in diabetic retinopathy (DR). Furthermore, we showed the involvement of (pro)renin receptor [(P)RR] in retinal RAS activation and its concurrent intracellular signal transduction (e.g., extracellular signal-regulated kinase); namely, the (P)RR-induced dual pathogenic bioactivity referred to as the receptor-associated prorenin system. Indeed, neovascular endothelial cells in the fibrovascular tissue collected from eyes with proliferative DR were immunoreactive for the receptor-associated prorenin system components including prorenin, (P)RR, phosphorylated extracellular signal-regulated kinase and VEGF-A. Protein levels of soluble (P)RR increased with its positive correlations with prorenin, renin enzymatic activity and VEGF in the vitreous of proliferative DR eyes, suggesting a close link between (P)RR and VEGF-A-driven angiogenic activity. Furthermore, we revealed an unsuspected, PAPS-independent role of (P)RR in glucose-induced oxidative stress. Recently, we developed an innovative single-strand ribonucleic acid interference molecule selectively targeting human and mouse (P)RR, and confirmed its efficacy in suppressing diabetes-induced retinal inflammation in mice. Our data using clinical samples and animal models suggested the significant implication of (P)RR in the pathogenesis of DR, and the potential usefulness of the ribonucleic acid interference molecule as a therapeutic agent to attenuate ocular inflammation and angiogenesis. © 2018 The Authors

  15. Angiotensin II-AT1-receptor signaling is necessary for cyclooxygenase-2-dependent postnatal nephron generation.

    PubMed

    Frölich, Stefanie; Slattery, Patrick; Thomas, Dominique; Goren, Itamar; Ferreiros, Nerea; Jensen, Boye L; Nüsing, Rolf M

    2017-04-01

    Deletion of cyclooxygenase-2 (COX-2) causes impairment of postnatal kidney development. Here we tested whether the renin angiotensin system contributes to COX-2-dependent nephrogenesis in mice after birth and whether a rescue of impaired renal development and function in COX-2 -/- mice was achievable. Plasma renin concentration in mouse pups showed a birth peak and a second peak around day P8 during the first 10 days post birth. Administration of the angiotensin II receptor AT1 antagonist telmisartan from day P1 to P3 did not result in cortical damage. However, telmisartan treatment from day P3 to P8, the critical time frame of renal COX-2 expression, led to hypoplastic glomeruli, a thinned subcapsular cortex and maturational arrest of superficial glomeruli quite similar to that observed in COX-2 -/- mice. In contrast, AT2 receptor antagonist PD123319 was without any effect on renal development. Inhibition of the renin angiotensin system by aliskiren and enalapril caused similar glomerular defects as telmisartan. Administration of the AT1 receptor agonist L162313 to COX-2 -/- pups improved kidney growth, ameliorated renal defects, but had no beneficial effect on reduced cortical mass. L162313 rescued impaired renal function by reducing serum urea and creatinine and mitigated pathologic albumin excretion. Moreover, glomerulosclerosis in the kidneys of COX-2 -/- mice was reduced. Thus, angiotensin II-AT1-receptor signaling is necessary for COX-2-dependent normal postnatal nephrogenesis and maturation. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  16. Angiotensin receptor blockers for management of hypertension.

    PubMed

    Catanzaro, Daniel F; Frishman, William H

    2010-07-01

    The renin-angiotensin-aldosterone system (RAAS) plays a major role in blood pressure regulation and is thus an important therapeutic target in the management of hypertension. Angiotensin receptor blockers (ARBs), which interrupt RAAS overactivity by blocking a specific receptor that mediates the pathogenic activity of angiotensin II, represent a major addition to the clinician's armamentarium for the management of hypertension. A solid body of clinical evidence demonstrates that ARBs are effective in the management of hypertension as monotherapy or in combination with other agents. Although comparable to angiotensin-converting enzyme inhibitors and other major classes of antihypertensive agents in the treatment of hypertension, the favorable tolerability profile of ARBs make them an attractive alternative for many patients. Recent evidence suggests that treatment persistence with ARB therapy during a 12-month period is typically higher than with other antihypertensive classes, a finding perhaps driven by fewer treatment-limiting side effects. The combination of clinical efficacy and tolerability should render ARBs as a major treatment alternative for hypertension.

  17. Interplay of vitamin D, erythropoiesis, and the renin-angiotensin system.

    PubMed

    Santoro, Domenico; Caccamo, Daniela; Lucisano, Silvia; Buemi, Michele; Sebekova, Katerina; Teta, Daniel; De Nicola, Luca

    2015-01-01

    For many years deficiency of vitamin D was merely identified and assimilated to the presence of bone rickets. It is now clear that suboptimal vitamin D status may be correlated with several disorders and that the expression of 1-α-hydroxylase in tissues other than the kidney is widespread and of clinical relevance. Recently, evidence has been collected to suggest that, beyond the traditional involvement in mineral metabolism, vitamin D may interact with other kidney hormones such as renin and erythropoietin. This interaction would be responsible for some of the systemic and renal effects evoked for the therapy with vitamin D. The administration of analogues of vitamin D has been associated with an improvement of anaemia and reduction in ESA requirements. Moreover, vitamin D deficiency could contribute to an inappropriately activated or unsuppressed RAS, as a mechanism for progression of CKD and/or cardiovascular disease. Experimental data on the anti-RAS and anti-inflammatory effects treatment with active vitamin D analogues suggest a therapeutic option particularly in proteinuric CKD patients. This option should be considered for those subjects that are intolerant to anti-RAS agents or, as add-on therapy, in those already treated with anti-RAS but not reaching the safe threshold level of proteinuria.

  18. Dietary calcium intake and renin angiotensin system polymorphisms alter the blood pressure response to aerobic exercise: a randomized control design.

    PubMed

    Pescatello, Linda S; Turner, Debbie; Rodriguez, Nancy; Blanchard, Bruce E; Tsongalis, Gregory J; Maresh, Carl M; Duffy, Valerie; Thompson, Paul D

    2007-01-04

    Dietary calcium intake and the renin angiotensin system (RAS) regulate blood pressure (BP) by modulating calcium homeostasis. Despite similar BP regulatory effects, the influence of dietary calcium intake alone and combined with RAS polymorphisms on the BP response following acute aerobic exercise (i.e., postexercise hypotension) has not been studied. Thus, we examined the effect of dietary calcium intake and selected RAS polymorphisms on postexercise hypotension. Subjects were men (n = 50, 43.8 +/- 1.3 yr) with high BP (145.3 +/- 1.5/85.9 +/- 1.1 mm Hg). They completed three experiments: non-exercise control and two cycle bouts at 40% and 60% of maximal oxygen consumption (VO2max). Subjects provided 3 d food records on five protocol-specific occasions. Dietary calcium intake was averaged and categorized as low (<880 mg/d = LowCa) or high (> or = 880 mg/d = HighCa). RAS polymorphisms (angiotensin converting enzyme insertion/deletion, ACE I/D; angiotensin II type 1 receptor, AT1R A/C) were analyzed with molecular methods. Genotypes were reduced from three to two: ACE II/ID and ACE DD; or AT1R AA and AT1R CC/AC. Repeated measure ANCOVA tested if BP differed among experiments, dietary calcium intake level and RAS polymorphisms. Systolic BP (SBP) decreased 6 mm Hg after 40% and 60% VO2max compared to non-exercise control for 10 h with LowCa (p < 0.01), but not with HighCa (p > or = 0.05). Under these conditions, diastolic BP (DBP) did not differ between dietary calcium intake levels (p > or = 0.05). With LowCa, SBP decreased after 60% VO2max versus non-exercise control for 10 h among ACE II/ID (6 mm Hg) and AT1R AA (8 mm Hg); and by 8 mm Hg after 40% VO2max among ACE DD and AT1R CC/CA (p < 0.01). With HighCa, SBP (8 mm Hg) and DBP (4 mm Hg) decreased after 60% VO2max compared to non-exercise control for 10 h (p < 0.05), but not after 40% VO2max (p > or = 0.05). SBP decreased after exercise compared to non-exercise control among men with low but not high dietary calcium

  19. Low Response of Renin–Angiotensin System to Sodium Intake Intervention in Chinese Hypertensive Patients

    PubMed Central

    Feng, Weijing; Cai, Qingqing; Yuan, Woliang; Liu, Yu; Bardeesi, Adham Sameer A.; Wang, Jingfeng; Chen, Jie; Huang, Hui

    2016-01-01

    Abstract The interactions of sodium balance and response of renin–angiotensin–aldosterone system are important for maintaining the hemodynamic stability in physiological conditions. However, the influence of short-term sodium intake intervention in the response of renin–angiotensin system (RAS) on hypertensive patients is still unclear. Thus, we conducted a clinical trial to investigate the effects of short-term sodium intake intervention on the response of RAS in hypertensive patients. One hundred twenty-five primary Chinese hypertensive patients were divided into high, moderate, and low sodium groups by 24-hour urinary sodium excretion (UNa+). All the patients received a 10-day dietary sodium intake intervention with standardized sodium (173.91mmol/day) and potassium (61.53mmol/day). Blood pressure, urinary sodium, urinary potassium, plasma sodium, potassium, creatinine, the levels of plasma renin activity, plasma angiotensin II concentrations (AT-II), and plasma aldosterone concentrations were detected before and after the intervention. Before the intervention, no differences were found in blood pressure and RAS among 3 groups. After standardized dietary sodium intake intervention, both UNa+ excretion and systolic pressure decreased in high-sodium group, while they increased in moderate and low-sodium groups. Intriguingly, there were no changes in the levels of plasma renin activity, AT-II, and plasma aldosterone concentrations among 3 groups during the intervention. The present study demonstrated that the influenced sodium excretion and blood pressure by short-term sodium intake intervention were independent of RAS quick response in Chinese hypertensive patients. PMID:26871780

  20. Beta2-adrenergic receptor genotype affects the renin-angiotensin-aldosterone system response to the Dietary Approaches to Stop Hypertension (DASH) dietary pattern.

    PubMed

    Sun, Bei; Williams, Jonathan S; Svetkey, Laura P; Kolatkar, Nikheel S; Conlin, Paul R

    2010-08-01

    Beta(2)-adrenergic receptor (beta2-AR) is a susceptibility locus for hypertension, and polymorphisms at this site relate to salt sensitivity and low plasma renin activity (PRA). The Dietary Approaches to Stop Hypertension (DASH) dietary pattern lowers blood pressure and appears to interact with the renin-angiotensin-aldosterone system (RAAS). We hypothesized that the DASH diet associates with increased RAAS activity, and genotype status at beta2-AR G46A modifies this response. We genotyped participants in the DASH-Sodium study (n = 372) at beta2-AR G46A to determine the association with blood pressure, RAAS components, and consumption of the DASH diet. We used 2-way mixed linear regression and an additive model for all primary analyses. Mean (+/-SEM) PRA was significantly higher in participants in the DASH group than in participants in the control group (0.68 +/- 0.03 compared with 0.54 +/- 0.03 ng x mL(-1) x h(-1), P = 0.002). Serum aldosterone, urinary aldosterone, and urinary potassium concentrations were also significantly higher in the DASH group (P < 0.01 for all). We observed significant gene-diet interactions for changes in systolic blood pressure (SBP) and concentrations of aldosterone and urinary potassium (P for interaction = 0.048, 0.017, and 0.001 for SBP and aldosterone and urinary potassium concentrations, respectively). There was an association between the A allele of beta2-AR G46A and greater blood pressure reduction and blunted aldosterone and PRA responses to the DASH diet. Our results indicate that the DASH diet lowers blood pressure and increases PRA and aldosterone concentrations. There is an association between the G46A polymorphism of beta2-AR and blood pressure and RAAS responses to the DASH diet, which suggests that beta2-AR may be a genetic modifier of DASH-diet responsiveness. This trial was registered at clinicaltrials.gov as NCT00000608.

  1. Aldosterone, Renin, and Diabetes Mellitus in African Americans: The Jackson Heart Study

    PubMed Central

    Joseph, Joshua J.; Echouffo-Tcheugui, Justin B.; Kalyani, Rita R.; Yeh, Hsin-Chieh; Bertoni, Alain G.; Effoe, Valery S.; Casanova, Ramon; Sims, Mario; Correa, Adolfo; Wu, Wen-Chih; Wand, Gary S.

    2016-01-01

    Context: Previous research has suggested that activation of the renin-angiotensin-aldosterone system may promote insulin resistance and β-cell dysfunction, but the association with incident diabetes in African Americans is unknown. Objective: We examined the association of aldosterone and renin with insulin resistance, β-cell function, and incident diabetes in a large African American cohort. Design: The Jackson Heart Study is a prospective study of the development and progression of cardiovascular disease in African Americans. Setting: Participants were recruited from the tricounty area of metropolitan Jackson, Mississippi. Participants: A total of 5301 African American adults, aged 21–94 years, were assessed at baseline and through 12 years of follow-up. Data on aldosterone, renin, and risk factors were collected at baseline (2000–2004). Diabetes (fasting glucose ≥ 126 mg/dL, physician diagnosis, use of diabetes drugs, or glycated hemoglobin ≥ 6.5%) was assessed at baseline and through 12 years of follow-up. Participants were excluded for missing data on baseline covariates or diabetes follow-up. Cox regression was used to estimate hazard ratios (HR) for incident diabetes using sequential modeling adjusting for age, sex, education, occupation, systolic blood pressure, current smoking, physical activity, dietary intake, and body mass index. Exposures: Aldosterone, renin, and diabetes risk factors were measured. Outcomes: Outcomes included the homeostatic model assessment of insulin resistance (HOMA-IR) and incident diabetes. Results: Among 3234 participants over a median of 8.0 years of follow-up, there were 554 cases of incident diabetes. Every 1% increase in log-transformed aldosterone was associated with a 0.18% higher log-transformed HOMA-IR in cross-sectional analyses of nondiabetic participants (P < .001). Log-transformed aldosterone and renin levels in the fifth vs first quintile were associated with a 78% (HR 1.78, 95% confidence interval 1.35

  2. Genetic variation in renin predicts the effects of thiazide diuretics.

    PubMed

    Huang, Chin-Chou; Chung, Chia-Min; Hung, Shuen-Iu; Leu, Hsin-Bang; Wu, Tao-Cheng; Huang, Po-Hsun; Lin, Shing-Jong; Pan, Wen-Harn; Chen, Jaw-Wen

    2011-08-01

    While genetic variants of renin-angiotensin-aldosterone system (RAAS) may modify the blood pressure (BP) response to thiazide diuretics, there was no evidence of genetic variations in renin (REN) playing a role. This study aimed to address the potential effects of genetic variations of RAAS on the response to initial treatment of hydrochlorothiazide (HCTZ). We enrolled nondiabetic hypertensive patients with a systolic blood pressure (SBP) ≥140 or a diastolic blood pressure (DBP) ≥90mmHg, who were either previously untreated or unsatisfactorily treated. After lifestyle modification and diet instruction for 2weeks, 90 patients with persistently elevated BP were given HCTZ 50 mg every morning for 2 weeks. Single nucleotide polymorphism markers were selected from genes involving in RAAS, including rs7079 and rs699 of angiotensinogen, rs4293 and rs4353 of angiotensin-converting enzyme and rs1464816 and rs11240688 of REN. The patients were divided into three groups according to the SBP response after HCTZ. The upper 1/3 responders had older age (P=0·035), higher SBP (P=0·039), higher pulse pressure (P=0·006) and lower plasma REN activity (PRA) (P=0·020) when compared with the lower 1/3 responders. Renin rs11240688 CC polymorphism (β=9·931, corrected P=0·012), Log PRA (β=7·451, P=0·004) and baseline SBP (β=0·299, P=0·006) were the independent predictors for the BP lowering response. In addition to PRA, renin rs11240688 CC polymorphism may also independently predict the effect of HCTZ. © 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.

  3. Up-regulation of renal renin-angiotensin system and inflammatory mechanisms in the prenatal programming by low-protein diet: beneficial effect of the post-weaning losartan treatment.

    PubMed

    Watanabe, I K M; Jara, Z P; Volpini, R A; Franco, M D C; Jung, F F; Casarini, D E

    2018-05-06

    Previous studies have shown that the renin-angiotensin system (RAS) is affected by adverse maternal nutrition during pregnancy. The aim of this study was to investigate the effects of a maternal low-protein diet on proinflammatory cytokines, reactive oxygen species and RAS components in kidney samples isolated from adult male offspring. We hypothesized that post-weaning losartan treatment would have beneficial effects on RAS activity and inflammatory and oxidative stress markers in these animals. Pregnant Sprague-Dawley rats were fed with a control (20% casein) or low-protein diet (LP) (6% casein) throughout gestation. After weaning, the LP pups were randomly assigned to LP and LP-losartan groups (AT1 receptor blockade: 10 mg/kg/day until 20 weeks of age). At 20 weeks of age, blood pressure levels were higher and renal RAS was activated in the LP group. We also observed several adverse effects in the kidneys of the LP group, including a higher number of CD3, CD68 and proliferating cell nuclear antigen-positive cells and higher levels of collagen and reactive oxygen species in the kidney. Further, our results revealed that post-weaning losartan treatment completely abolished immune cell infiltration and intrarenal RAS activation in the kidneys of LP rats. The prevention of augmentation of angiotensin (Ang II) concentration abolished inflammatory and fibrotic events, indicating that Ang II via the AT1 receptor is essential for pathological initiation. Our results suggest that the prenatal programming of hypertension is dependent on the up-regulation of local RAS and presence of immune cells in the kidney.

  4. Controlled treatment of primary hypertension with propranolol and spironolactone. A crossover study with special reference to initial plasma renin activity.

    PubMed

    Karlberg, B E; Kågedal, B; Tegler, L; Tolagen, K; Bergman, B

    1976-03-31

    Twenty-seven patients with hypertension were randomly allocated to a 10 month crossover study. Treatment consisted of spironolactone (200 mg/day for 2 months), propranolol (320 mg/day for 2 months) and combined administration of both drugs at half the dosage. Between treatment periods placebo was given for 2 months. Fourteen patients were previously untreated. The average pretreatment blood pressure for the entire group was 188/114 +/- 16/7(mean +/- standard deviation) mm Hg supine and 188/118 +/- 20/9 mm Hg standing. Both spironolactone and propranolol reduced blood pressure significantly in both the supine and standing positions. Upright plasma renin activity was determined by radioimmunoassay of angiotensin I. The average initial level was 1.9 +/- 1.2 (range 0.4 to 5.0) ng/ml/hr. There was a close correlation between plasma renin activity and the effects of the drugs: With increasing renin level the response to propranolol was better whereas the opposite was true for spironolactone. The combination of spironolactone and propranolol decreased the blood pressure still further in the supine and standing positions, irrespective of initial plasma renin activity. All patients achieved a normal supine pressure. Blood pressure and plasma renin activity returned toward pretreatment values during placebo administration. It is concluded that pretreatment levels of plasma renin activity can predict the antihypertensive response to propranolol and spironolactone. The combination of the two drugs, which have different modes of action, will effectively reduce blood pressure in hypertension. The results support the concept that the renin-angiotensin-aldo-sterone system may be involved in primary hypertension.

  5. Enhancement of Adipocyte Browning by Angiotensin II Type 1 Receptor Blockade.

    PubMed

    Tsukuda, Kana; Mogi, Masaki; Iwanami, Jun; Kanno, Harumi; Nakaoka, Hirotomo; Wang, Xiao-Li; Bai, Hui-Yu; Shan, Bao-Shuai; Kukida, Masayoshi; Higaki, Akinori; Yamauchi, Toshifumi; Min, Li-Juan; Horiuchi, Masatsugu

    2016-01-01

    Browning of white adipose tissue (WAT) has been highlighted as a new possible therapeutic target for obesity, diabetes and lipid metabolic disorders, because WAT browning could increase energy expenditure and reduce adiposity. The new clusters of adipocytes that emerge with WAT browning have been named 'beige' or 'brite' adipocytes. Recent reports have indicated that the renin-angiotensin system (RAS) plays a role in various aspects of adipose tissue physiology and dysfunction. The biological effects of angiotensin II, a major component of RAS, are mediated by two receptor subtypes, angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R). However, the functional roles of angiotensin II receptor subtypes in WAT browning have not been defined. Therefore, we examined whether deletion of angiotensin II receptor subtypes (AT1aR and AT2R) may affect white-to-beige fat conversion in vivo. AT1a receptor knockout (AT1aKO) mice exhibited increased appearance of multilocular lipid droplets and upregulation of thermogenic gene expression in inguinal white adipose tissue (iWAT) compared to wild-type (WT) mice. AT2 receptor-deleted mice did not show miniaturization of lipid droplets or alteration of thermogenic gene expression levels in iWAT. An in vitro experiment using adipose tissue-derived stem cells showed that deletion of the AT1a receptor resulted in suppression of adipocyte differentiation, with reduction in expression of thermogenic genes. These results indicate that deletion of the AT1a receptor might have some effects on the process of browning of WAT and that blockade of the AT1 receptor could be a therapeutic target for the treatment of metabolic disorders.

  6. Angiotensin converting enzyme DD genotype is associated with hypertensive crisis.

    PubMed

    Sunder-Plassmann, Gere; Kittler, Harald; Eberle, Corinna; Hirschl, Michael M; Woisetschläger, Christian; Derhaschnig, Ulla; Laggner, Anton N; Hörl, Walter H; Födinger, Manuela

    2002-10-01

    The genetic background of hypertensive crisis is unknown. We examined the association of polymorphisms in genes involved in the renin-angiotensin-aldosterone-system with hypertensive crisis. Population-based case-control study. Emergency department at a tertiary care university hospital. A total of 182 patients with essential hypertension who were admitted to an emergency department for treatment of hypertensive crisis and 182 age- and sex-matched healthy individuals. None. Analysis of polymorphisms in genes coding for angiotensinogen (AJT 704T-->C), angiotensin II receptor 1 (AGTR1 1166A-->C), renin (REN 2646G-->A), renin-binding protein (RENBP 61T-->C), alpha-adducin (ADD1 1378G-->T), beta-2-adrenergic receptor (ADRB2 46A-->G, 79C-->G), and angiotensin I converting enzyme (ACE I/D) was performed by polymerase chain reaction and restriction fragment length polymorphism analysis. MAIN RESULTS Among patients, the ACE I/D polymorphism showed a deviation from Hardy-Weinberg equilibrium (p =.01). In controls, all polymorphisms were in the Hardy-Weinberg equilibrium. The frequency of the DD genotype was increased in patients (n = 70, 38.5%) vs. controls (n = 51; 28.0%;p =.03; odds ratio, 1.61; 95% confidence interval, 1.03-2.50), which was due to the DD genotype in 40 male patients (44%) vs. 23 in male controls (25.3%;p =.004; odds ratio, 3.48; 95% confidence interval, 1.47-8.30). There were no differences in genotype distributions among other polymorphisms. We demonstrate a possible association of the DD genotype with hypertensive crisis in men.

  7. Angiotensin II-mediated microvascular thrombosis

    PubMed Central

    Senchenkova, Elena Y.; Russell, Janice; Almeida-Paula, Lidiana D.; Harding, Joseph W.; Granger, D. Neil

    2010-01-01

    Hypertension is associated with an increased risk of thrombosis that appears to involve an interaction between the renin-angiotensin system and hemostasis. In this study we determined whether angiotensin II-mediatedthrombosis occurs in arterioles and/or venules, and assessed the involvement of type-1 (AT1), type-2 (AT2) and type 4 (AT4) angiotensin II receptors, as well as receptors for endothelin-1 (ET-1) and bradykinin (BK-1, BK-2) in angiotensin II-enhanced microvascular thrombosis. Thrombus development in mouse cremaster microvessels was quantified after light/dye injury using the time of onset of the thrombus and time to blood flow cessation. Wild type and AT1-receptor deficient mice were implanted with an angiotensin II-loaded Alzet pump for 2 wks. Angiotensin II administration in both wild type and AT1-receptor deficient mice significantly accelerated thrombosis in arterioles. Genetic deficiency and pharmacological antagonism of AT1-receptors did not alter the thrombosis response to angiotensin II. Isolated murine platelets aggregated in response to low (pM), but not high (nM), concentrations of angiotensin II. The platelet aggregation response to angiotensin II was dependent on AT1-receptors. Antagonism of AT2-receptors in vivo significantly prolonged the onset of angiotensin II enhanced thrombosis, while an AT4-receptor antagonist prolonged the time to flow cessation. Selective antagonism of either ET-1 or BK-1 receptors largely prevented both the onset and flow cessation responses to chronic angiotensin II infusion. Our findings indicate that angiotensin II-induced hypertension is accompanied by enhanced thrombosis in arterioles and this response is mediated by a mechanism that involves AT2, AT4, BK-1 and ET-1 receptor-mediated signaling. PMID:20975035

  8. High, but not low, exercise volume shifts the balance of renin-angiotensin system toward ACE2/Mas receptor axis in skeletal muscle in obese rats.

    PubMed

    Frantz, Eliete Dalla Corte; Giori, Isabele Gomes; Machado, Marcus Vinícius; Magliano, D'Angelo Carlo; Freitas, Fernanda Marques; Andrade, Mariana Sodré Boêta; Vieira, Aline Bomfim; Nóbrega, Antonio Claudio Lucas; Tibiriçá, Eduardo

    2017-10-01

    Metabolic syndrome is a cluster of metabolic risk factors that is linked to central obesity, elevated blood pressure, insulin resistance (IR), and dyslipidemia, where the renin-angiotensin system (RAS) may provide a link among them. This study aimed to evaluate volume exercise effects comparing low vs. high volume of chronic aerobic exercise on RAS axes in skeletal muscle in a diet-induced obesity (DIO) rat model. For this, male Wistar-Kyoto rats were fed a standard chow (SC) diet or a high-fat (HF) diet for 32 wk. Animals receiving the HF diet were randomly divided into low exercise volume (LEV, 150 min/wk) and high exercise volume (HEV, 300 min/wk) at the 20th week. After 12 wk of aerobic treadmill training, the body mass and composition, blood pressure, glucose and lipid metabolism, RAS axes, insulin signaling, and inflammatory pathway were performed. HEV slowed the body mass gain, reduced intra-abdominal fat pad and leptin levels, improved total and peripheral body composition and inflammatory cytokine, reduced angiotensin II type 1 receptor expression, and increased Mas receptor protein expression compared with the HF animals. Sedentary groups (SC and HF) presented lower time to exhaustion and maximal velocity compared with the LEV and HEV groups. Both exercise training groups showed reduced resting systolic blood pressure and heart rate, improved glucose tolerance, IR, insulin signaling, and lipid profile. We conclude that the HEV, but not LEV, shifted the balance of RAS toward the ACE2/Mas receptor axis in skeletal muscle, presenting protective effects against the DIO model. Copyright © 2017 the American Physiological Society.

  9. Prenatal Exposure to Angiotensin II Receptor Blockers and Hemodynamic Effects on the Newborn.

    PubMed

    Rodríguez-Castaño, MaJosé; Corredera, Araceli; Aleo, Esther; Arruza, Luis

    2015-04-01

    Angiotensin II receptor blockers (ARBs) are potent antihypertensive agents that block the renin angiotensin aldosterone system (RAS). Their use in pregnancy may cause malformations, oligoanuria, hypotension, and death. Hypotension is observed up to 15% of cases and is described as refractory to volume and inotropic support, although its pathophysiology is unknown. We present a case of prenatal exposure to ARBs in order to characterize the hemodynamic compromise in the newborn, help in decision-making, and guide the therapeutic approach to these patients.

  10. In Vitro Modulation of Renin-Angiotensin System Enzymes by Amaranth (Amaranthus hypochondriacus) Protein-Derived Peptides: Alternative Mechanisms Different from ACE Inhibition.

    PubMed

    Quiroga, Alejandra V; Aphalo, Paula; Nardo, Agustina E; Añón, María C

    2017-08-30

    Among the factors affecting the development of cardiovascular diseases, hypertension is one of the most important. Research done on amaranth proteins has demonstrated their hypotensive capacity in vivo and in vitro; nevertheless, the mechanism underlying this effect remains unclear. The aim of this study was to analyze in vitro the inhibition of peptides derived from an amaranth hydrolysate (AHH) on other RAS enzymes other than ACE. The chymase and renin activities were studied. AHH was not able to inhibit chymase activity, although a dose-response effect was found on renin activity (IC 50 0.6 mg/mL). To provide an approach to the renin inhibition mechanism, we analyzed AHH renin inhibition kinetics and performed a structural characterization of the peptides involved in the effect in terms of molecular size and hydrophobicity. Results suggest that amaranth peptides exhibit renin competitive inhibition behavior. Renin inhibition potency was directly related to peptide hydrophobicity. RP-HPLC separation of AHH and subsequent analysis of the peptide sequences showed 6 peptides belonging to 11S globulin (that can be grouped into 3 families) that would be responsible for renin inhibition. These results demonstrate that Amaranthus hypochondriacus seeds are an adequate source of peptides with renin inhibitory properties that could be used in functional food formulations.

  11. The Association Between Renin-Angiotensin System Blockade and Long-term Outcomes in Renal Transplant Recipients: The Wisconsin Allograft Recipient Database (WisARD).

    PubMed

    Shin, Jung-Im; Palta, Mari; Djamali, Arjang; Kaufman, Dixon B; Astor, Brad C

    2016-07-01

    Renin-angiotensin system (RAS) blockade reduces mortality in the general population and among non-dialysis-dependent patients with chronic kidney disease. The RAS blockade also decreases proteinuria and protects renal function in non-transplant patients with chronic kidney disease. It remains controversial, however, whether this translates to improved patient or graft survival among transplant recipients. We analyzed 2684 primary kidney transplant recipients at the University of Wisconsin in 1994 to 2010 who had a functioning graft at 6 months after transplantation. We assessed the association of RAS blockade with patient and graft survival using time-dependent Cox and marginal structural models. Three hundred seventy-seven deaths and 329 graft failures before death (638 total graft losses) occurred during a median of 5.4 years of follow-up. The RAS blockade was associated with an adjusted-hazard ratio of 0.63 (95% confidence interval, 0.53-0.75) for total graft loss, 0.69 (0.55-0.86) for death, and 0.62 (0.49-0.78) for death-censored graft failure. The associations of RAS blockade with a lower risk of total graft loss and mortality were stronger with more severe proteinuria. The RAS blockade was associated with a 2-fold higher risk of hyperkalemia. Our findings suggest RAS blockade is associated with better patient and graft survival in renal transplant recipients.

  12. Synergic effects of renin and aldosterone on right ventricular function in hypertension: a tissue Doppler study.

    PubMed

    Gregori, Mario; Giammarioli, Benedetta; Tocci, Giuliano; Befani, Alberto; Ciavarella, Giuseppino Massimo; Ferrucci, Andrea; Paneni, Francesco

    2015-12-01

    Right ventricular dysfunction (RVD) is associated with poor cardiovascular outcome. The renin-angiotensin-aldosterone system is involved in alterations of the left ventricular geometry and function. Detrimental effects of the renin-angiotensin-aldosterone system on the right ventricular function are being postulated, but data supporting this assumption are still lacking. The aim of the study was to assess the impact of hyperreninemia, hyperaldosteronism or their combination on right ventricular function in hypertensive individuals. Plasma renin activity (PRA) and plasma aldosterone concentrations (PACs) were measured in 116 hypertensive patients, divided as follows: normal PRA and PAC (n = 38); high PRA and normal PAC (hypereninemia) (n = 26); normal PRA and high PAC (hyperaldosternism) (n = 27); high PRA and PAC (HRA) (n = 25). Echocardiographic evaluation of the left and right ventricles (RV), including tissue Doppler imaging, was performed. RVD was identified by tissue Doppler Imaging-derived Myocardial Performance Index, calculated with a multisegmental approach. Indices of the right ventricular structure and function, as well as the prevalence of RVD, were higher in hyperreninemia and hyperaldosternism groups as compared with the normal group, and a further increase was observed in the HRA patients. Regression models showed a similar risk of RVD in the hyperreninemia and hyperaldosternism patients, regardless of systemic and pulmonary pressure, as well as left ventricular dysfunction. Notably, patients with both hyperreninemia and hyperaldosternism exhibited the strongest association with RVD as compared with patients with only hyperreninemia or hyperaldosternism. Isolated hyperreninemia or hyperaldosternism determines a similar impairment of the right ventricular function, whereas their combination is further detrimental. Renin and aldosterone may represent early biomarkers of right ventricular dysfunction in hypertension.

  13. Subcellular characteristics of functional intracellular renin–angiotensin systems☆

    PubMed Central

    Abadir, Peter M.; Walston, Jeremy D.; Carey, Robert M.

    2013-01-01

    The renin–angio tensin system (RAS) is now regarded as an integral component in not only the development of hypertension, but also in physiologic and pathophysiologic mechanisms in multiple tissues and chronic disease states. While many of the endocrine (circulating), paracrine (cell-to-different cell) and autacrine (cell-to-same cell) effects of the RAS are believed to be mediated through the canonical extracellular RAS, a complete, independent and differentially regulated intracellular RAS (iRAS) has also been proposed. Angiotensinogen, the enzymes renin and angiotensin-converting enzyme (ACE) and the angiotensin peptides can all be synthesized and retained intracellularly. Angiotensin receptors (types I and 2) are also abundant intracellularly mainly at the nuclear and mitochondrial levels. The aim of this review is to focus on the most recent information concerning the subcellular localization, distribution and functions of the iRAS and to discuss the potential consequences of activation of the subcellular RAS on different organ systems. PMID:23032352

  14. [Up-regulation of intrarenal renin-angiotensin system contributes to renal damage in high-salt induced hypertension rats].

    PubMed

    Wu, Hai-yan; Liang, Yao-xian; Bai, Qiong; Zhuang, Zhen; A, La-ta; Zheng, Dan-xia; Wang, Yue

    2015-02-18

    To test the hypothesis that in a high-salt induced hypertension in normal rats, whether the changes of intrarenal renin-agiotensin system (RAS) play a critical role in renal damage and could be reflected by urinary angiotensinogen (AGT). In the study, 27 normotensive male Wistar-Kyoto rats were divided into control group [0.3% (mass faction) NaCl in chow, n=9, NS], high-salt diet group [8% (mass faction) NaCl in chow, n=9, HS] and high-salt diet with Losartan group [8% (mass faction) NaCl in chow and 20 mg/(kg×d) Losartan in gavages, n=9, HS+L)], and were fed for six weeks. The blood pressure was monitored and urine samples were collected every 2 weeks. AGTs in plasma, kidney and urine were measured by ELISA kits. The renal cortex expression of mRNA and protein of AGT were measured by Real-time PCR and immunohistochemistry (IHC). The renin activity and ANG II were measured by radioimmunoassay (RIA) kits. Compared with NS, the systolic blood pressure (SBP) [(156 ± 2) mmHg vs. (133 ± 3) mmHg, P<0.05] increased significantly at the end of the 2nd week, and the urinary protein [(14.07 ± 2.84) mg/24 h vs. (7.62 ± 3.02) mg/24 h, P<0.05] increased significantly at the end of the 6th week in HS. Compared with HS, there was no significant difference in SBP (P>0.05) but the proteinuria [(9.69 ± 2.73) mg/24 h vs. (14.07 ± 2.84) mg/24 h, P<0.01] decreased significantly in HS+L. Compared with NS, there was no significant difference in the plasma renin activity, angiotensinogen and ANG II level in HS (P>0.05), but the renal cortex renin content [(8.72 ± 1.98) ng/(mL × h) vs. (4.37 ± 1.26) ng/(mL × h), P<0.05], AGT formation [(4.02 ± 0.60) ng/mg vs. (2.59 ± 0.42) ng/mg, P<0.01], ANG II level [(313.8 ± 48.76) pmol/L vs. (188.9 ± 46.95) pmol/L, P<0.05] were increased significantly in HS, and the urinary AGT and ANG II excretion rates increased significantly (P<0.05). Compared with HS, the plasma renin activity, angiotensinogen and ANG II level were significantly

  15. Recent Advances in the Gastric Mucosal Protection Against Stress-induced Gastric Lesions. Importance of Renin-angiotensin Vasoactive Metabolites, Gaseous Mediators and Appetite Peptides.

    PubMed

    Brzozowski, Tomasz; Magierowska, Katarzyna; Magierowski, Marcin; Ptak-Belowska, Agata; Pajdo, Robert; Kwiecien, Slawomir; Olszanecki, Rafal; Korbut, Ryszard

    2017-01-01

    Stress is known to cause severe adverse effects in the human gastrointestinal tract including mucosal microbleedings and erosions or even gastric ulceration but the mechanism of these complications has not been fully elucidated. The pathogenesis of stress-induced gastric damage involves the fall in Gastric Blood Flow (GBF), an increase in gastric acid secretion and gastric motility, enhanced adrenergic and cholinergic nerve activity and the rise in gastric mucosal generation of reactive oxygen species. The gastric mucosal defense mechanisms against the deleterious effect of stress include the activation of the hypothalamic-pituitary-adrenal axis which has been linked with glucocorticoids release capable of counteracting of stress-induced gastric lesions. Here we summarize the novel gastroprotective mechanisms against stress damage exhibited by angiotensin-(1-7), the newly discovered metabolite of Renin-Angiotensin System (RAS), the gaseous mediators such as nitric oxide (NO), hydrogen sulfide (H2S) or Carbon Monoxide (CO), and the food intake controlling peptides ghrelin, nesfatin- 1 and apelin possibly acting via brain-gut axis. These bioactive molecules such as RAS vasoactive metabolite angiotensin-(1-7) and appetite peptides have been shown to afford gastroprotective effect against stressinduced gastric lesions mainly mediated by an increase in gastric microcirculation. Gaseous mediators protect the gastric mucosa against stress lesions by mechanism involving the activation of PG/COX and CO/HO-1 biosynthetic pathways, and their anti-inflammatory and anti-oxidizing properties. Thus, these new components add new mechanistic aspects to the common cooperation of NO/NO-synthase, PG/COX systems and vasoactive sensory neuropeptides including CGRP but their gastroprotective efficacy against experimental stress ulcerogenesis requires the confirmation in human clinical trials. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Study of the rat adrenal renin-angiotensin system at a cellular level.

    PubMed Central

    Chiou, C Y; Williams, G H; Kifor, I

    1995-01-01

    To address the question as to how zona glomerulosa (ZG) cell angiotensin II (Ang II) secretion is regulated, we developed an immuno-cell blot assay to measure its secretion from single cells. We compared these results with those obtained from population studies using a superfusion system. Modulation of Ang II secretion was investigated acutely (by administrating potassium [K+] or captopril) and chronically (by feeding the animals low or high sodium diets). The area of secretory cells, halo areas, and halo intensities varied widely but were highly significantly correlated (P < 0.001) with each other. A disproportionate amount of Ang II was secreted by a small number of large cells. When K+ concentration was increased from 3.6 to 0 mM, superfused ZG cells increased their Ang II secretion 2.32 +/- 0.59-fold. Administration of captopril reduced the K(+)-stimulated Ang II secretion 1.24 +/- 0.07 fold. These findings were reflected in the cell blot assay as a change in the frequency distribution of halo area by K+ and captopril in the same direction as in the population study. In both conditions, the percentage of secretory cells did not change significantly from control. Superfused ZG cells from rats on a low sodium diet secreted 1.85 +/- 0.58-fold more Ang II than cells from sodium-loaded rats (p < 0.05, n = 6). The cell blot assay confirmed these findings with sodium restriction significantly increasing (P < 0.001) both the halo area and its frequency distribution to a larger portion of high secreting cells. However, in contrast to acute treatment with K+ or captopril, the number of secretory cells also doubled. Thus, the individual ZG cell uses two mechanisms to modify Ang II production. In response to acute stimulation and suppression, the amount of Ang II secreted per cell is modified without changing the number of secretary cells. With chronic stimulation, both the amount of Ang II secreted per cell and the number of secretary cells increase. Images PMID:7657812

  17. Murine recombinant angiotensin-converting enzyme 2 attenuates kidney injury in experimental Alport syndrome.

    PubMed

    Bae, Eun Hui; Fang, Fei; Williams, Vanessa R; Konvalinka, Ana; Zhou, Xiaohua; Patel, Vaibhav B; Song, Xuewen; John, Rohan; Oudit, Gavin Y; Pei, York; Scholey, James W

    2017-06-01

    Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase in the renin-angiotensin system that catalyzes the breakdown of angiotensin II to angiotensin 1-7. We have reported that ACE2 expression in the kidney is reduced in experimental Alport syndrome but the impact of this finding on disease progression has not been studied. Accordingly, we evaluated effects of murine recombinant ACE2 treatment in Col4a3 knockout mice, a model of Alport syndrome characterized by proteinuria and progressive renal injury. Murine recombinant ACE2 (0.5 mg/kg/day) was administered from four to seven weeks of age via osmotic mini-pump. Pathological changes were attenuated by murine recombinant ACE2 treatment which ameliorated kidney fibrosis as shown by decreased expression of COL1α1 mRNA, less accumulation of extracellular matrix proteins, and inhibition of transforming growth factor-β signaling. Further, increases in proinflammatory cytokine expression, macrophage infiltration, inflammatory signaling pathway activation, and heme oxygenase-1 levels in Col4a3 knockout mice were also reduced by murine recombinant ACE2 treatment. Lastly, murine recombinant ACE2 influenced the turnover of renal ACE2, as it suppressed the expression of tumor necrosis factor-α converting enzyme, a negative regulator of ACE2. Thus, treatment with exogenous ACE2 alters angiotensin peptide metabolism in the kidneys of Col4a3 knockout mice and attenuates the progression of Alport syndrome nephropathy. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  18. Neprilysin Is Required for Angiotensin-(1-7)'s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1-2).

    PubMed

    Brar, Gurkirat S; Barrow, Breanne M; Watson, Matthew; Griesbach, Ryan; Choung, Edwina; Welch, Andrew; Ruzsicska, Bela; Raleigh, Daniel P; Zraika, Sakeneh

    2017-08-01

    Recent work has renewed interest in therapies targeting the renin-angiotensin system (RAS) to improve β-cell function in type 2 diabetes. Studies show that generation of angiotensin-(1-7) by ACE2 and its binding to the Mas receptor (MasR) improves glucose homeostasis, partly by enhancing glucose-stimulated insulin secretion (GSIS). Thus, islet ACE2 upregulation is viewed as a desirable therapeutic goal. Here, we show that, although endogenous islet ACE2 expression is sparse, its inhibition abrogates angiotensin-(1-7)-mediated GSIS. However, a more widely expressed islet peptidase, neprilysin, degrades angiotensin-(1-7) into several peptides. In neprilysin-deficient mouse islets, angiotensin-(1-7) and neprilysin-derived degradation products angiotensin-(1-4), angiotensin-(5-7), and angiotensin-(3-4) failed to enhance GSIS. Conversely, angiotensin-(1-2) enhanced GSIS in both neprilysin-deficient and wild-type islets. Rather than mediating this effect via activation of the G-protein-coupled receptor (GPCR) MasR, angiotensin-(1-2) was found to signal via another GPCR, namely GPCR family C group 6 member A (GPRC6A). In conclusion, in islets, intact angiotensin-(1-7) is not the primary mediator of beneficial effects ascribed to the ACE2/angiotensin-(1-7)/MasR axis. Our findings warrant caution for the concurrent use of angiotensin-(1-7) compounds and neprilysin inhibitors as therapies for diabetes. © 2017 by the American Diabetes Association.

  19. The Relationship Between the Renin-Angiotensin-Aldosterone System and NMDA Receptor-Mediated Signal and the Prevention of Retinal Ganglion Cell Death.

    PubMed

    Kobayashi, Mamoru; Hirooka, Kazuyuki; Ono, Aoi; Nakano, Yuki; Nishiyama, Akira; Tsujikawa, Akitaka

    2017-03-01

    Excitotoxicity, which is due to glutamate-induced toxic effects on the retinal ganglion cell (RGC), is one of several mechanisms of RGC loss. The renin-angiotensin-aldosterone system (RAAS) has also been implicated in RGC death. Therefore, it is important to determine the exact relationship between the RAAS and N-methyl-d-aspartate (NMDA) receptor-mediated signal in order to prevent RGC death. N-methyl-d-aspartate or aldosterone was injected into the vitreous body. After intravitreal injection of NMDA or aldosterone, animals were treated with spironolactone or memantine. Retinal damage was evaluated by measuring the number of RGCs at 4 weeks after local administration of aldosterone or at 2 weeks after local administration of NMDA. Vitreous humor levels of aldosterone were measured using enzyme immunoassay kits. A significantly decreased number of RGCs were observed after intravitreal injection of NMDA. Although spironolactone did not show any neuroprotective effects, memantine significantly reduced NMDA-induced degeneration in the retina. Furthermore, a significant decrease in the number of RGCs was observed after an intravitreal injection of aldosterone. While memantine did not exhibit any neuroprotective effects, spironolactone caused a significant reduction in the aldosterone-induced degeneration in the retina. There was no change in the aldosterone concentration in the vitreous humor after an NMDA injection. Our findings indirectly show that there is no relationship between the RAAS and NMDA receptor-mediated signal with regard to RGC death.

  20. The Impact of Renin-Angiotensin System Blockade on Renal Outcomes and Mortality in Pre-Dialysis Patients with Advanced Chronic Kidney Disease.

    PubMed

    Oh, Yun Jung; Kim, Sun Moon; Shin, Byung Chul; Kim, Hyun Lee; Chung, Jong Hoon; Kim, Ae Jin; Ro, Han; Chang, Jae Hyun; Lee, Hyun Hee; Chung, Wookyung; Lee, Chungsik; Jung, Ji Yong

    2017-01-01

    Renin-angiotensin-system (RAS) blockade is thought to slow renal progression in patients with chronic kidney disease (CKD). However, it remains uncertain if the habitual use of RAS inhibitors affects renal progression and outcomes in pre-dialysis patients with advanced CKD. In this multicenter retrospective cohort study, we identified 2,076 pre-dialysis patients with advanced CKD (stage 4 or 5) from a total of 33,722 CKD patients. RAS blockade users were paired with non-users for analyses using inverse probability of treatment-weighted (IPTW) and propensity score (PS) matching. The outcomes were renal death, all-cause mortality, hospitalization for hyperkalemia, and interactive factors as composite outcomes. RAS blockade users showed an increased risk of renal death in PS-matched analysis (hazard ratio [HR], 1.381; 95% CI, 1.071-1.781; P = 0.013), which was in agreement with the results of IPTW analysis (HR, 1.298; 95% CI, 1.123-1.500; P < 0.001). The risk of composite outcomes was higher in RAS blockade users in IPTW (HR, 1.154; 95% CI, 1.016-1.310; P = 0.027), but was marginal significance in PS matched analysis (HR, 1.243; 95% CI, 0.996-1.550; P = 0.054). The habitual use of RAS blockades in pre-dialysis patients with advanced CKD may have a detrimental effect on renal outcome without improving all-cause mortality. Further studies are warranted to determine whether withholding RAS blockade may lead to better outcomes in these patients.

  1. Renin-Angiotensin-Aldosterone Signaling Inhibitors-Losartan, Enalapril, and Cardosten-Prevent Infarction-induced Heart Failure Development in Rats.

    PubMed

    Kiss, Krisztina; Fekete, Veronika; Pálóczi, János; Sárközy, Márta; Murlasits, Zsolt; Pipis, Judit; Kheyfets, Irina A; Dugina, Julia L; Sergeeva, Svetlana A; Epstein, Oleg I; Csonka, Csaba; Csont, Tamás; Ferdinandy, Péter; Bencsik, Péter

    2016-01-01

    The activation of the renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathophysiology of congestive heart failure, which is the reason that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin 2 receptor blockers (ARBs) have become established therapies for heart failure. However, it is still not known whether preventive treatment with losartan or enalapril can reduce symptoms of infarction-induced heart failure. Ultra-low dose (ULD) drug therapy is thought to exert specific activity, with a lower chance of side effects. OBJECTIVES • The research team had hypothesized that preventive treatment with inhibitors of RAAS signaling-losartan, enalapril, and a preparation of a ULD antibody (ie, cardosten), which target the angiotensin type 1 (AT1) receptor-might alleviate pathological hypertrophy and/or functional decline in infarction-induced heart failure. The research team treated male Wistar rats orally for 30 d with 20 mg/kg of losartan, 10 mg/kg enalapril, 5 or 7.5 mL/kg of cardosten, or a control solution, started 1 d prior to permanent coronary occlusion. A sham-operated group functioned as a second control group. The study was conducted at the Department of Biochemistry of the Faculty of Medicine at the University of Szeged in Szeged, Hungary, in cooperation with the Pharmahungary Group, also in Szeged, Hungary, and with OOO "NPF" Materia Medica Holding Ltd in Moscow, Russia. To determine cardiac functional parameters in vivo, the research team inserted a catheter into the left ventricle of the rats and measured the parameters of ventricular pressure, and cardiac output was determined by thermodilution. Morphological parameters were measured after heart isolation in transverse sections by a digital caliper. A total of 30 d after permanent coronary ligation, both losartan and enalapril, significantly decreased mean arterial blood pressure (MABP), attenuated the development of the left-ventricular anterior-wall and septum

  2. A century old renin-angiotensin system still grows with endless possibilities: AT1 receptor signaling cascades in cardiovascular physiopathology.

    PubMed

    Balakumar, Pitchai; Jagadeesh, Gowraganahalli

    2014-10-01

    Ang II, the primary effector pleiotropic hormone of the renin-angiotensin system (RAS) cascade, mediates physiological control of blood pressure and electrolyte balance through its action on vascular tone, aldosterone secretion, renal sodium absorption, water intake, sympathetic activity and vasopressin release. It affects the function of most of the organs far beyond blood pressure control including heart, blood vessels, kidney and brain, thus, causing both beneficial and deleterious effects. However, the protective axis of the RAS composed of ACE2, Ang (1-7), alamandine, and Mas and MargD receptors might oppose some harmful effects of Ang II and might promote beneficial cardiovascular effects. Newly identified RAS family peptides, Ang A and angioprotectin, further extend the complexities in understanding the cardiovascular physiopathology of RAS. Most of the diverse actions of Ang II are mediated by AT1 receptors, which couple to classical Gq/11 protein and activate multiple downstream signals, including PKC, ERK1/2, Raf, tyrosine kinases, receptor tyrosine kinases (EGFR, PDGF, insulin receptor), nuclear factor κB and reactive oxygen species (ROS). Receptor activation via G12/13 stimulates Rho-kinase, which causes vascular contraction and hypertrophy. The AT1 receptor activation also stimulates G protein-independent signaling pathways such as β-arrestin-mediated MAPK activation and Src-JAK/STAT. AT1 receptor-mediated activation of NADPH oxidase releases ROS, resulting in the activation of pro-inflammatory transcription factors and stimulation of small G proteins such as Ras, Rac and RhoA. The components of the RAS and the major Ang II-induced signaling cascades of AT1 receptors are reviewed. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Combined Inhibition of the Renin-Angiotensin System and Neprilysin Positively Influences Complex Mitochondrial Adaptations in Progressive Experimental Heart Failure

    PubMed Central

    Reinders, Jörg; Schröder, Josef; Dietl, Alexander; Schmid, Peter M.; Jungbauer, Carsten; Resch, Markus; Maier, Lars S.; Luchner, Andreas; Birner, Christoph

    2017-01-01

    Background Inhibitors of the renin angiotensin system and neprilysin (RAS-/NEP-inhibitors) proved to be extraordinarily beneficial in systolic heart failure. Furthermore, compelling evidence exists that impaired mitochondrial pathways are causatively involved in progressive left ventricular (LV) dysfunction. Consequently, we aimed to assess whether RAS-/NEP-inhibition can attenuate mitochondrial adaptations in experimental heart failure (HF). Methods and Results By progressive right ventricular pacing, distinct HF stages were induced in 15 rabbits, and 6 animals served as controls (CTRL). Six animals with manifest HF (CHF) were treated with the RAS-/NEP-inhibitor omapatrilat. Echocardiographic studies and invasive blood pressure measurements were undertaken during HF progression. Mitochondria were isolated from LV tissue, respectively, and further worked up for proteomic analysis using the SWATH technique. Enzymatic activities of citrate synthase and the electron transfer chain (ETC) complexes I, II, and IV were assessed. Ultrastructural analyses were performed by transmission electron microscopy. During progression to overt HF, intricate expression changes were mainly detected for proteins belonging to the tricarboxylic acid cycle, glucose and fat metabolism, and the ETC complexes, even though ETC complex I, II, or IV enzymatic activities were not significantly influenced. Treatment with a RAS-/NEP-inhibitor then reversed some maladaptive metabolic adaptations, positively influenced the decline of citrate synthase activity, and altered the composition of each respiratory chain complex, even though this was again not accompanied by altered ETC complex enzymatic activities. Finally, ultrastructural evidence pointed to a reduction of autophagolytic and degenerative processes with omapatrilat-treatment. Conclusions This study describes complex adaptations of the mitochondrial proteome in experimental tachycardia-induced heart failure and shows that a combined RAS

  4. Diabetic retinopathy and blockade of the renin-angiotensin system: new data from the DIRECT study programme.

    PubMed

    Wright, A D; Dodson, P M

    2010-01-01

    The pathogenesis and medical management of diabetic retinopathy is reviewed. The importance of good control of blood glucose and blood pressure remain key elements in the prevention and treatment of diabetic retinopathy, and a number of specific metabolic pathways have been identified that may be useful additional targets for therapeutic intervention. Trial data, however, aimed specifically to answer the questions of optimum medical management are limited, so the DIRECT study of renin-angiotensin blockade using oral candesartan 32 mg daily is a welcome addition to our knowledge. This arose from the promising improvement of retinopathy outcomes in the EUCLID study of lisinopril in type I diabetes. In DIRECT, 5 years of candesartan treatment in type I diabetes reduced the incidence of retinopathy by two or more steps (EDTRS) in severity by 18% (P=0.0508) and, in a post hoc analysis, reduced the incidence of retinopathy by three-step progression by 35% (P=0.034). In type I diabetes patients there was no effect on progression of established retinopathy. In contrast, in type II diabetes, 5 years of candesartan treatment resulted in 34% regression of retinopathy (P=0.009). Importantly, an overall significant change towards less-severe retinopathy was noted in both type I and II diabetes (P

  5. The Arrestin-selective Angiotensin AT1 Receptor Agonist [Sar1,Ile4,Ile8]-AngII Negatively Regulates Bradykinin B2 Receptor Signaling via AT1-B2 Receptor Heterodimers*

    PubMed Central

    Wilson, Parker C.; Lee, Mi-Hye; Appleton, Kathryn M.; El-Shewy, Hesham M.; Morinelli, Thomas A.; Peterson, Yuri K.; Luttrell, Louis M.; Jaffa, Ayad A.

    2013-01-01

    The renin-angiotensin and kallikrein-kinin systems are key regulators of vascular tone and inflammation. Angiotensin II, the principal effector of the renin-angiotensin system, promotes vasoconstriction by activating angiotensin AT1 receptors. The opposing effects of the kallikrein-kinin system are mediated by bradykinin acting on B1 and B2 bradykinin receptors. The renin-angiotensin and kallikrein-kinin systems engage in cross-talk at multiple levels, including the formation of AT1-B2 receptor heterodimers. In primary vascular smooth muscle cells, we find that the arrestin pathway-selective AT1 agonist, [Sar1,Ile4,Ile8]-AngII, but not the neutral AT1 antagonist, losartan, inhibits endogenous B2 receptor signaling. In a transfected HEK293 cell model that recapitulates this effect, we find that the actions of [Sar1,Ile4, Ile8]-AngII require the AT1 receptor and result from arrestin-dependent co-internalization of AT1-B2 heterodimers. BRET50 measurements indicate that AT1 and B2 receptors efficiently heterodimerize. In cells expressing both receptors, pretreatment with [Sar1,Ile4,Ile8]-AngII blunts B2 receptor activation of Gq/11-dependent intracellular calcium influx and Gi/o-dependent inhibition of adenylyl cyclase. In contrast, [Sar1,Ile4,Ile8]-AngII has no effect on B2 receptor ligand affinity or bradykinin-induced arrestin3 recruitment. Both radioligand binding assays and quantitative microscopy-based analysis demonstrate that [Sar1,Ile4,Ile8]-AngII promotes internalization of AT1-B2 heterodimers. Thus, [Sar1,Ile4,Ile8]-AngII exerts lateral allosteric modulation of B2 receptor signaling by binding to the orthosteric ligand binding site of the AT1 receptor and promoting co-sequestration of AT1-B2 heterodimers. Given the opposing roles of the renin-angiotensin and kallikrein-kinin systems in vivo, the distinct properties of arrestin pathway-selective and neutral AT1 receptor ligands may translate into different pharmacologic actions. PMID:23661707

  6. The arrestin-selective angiotensin AT1 receptor agonist [Sar1,Ile4,Ile8]-AngII negatively regulates bradykinin B2 receptor signaling via AT1-B2 receptor heterodimers.

    PubMed

    Wilson, Parker C; Lee, Mi-Hye; Appleton, Kathryn M; El-Shewy, Hesham M; Morinelli, Thomas A; Peterson, Yuri K; Luttrell, Louis M; Jaffa, Ayad A

    2013-06-28

    The renin-angiotensin and kallikrein-kinin systems are key regulators of vascular tone and inflammation. Angiotensin II, the principal effector of the renin-angiotensin system, promotes vasoconstriction by activating angiotensin AT1 receptors. The opposing effects of the kallikrein-kinin system are mediated by bradykinin acting on B1 and B2 bradykinin receptors. The renin-angiotensin and kallikrein-kinin systems engage in cross-talk at multiple levels, including the formation of AT1-B2 receptor heterodimers. In primary vascular smooth muscle cells, we find that the arrestin pathway-selective AT1 agonist, [Sar(1),Ile(4),Ile(8)]-AngII, but not the neutral AT1 antagonist, losartan, inhibits endogenous B2 receptor signaling. In a transfected HEK293 cell model that recapitulates this effect, we find that the actions of [Sar(1),Ile(4), Ile(8)]-AngII require the AT1 receptor and result from arrestin-dependent co-internalization of AT1-B2 heterodimers. BRET50 measurements indicate that AT1 and B2 receptors efficiently heterodimerize. In cells expressing both receptors, pretreatment with [Sar(1),Ile(4),Ile(8)]-AngII blunts B2 receptor activation of Gq/11-dependent intracellular calcium influx and Gi/o-dependent inhibition of adenylyl cyclase. In contrast, [Sar(1),Ile(4),Ile(8)]-AngII has no effect on B2 receptor ligand affinity or bradykinin-induced arrestin3 recruitment. Both radioligand binding assays and quantitative microscopy-based analysis demonstrate that [Sar(1),Ile(4),Ile(8)]-AngII promotes internalization of AT1-B2 heterodimers. Thus, [Sar(1),Ile(4),Ile(8)]-AngII exerts lateral allosteric modulation of B2 receptor signaling by binding to the orthosteric ligand binding site of the AT1 receptor and promoting co-sequestration of AT1-B2 heterodimers. Given the opposing roles of the renin-angiotensin and kallikrein-kinin systems in vivo, the distinct properties of arrestin pathway-selective and neutral AT1 receptor ligands may translate into different pharmacologic

  7. Reliability of a Bayesian network to predict an elevated aldosterone-to-renin ratio.

    PubMed

    Ducher, Michel; Mounier-Véhier, Claire; Lantelme, Pierre; Vaisse, Bernard; Baguet, Jean-Philippe; Fauvel, Jean-Pierre

    2015-05-01

    Resistant hypertension is common, mainly idiopathic, but sometimes related to primary aldosteronism. Thus, most hypertension specialists recommend screening for primary aldosteronism. To optimize the selection of patients whose aldosterone-to-renin ratio (ARR) is elevated from simple clinical and biological characteristics. Data from consecutive patients referred between 1 June 2008 and 30 May 2009 were collected retrospectively from five French 'European excellence hypertension centres' institutional registers. Patients were included if they had at least one of: onset of hypertension before age 40 years, resistant hypertension, history of hypokalaemia, efficient treatment by spironolactone, and potassium supplementation. An ARR>32 ng/L and aldosterone>160 ng/L in patients treated without agents altering the renin-angiotensin system was considered as elevated. Bayesian network and stepwise logistic regression were used to predict an elevated ARR. Of 334 patients, 89 were excluded (31 for incomplete data, 32 for taking agents that alter the renin-angiotensin system and 26 for other reasons). Among 245 included patients, 110 had an elevated ARR. Sensitivity reached 100% or 63.3% using Bayesian network or logistic regression, respectively, and specificity reached 89.6% or 67.2%, respectively. The area under the receiver-operating-characteristic curve obtained with the Bayesian network was significantly higher than that obtained by stepwise regression (0.93±0.02 vs. 0.70±0.03; P<0.001). In hypertension centres, Bayesian network efficiently detected patients with an elevated ARR. An external validation study is required before use in primary clinical settings. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  8. Inadequate RAAS suppression is associated with excessive left ventricular mass and systo-diastolic dysfunction.

    PubMed

    Gregori, Mario; Tocci, Giuliano; Marra, Andrea; Pignatelli, Giulia; Santolamazza, Caterina; Befani, Alberto; Ciavarella, Giuseppino Massimo; Ferrucci, Andrea; Paneni, Francesco

    2013-10-01

    Inadequate suppression of renin-angiotensin-aldosterone system (RAAS) following postural maneuvers may have detrimental effects on cardiac structure and function. In this study, we aimed to appraise the clinical significance of this phenomenon by assessing its relation with inappropriate ventricular mass (ILVM), an adverse phenotype of LV remodeling and dysfunction. Both supine and upright plasma renin activity (PRA) and aldosterone concentrations (PAC) were measured in 115 young newly diagnosed hypertensive subjects. 24-h ambulatory blood pressure monitoring and echocardiographic evaluation including tissue Doppler imaging (TDI) were also performed. Patients were divided as follows: (1) normal PRA and PAC (N) (n = 63); (2) suppressible RAAS (SR) in supine position (n = 27); (3) not suppressible RAAS (NSR) (n = 25). ILVM was expressed as the observed/predicted LV mass ratio ×100 (%PLVM), while LV dysfunction (LVD) was identified by TDI-derived myocardial performance index (MPI). NSR showed a higher prevalence of ILVM than SR and N. As compared with N and SR, NSR patients had reduced indices of systolic and diastolic function. MPI of the LV as well as prevalence of LVD was also significantly higher in the NSR group. Regression models showed that lack of RAAS suppression was independently associated with ILVM and LVD. Prevalence of ILVM and LVD is higher in patients without clinostatic RAAS suppression. Our findings encourage the assessment of RAAS deregulation to better estimate individual cardiovascular risk in patients with arterial hypertension.

  9. Central endogenous angiotensin-(1-7) protects against aldosterone/NaCl-induced hypertension in female rats.

    PubMed

    Xue, Baojian; Zhang, Zhongming; Johnson, Ralph F; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2013-09-01

    In comparison to male rodents, females are protected against angiotensin (ANG) II- and aldosterone (Aldo)-induced hypertension. However, the mechanisms underlying this protective effect are not well understood. ANG-(1-7) is formed from ANG II by angiotensin-converting enzyme 2 (ACE2) and has an antihypertensive effect in the central nervous system (CNS). The present study tested the hypothesis that central ANG-(1-7) plays an important protective role in attenuating the development of Aldo/NaCl-hypertension in female rats. Systemic infusion of Aldo into intact female rats with 1% NaCl as their sole drinking fluid resulted in a slight increase in blood pressure (BP). Intracerebroventricular (icv) infusion of A-779, an ANG-(1-7) receptor (Mas-R) antagonist, significantly augmented the pressor effects of Aldo/NaCl. In contrast, systemic Aldo/NaCl induced a significant increase in BP in ovariectomized (OVX) female rats, and central infusion of ANG-(1-7) significantly attenuated this Aldo/NaCl pressor effect. The inhibitory effect of ANG-(1-7) on the Aldo/NaCl pressor effect was abolished by concurrent infusion of A-779. RT-PCR analyses showed that there was a corresponding change in mRNA expression of several renin-angiotensin system components, estrogen receptors and an NADPH oxidase subunit in the lamina terminalis. Taken together these results suggest that female sex hormones regulate an antihypertensive axis of the brain renin-angiotensin system involving ACE2/ANG-(1-7)/Mas-R that plays an important counterregulatory role in protecting against the development of Aldo/NaCl-induced hypertension.

  10. Effects of a combined oral contraceptive containing 20 mcg of ethinylestradiol and 3 mg of drospirenone on the blood pressure, renin-angiotensin-aldosterone system, insulin resistance, and androgenic profile of healthy young women.

    PubMed

    Giribela, Cassiana Rosa Galvão; Consolim-Colombo, Fernanda Marciano; Nisenbaum, Marcelo Gil; Moraes, Tercio Lemos de; Giribela, Aricia Helena Galvão; Baracat, Edmund Chada; Melo, Nilson Roberto de

    2015-01-01

    Combined oral contraceptives (COCs) may increase the risk for cardiovascular disease depending on the ethynyl estradiol (EE) dose and the androgenicity of the progestogens. Our objective was to evaluate the impact of a COC containing 20 mcg EE + 3 mg drospirenone on blood pressure (BP), renin-angiotensin-aldosterone system, insulin resistance, and androgenic profile of healthy young women. Eighty-one healthy young women aged 30 ± 1 years (case group, n = 49, received COC; control group, n = 32, used no COC) were assessed twice, before and after the 6-month study. Statistical analysis employed the paired t-tests and expressed the data in mean and standard deviation. Results were as follows: no changes in BP or in BMI; a significant increase in aldosterone, plasma renin activity, triglycerides, and total cholesterol levels, but a non-significant increase in HDL and no significant changes in LDL levels (these parameters remained within normal ranges); a significant increase in the HOMA-IR index and a significant decrease in dehydroepiandrosterone sulfate (SDHEA), androstenedione, total testosterone, and free testosterone levels; no significant variations in the control group parameters. An oral contraceptive combination of a low EE dose and an anti-androgenic progestogen does not negatively influence the risk factors for a cardiovascular disease.

  11. Comparative Effectiveness of Renin-Angiotensin System Antagonists in Maintenance Dialysis Patients

    PubMed Central

    Shireman, Theresa I.; Mahnken, Jonathan D.; Phadnis, Milind A.; Ellerbeck, Edward F.; Wetmore, James B.

    2017-01-01

    Background/Aims Whether angiotensin converting enzyme inhibitors (ACE) and angiotensin receptor blockers (ARB) are differentially associated with reductions in cardiovascular events and mortality in patients receiving maintenance dialysis is uncertain. We compared outcomes between ACE and ARB users among hypertensive, maintenance dialysis patients. Methods National retrospective cohort study of hypertensive, Medicare-Medicaid eligible patients initiating chronic dialysis between 1/1/2000 to 12/31/2005. The exposure of interest was new use of either an ACEI or ARB. Outcomes were all-cause mortality (ACM) and combined cardiovascular hospitalization or death (CV-endpoint). Cox proportion hazards models were used to compare the effect of ACEI vs ARB use on ACM and, separately, CV-endpoint. Results ACM models were based on 3,555 ACEI and 1,442 ARB new users, while CV-endpoint models included 3,289 ACEI and 1,346 ARB new users. After statistical adjustments, ACEI users had higher hazard ratios for ACM (AHR = 1.22, 99% CI 1.05–1.42) and CV-endpoint (AHR = 1.12, 99% CI 0.99–1.27). Conclusions Patients initiating maintenance dialysis who received an ACEI faced an increased risk for mortality and a trend towards an increased risk for CV-endpoints when compared to patients who received an ARB. Validation of these results in a rigorous clinical trial is warranted. PMID:27871075

  12. Comparative Effectiveness of Renin-Angiotensin System Antagonists in Maintenance Dialysis Patients.

    PubMed

    Shireman, Theresa I; Mahnken, Jonathan D; Phadnis, Milind A; Ellerbeck, Edward F; Wetmore, James B

    2016-01-01

    Whether angiotensin converting enzyme inhibitors (ACE) and angiotensin receptor blockers (ARB) are differentially associated with reductions in cardiovascular events and mortality in patients receiving maintenance dialysis is uncertain. We compared outcomes between ACE and ARB users among hypertensive, maintenance dialysis patients. National retrospective cohort study of hypertensive, Medicare-Medicaid eligible patients initiating chronic dialysis between 1/1/2000 to 12/31/2005. The exposure of interest was new use of either an ACEI or ARB. Outcomes were all-cause mortality (ACM) and combined cardiovascular hospitalization or death (CV-endpoint). Cox proportion hazards models were used to compare the effect of ACEI vs ARB use on ACM and, separately, CV-endpoint. ACM models were based on 3,555 ACEI and 1,442 ARB new users, while CV-endpoint models included 3,289 ACEI and 1,346 ARB new users. After statistical adjustments, ACEI users had higher hazard ratios for ACM (AHR = 1.22, 99% CI 1.05-1.42) and CV-endpoint (AHR = 1.12, 99% CI 0.99-1.27). Patients initiating maintenance dialysis who received an ACEI faced an increased risk for mortality and a trend towards an increased risk for CV-endpoints when compared to patients who received an ARB. Validation of these results in a rigorous clinical trial is warranted. © 2016 The Author(s) Published by S. Karger AG, Basel.

  13. Plasma renin is increased in young rats exposed to lead in utero and during nursing

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Victery, W.; Vander, A.J.; Schoeps, P.

    Rats were exposed continuously to Pb in utero and after birth by giving their mothers, during pregnancy and lactation, drinking water containing 0, 5, 25, 100, or 500 ppm Pb (as Pb acetate); they were sacrificed at 1 month of age, at which time their mean blood Pb concentrations were, respectively, approximately 3, 9, 19, 30, and 70 ..mu..g/dl. All Pb-exposed groups sacrificed by decapitation had elevated mean plasma renin activities (PRA), relative to controls. Pentobarbital-anesthesia and laparotomy markedly increased PRA in the 0, 100, and 500 ppm groups, but the increase was significantly less in the 100 ppm group.more » Renal renin concentration was normal in the 5 and 25 ppm groups, but was significantly increased in the 100 and 500 ppm groups. The ratio of plasma angiotensin II to PRA was normal in the 100 ppm group but significantly reduced in the 500 ppm group. We conclude that exposure of rats to those generally present in human populations stimulates basal renin secretion in 1-month-old rats, but partially inhibits the response to renin-releasing stimuli. The highest dose reduces plasma angiotensin II at any given PRA. These results, taken with previous publications, emphasize that the effects of lead on plasma renin even within a single species are greatly affected by the timing of the exposure.« less

  14. Predominance of AT1 Blockade Over Mas–Mediated Angiotensin-(1–7) Mechanisms in the Regulation of Blood Pressure and Renin–Angiotensin System in mRen2.Lewis Rats

    PubMed Central

    2013-01-01

    BACKGROUND We investigated whether the antihypertensive actions of the angiotensin II (Ang II) receptor (AT1-R) blocker, olmesartan medoxomil, may in part be mediated by increased Ang-(1–7) in the absence of significant changes in plasma Ang II. METHODS mRen2.Lewis congenic hypertensive rats were administered either a vehicle (n = 14) or olmesartan (0.5mg/kg/day; n = 14) by osmotic minipumps. Two weeks later, rats from both groups were further randomized to receive either the mas receptor antagonist A-779 (0.5mg/kg/day; n = 7 per group) or its vehicle (n = 7 per group) for the next 4 weeks. Blood pressure was monitored by telemetry, and circulating and tissue components of the renin–angiotensin system (RAS) were measured at the completion of the experiments. RESULTS Antihypertensive effects of olmesartan were associated with an increase in plasma renin concentration, plasma Ang I, Ang II, and Ang-(1–7), whereas serum aldosterone levels and kidney Ang II content were reduced. Preserved Ang-(1–7) content in kidneys was associated with increases of ACE2 protein but not activity and no changes on serum and kidney ACE activity. There was no change in cardiac peptide levels after olmesartan treatment. The antihypertensive effects of olmesartan were not altered by concomitant administration of the Ang-(1–7) receptor antagonist except for a mild further increase in plasma renin concentration. CONCLUSIONS Our study highlights the independent regulation of RAS among plasma, heart, and kidney tissue in response to AT1-R blockade. Ang-(1–7) through the mas receptor does not mediate long-term effects of olmesartan besides counterbalancing renin release in response to AT1-R blockade. PMID:23459599

  15. 8D.07: GENE EXPRESSION ANALYSIS AND BIOINFORMATICS REVEALED POTENTIAL TRANSCRIPTION FACTORS ASSOCIATED WITH RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM IN ATHEROMA.

    PubMed

    Nehme, A; Zibara, K; Cerutti, C; Bricca, G

    2015-06-01

    The implication of the renin-angiotensin-aldosterone system (RAAS) in atheroma development is well described. However, a complete view of the local RAAS in atheroma is still missing. In this study we aimed to reveal the organization of RAAS in atheroma at the transcriptomic level and identify the transcriptional regulators behind it. Extended RAAS (extRAAS) was defined as the set of 37 genes coding for classical and novel RAAS participants (Figure 1). Five microarray datasets containing overall 590 samples representing carotid and peripheral atheroma were downloaded from the GEO database. Correlation-based hierarchical clustering (R software) of extRAAS genes within each dataset allowed the identification of modules of co-expressed genes. Reproducible co-expression modules across datasets were then extracted. Transcription factors (TFs) having common binding sites (TFBSs) in the promoters of coordinated genes were identified using the Genomatix database tools and analyzed for their correlation with extRAAS genes in the microarray datasets. Expression data revealed the expressed extRAAS components and their relative abundance displaying the favored pathways in atheroma. Three co-expression modules with more than 80% reproducibility across datasets were extracted. Two of them (M1 and M2) contained genes coding for angiotensin metabolizing enzymes involved in different pathways: M1 included ACE, MME, RNPEP, and DPP3, in addition to 7 other genes; and M2 included CMA1, CTSG, and CPA3. The third module (M3) contained genes coding for receptors known to be implicated in atheroma (AGTR1, MR, GR, LNPEP, EGFR and GPER). M1 and M3 were negatively correlated in 3 of 5 datasets. We identified 19 TFs that have enriched TFBSs in the promoters of genes of M1, and two for M3, but none was found for M2. Among the extracted TFs, ELF1, MAX, and IRF5 showed significant positive correlations with peptidase-coding genes from M1 and negative correlations with receptors-coding genes from

  16. Horizon 2020 in Diabetic Kidney Disease: The Clinical Trial Pipeline for Add-On Therapies on Top of Renin Angiotensin System Blockade

    PubMed Central

    Perez-Gomez, Maria Vanessa; Sanchez-Niño, Maria Dolores; Sanz, Ana Belen; Martín-Cleary, Catalina; Ruiz-Ortega, Marta; Egido, Jesus; Navarro-González, Juan F.; Ortiz, Alberto; Fernandez-Fernandez, Beatriz

    2015-01-01

    Diabetic kidney disease is the most frequent cause of end-stage renal disease. This implies failure of current therapeutic approaches based on renin-angiotensin system (RAS) blockade. Recent phase 3 clinical trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced diabetic kidney disease failed to meet the primary endpoint or terminated on safety concerns, respectively. However, various novel strategies are undergoing phase 2 and 3 randomized controlled trials targeting inflammation, fibrosis and signaling pathways. Among agents currently undergoing trials that may modify the clinical practice on top of RAS blockade in a 5-year horizon, anti-inflammatory agents currently hold the most promise while anti-fibrotic agents have so far disappointed. Pentoxifylline, an anti-inflammatory agent already in clinical use, was recently reported to delay estimated glomerular filtration rate (eGFR) loss in chronic kidney disease (CKD) stage 3–4 diabetic kidney disease when associated with RAS blockade and promising phase 2 data are available for the pentoxifylline derivative CTP-499. Among agents targeting chemokines or chemokine receptors, the oral small molecule C-C chemokine receptor type 2 (CCR2) inhibitor CCX140 decreased albuminuria and eGFR loss in phase 2 trials. A dose-finding trial of the anti-IL-1β antibody gevokizumab in diabetic kidney disease will start in 2015. However, clinical development is most advanced for the endothelin receptor A blocker atrasentan, which is undergoing a phase 3 trial with a primary outcome of preserving eGFR. The potential for success of these approaches and other pipeline agents is discussed in detail. PMID:26239562

  17. Erythropoietin alleviates post-resuscitation myocardial dysfunction in rats potentially through increasing the expression of angiotensin II receptor type 2 in myocardial tissues

    PubMed Central

    Zhou, Hourong; Huang, Jia; Zhu, Li; Cao, Yu

    2018-01-01

    Activation of renin-angiotensin system (RAS) is one of the pathological mechanisms associated with myocardial ischemia-reperfusion injury following resuscitation. The present study aimed to determine whether erythropoietin (EPO) improves post-resuscitation myocardial dysfunction and how it affects the renin-angiotensin system. Sprague-Dawley rats were randomly divided into sham, vehicle, epinephrine (EP), EPO and EP + EPO groups. Excluding the sham group, all groups underwent cardiopulmonary resuscitation (CPR) 4 min after asphyxia-induced cardiac arrest (CA). EP and/or EPO was administrated by intravenous injection when CPR began. The results demonstrated that the vehicle group exhibited lower mean arterial pressure, left ventricular systolic pressure, maximal ascending rate of left ventricular pressure during left ventricular isovolumic contraction and maximal descending rate of left ventricular pressure during left ventricular isovolumic relaxation (+LVdP/dt max and -LVdP/dt max, respectively), and higher left ventricular end-diastolic pressure, compared with the sham group following return of spontaneous circulation (ROSC). Few significant differences were observed concerning the myocardial function between the vehicle and EP groups; however, compared with the vehicle group, EPO reversed myocardial function indices following ROSC, excluding-LVdP/dt max. Serum renin and angiotensin (Ang) II levels were measured by ELISA. The serum levels of renin and Ang II were significantly increased in the vehicle group compared with the sham group, which was also observed for the myocardial expression of renin and Ang II receptor type 1 (AT1R), as determined by reverse transcription-quantitative polymerase chain reaction and western blotting. EPO alone did not significantly reduce the high serum levels of renin and Ang II post-resuscitation, but changed the protein levels of renin and AT1R expression in myocardial tissues. However, EPO enhanced the myocardial expression of

  18. Urinary Angiotensinogen and Renin Excretion are Associated with Chronic Kidney Disease.

    PubMed

    Juretzko, Annett; Steinbach, Antje; Hannemann, Anke; Endlich, Karlhans; Endlich, Nicole; Friedrich, Nele; Lendeckel, Uwe; Stracke, Sylvia; Rettig, Rainer

    2017-01-01

    Several studies sought to identify new biomarkers for chronic kidney disease (CKD). As the renal renin-angiotensin system is activated in CKD, urinary angiotensinogen or renin excretion may be suitable candidates. We tested whether urinary angiotensinogen or renin excretion is elevated in CKD and whether these parameters are associated with estimated glomerular filtration rate (eGFR). We further tested whether urinary angiotensinogen or renin excretion may convey additional information beyond that provided by albuminuria. We measured urinary and plasma angiotensinogen, renin, albumin and creatinine in 177 CKD patients from the Greifswald Approach to Individualized Medicine project and in 283 healthy controls from the Study of Health in Pomerania. The urinary excretion of specific proteins is given as protein-to-creatinine ratio. Receiver operating characteristic (ROC) curves, spearman correlation coefficients and linear regression models were calculated. Urinary angiotensinogen [2,511 (196-31,909) vs. 18.6 (8.3-44.0) pmol/g, *P<0.01] and renin excretion [0.311 (0.135-1.155) vs. 0.069 (0.045-0.148) pmol/g, *P<0.01] were significantly higher in CKD patients than in healthy controls. The area under the ROC curve was significantly larger when urinary angiotensinogen, renin and albumin excretion were combined than with urinary albumin excretion alone. Urinary angiotensinogen (ß-coefficient -2.405, standard error 0.117, P<0.01) and renin excretion (ß-coefficient -0.793, standard error 0.061, P<0.01) were inversely associated with eGFR. Adjustment for albuminuria, age, sex, systolic blood pressure and body mass index did not significantly affect the results. Urinary angiotensinogen and renin excretion are elevated in CKD patients. Both parameters are negatively associated with eGFR and these associations are independent of urinary albumin excretion. In CKD patients urinary angiotensinogen and renin excretion may convey additional information beyond that provided by

  19. Increase of plasma renin activity in male and female rabbits subjected to dysbaric conditions

    NASA Technical Reports Server (NTRS)

    Chryssanthou, C.; Kircikoglu, H.; Strugar, J.

    1985-01-01

    The renin-angiotensin-aldosterone system may be implicated in hemodynamic alterations occurring in dysbaric disorders. This report concerns changes in plasma renin activity (PRA) induced by exposure of rabbits to a compression-decompression schedule that does not normally produce clinical manifestations of decompression sickness. The results revealed a significant increase in PRA in 19 of 23 animals following dysbaric exposure. Mean PRA rose from 1.18 ng ang I/ml hr (preexposure) to 2.40 ng ang I/ml hr (postexposure). The increase was particularly pronounced in female animals (217 percent). Asymptomatic intravascular gas bubbles (silent bubbles) were detected by gross or microscopic examination in the majority of the animals. Renin elaboration and secretion in asymptomatic dysbaric exposures may be mediated by bradykinin and/or prostaglandins released or activated in a chain reaction triggered by silent gas bubbles. This hypothesis is also applicable to increased PRA in altitude decompression. Alternatively elevation of PRA may result from decreased renal perfusion when dysbaric disorders are complicated by significant hypovolemia.

  20. Plasma volume, osmolality, vasopressin, and renin activity during graded exercise in man

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.; Keil, L. C.; Bernauer, E. M.; Greenleaf, J. E.

    1981-01-01

    The influence of work intensity on plasma volume, osmolality, vasopressin and renin activity and the interrelationships between these responses are investigated. Plasma volume, renin activity and osmotic, sodium and arginine vasopressin concentrations were measured in venous blood samples taken from 15 healthy male subjects before and after six minutes of bicycle ergometer exercise at 100, 175 and 225 W. Plasma volume is found to decrease significantly with increasing work intensity, while increases in Na(+) concentration, osmolality and vasopressin are only observed to be significant when the work intensity exceeds 40% maximal aerobic capacity and plasma resin activity increased linearly at all work levels. In addition, significant correlations are observed between plasma volume and osmolality and sodium changes, and between vasopressin and osmolality and sodium content changes. Data thus support the hypotheses that (1) vasopressin may be the primary controlling endocrine for fluid and electrolyte levels following exercise; (2) an exercise intensity greater than 40% maximal aerobic capacity is required to stimulate vasopressin release through changes in plasma osmolality; and (3) the stimulation of the renin-angiotensin system is a more general stress response.

  1. Cognitive benefits of Angiotensin IV and Angiotensin-(1-7): a systematic review of experimental studies.

    PubMed

    Ho, Jean K; Nation, Daniel A

    2018-05-04

    To explore effects of the brain renin-angiotensin system (RAS) on cognition. Systematic review of experimental (non-human) studies assessing cognitive effects of RAS peptides angiotensin-(3-8) [Ang IV] and angiotensin-(1-7) [Ang-(1-7)] and their receptors, the Ang IV receptor (AT4R) and the Mas receptor. Of 450 articles identified, 32 met inclusion criteria. Seven of 11 studies of normal animals found Ang IV had beneficial effects on tests of passive or conditioned avoidance and object recognition. In models of cognitive deficit, eight of nine studies found Ang IV and its analogs (Nle 1 -Ang IV, dihexa, LVV-hemorphin-7) improved performance on spatial working memory and passive avoidance tasks. Two of three studies examining Ang-(1-7) found it benefited memory. Mas receptor removal was associated with reduced fear memory in one study. Studies of cognitive impairment show salutary effects of acute administration of Ang IV and its analogs, as well as AT4R activation. Brain RAS peptides appear most effective administered intracerebroventricularly, close to the time of learning acquisition or retention testing. Ang-(1-7) shows anti-dementia qualities. Copyright © 2018. Published by Elsevier Ltd.

  2. Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study

    PubMed Central

    Mansfield, Kathryn E; Bhaskaran, Krishnan; Nitsch, Dorothea; Sørensen, Henrik Toft; Smeeth, Liam; Tomlinson, Laurie A

    2017-01-01

    Objective To examine long term cardiorenal outcomes associated with increased concentrations of creatinine after the start of angiotensin converting enzyme inhibitor/angiotensin receptor blocker treatment. Design Population based cohort study using electronic health records from the Clinical Practice Research Datalink and Hospital Episode Statistics. Setting UK primary care, 1997-2014. Participants Patients starting treatment with angiotensin converting enzyme inhibitors or angiotensin receptor blockers (n=122 363). Main outcome measures Poisson regression was used to compare rates of end stage renal disease, myocardial infarction, heart failure, and death among patients with creatinine increases of 30% or more after starting treatment against those without such increases, and for each 10% increase in creatinine. Analyses were adjusted for age, sex, calendar period, socioeconomic status, lifestyle factors, chronic kidney disease, diabetes, cardiovascular comorbidities, and use of other antihypertensive drugs and non-steroidal anti-inflammatory drugs. Results Among the 2078 (1.7%) patients with creatinine increases of 30% or more, a higher proportion were female, were elderly, had cardiorenal comorbidity, and used non-steroidal anti-inflammatory drugs, loop diuretics, or potassium sparing diuretics. Creatinine increases of 30% or more were associated with an increased adjusted incidence rate ratio for all outcomes, compared with increases of less than 30%: 3.43 (95% confidence interval 2.40 to 4.91) for end stage renal disease, 1.46 (1.16 to 1.84) for myocardial infarction, 1.37 (1.14 to 1.65) for heart failure, and 1.84 (1.65 to 2.05) for death. The detailed categorisation of increases in creatinine concentrations (<10%, 10-19%, 20-29%, 30-39%, and ≥40%) showed a graduated relation for all outcomes (all P values for trends <0.001). Notably, creatinine increases of less than 30% were also associated with increased incidence rate ratios for all outcomes

  3. Tetrapod-type [Asp1] angiotensin is present in a holostean fish, Amia calva.

    PubMed

    Takei, Y; Itahara, Y; Butler, D G; Watanabe, T X; Oudit, G Y

    1998-05-01

    The renin-angiotensin system has been identified in various vertebrates, from elasmobranchs to mammals. Tetrapod (amphibians to mammals) angiotensin (ANG) has Asp at the N-terminus, but Asp is replaced by Asn in elasmobranch and teleost fish. ANG I has been isolated from incubates of plasma and kidney extracts of the bowfin Amia calva, a holostean fish, using the eel vasopressor activity as an assay system; its sequence was found to be H-Asp-Arg-Val-Tyr-Val-His-Pro-Phe-Asn-Leu-OH after sequence analysis, mass spectrometry, and comparison with the synthetic peptide. This sequence is identical to bullfrog ANG I. [Asn1] ANG I was not detected. Thus the bowfin is the first fish species which contains only [Asp1] ANG I. The bowfin ANG I and II were no more vasopressor than eel peptides in the bowfin, indicating that bowfin ANG II receptors do not distinguish between [Asp1] and [Asn1] peptides. In the rat, bowfin ANG I and rat [Ile5, His9] ANG I have equipressor activities when examined in different animals, but the vasopressor activity of bowfin ANG I decreased following rat ANG I in the same animals, although the activity of rat ANG I was unaffected after bowfin ANG I. The present study directly demonstrates the presence of the renin-angiotensin system in a holostean fish and showed that its ANG II receptors have not yet fully coevolved with the homologous [Asp1] peptide.

  4. INCREASED HYPOTHALAMIC ANGIOTENSIN-(1-7) LEVELS IN RATS WITH AORTIC COARCTATION-INDUCED HYPERTENSION

    PubMed Central

    Gironacci, Mariela M.; Brosnihan, K. Bridget; Ferrario, Carlos M.; Gorzalczany, Susana; Lopez Verrilli, María A.; Pascual, Mariano; Taira, Carlos; Peña, Clara

    2007-01-01

    Since angiotensin (Ang) (1-7) injected into the brain blocked Ang II pressor actions in rats made hypertensive by aortic coarctation (CH), we examined systemic and tissue angiotensin peptide levels, specifically concentrating on the hypothalamic Ang-(1-7) levels. Plasma, heart and kidney isolated from CH rats showed increased levels of Ang I, Ang II and Ang-(1-7) compared with the normotensive group, with Ang II being the predominant peptide in heart and kidney. In the hypothalamus, equimolar amounts of Ang II and Ang-(1-7) were found in the sham group, whereas only Ang-(1-7) levels increased in CH rats. We conclude that aortic coarctation activates systemic and tissue renin-angiotensin system. The increased central levels of Ang-(1-7) in the CH rats suggest a potential mitigating role of this peptide in central control of the hypertensive process. PMID:17646033

  5. Acute kidney injury secondary to a combination of renin-angiotensin system inhibitors, diuretics and NSAIDS: "The Triple Whammy".

    PubMed

    Camin, Rosa Maria Garcia; Cols, Montse; Chevarria, Julio Leonel; Osuna, Rosa García; Carreras, Marc; Lisbona, Josep Maria; Coderch, Jordi

    2015-01-01

    Renin-angiotensin system inhibitors (ACEI/ARB-II), diuretics and NSAIDs, a combination known as "Triple Whammy", can result in decreased glomerular filtration rate (GFR) and acute kidney injury (AKI). Objectives: To describe the incidence of AKI for each drug type and their combinations. To define the profile of patients admitted for drug-related AKI secondary to Triple Whammy drugs (AKITW), with an assessment of costs and mortality. A retrospective observational 15-month study developed in three stages: - First: a cross-sectional stage to identify and describe hospitalizations due to AKITW. - Second: a follow-up stage of an outpatient cohort consuming these drugs (15,307 subjects). - Third: a cohort stage to assess costs and mortality, which compared 62 hospitalized patients with AKITW and 62 without AKI, paired by medical specialty, sex, age and comorbidity according to their Clinical Risk Groups. There were 85 hospitalization episodes due to AKITW, and 78% of patients were over the age of 70. The incidence of AKITW in the population was 3.40 cases/1000 users/year (95% CI: 2.59-4.45). By categories, these were: NSAIDs + diuretics 8.99 (95% CI: 3.16-25.3); Triple Whammy 8.82 (95% CI: 4.4-17.3); ACEI/ARB-II + diuretics 6.87 (95% CI: 4.81-9.82); and monotherapy with diuretics 3.31 (95% CI: 1.39-7.85). Mean hospital stay was 7.6 days (SD 6.4), and mean avoidable costs were estimated at €214,604/100,000 inhabitants/year. Mortality during hospitalization and at 12 months was 11.3% and 38.7% respectively, and there were no significant differences when compared with the control group. Treatment with ACEI, ARB-II, diuretics and/or NSAIDs shows a high incidence of hospitalization episodes due to AKI; diuretics as monotherapy or dual and triple combination therapy cause the highest incidence. AKITW involves high health care costs and avoidable mortality. Copyright © 2015. Published by Elsevier España, S.L.U.

  6. Synergistic effects of gene polymorphisms of the renin-angiotensin-aldosterone system on essential hypertension in Kazakhs in Xinjiang.

    PubMed

    Niu, Shudong; Zhang, Bin; Zhang, Keyong; Zhu, Pengcheng; Li, Jingping; Sun, Yujing; He, Ning; Zhang, Mingtao; Gao, Zhiying; Li, Xueyan; Simayi, Amuti; Ge, Jie; Cong, Mingyu; Zhou, Wenna; Qiu, Changchun

    2016-01-01

    To assess the synergistic effects of gene polymorphisms of the renin-angiotensin-aldosterone system (RAAS) on essential hypertension (EH) in Kazakhs in Xinjiang. A cross-sectional case-control association study was conducted in 52 1 hypertensive and 623 normotensive subjects of Kazakh ethnicity on eight common single nucleotide polymorphisms (SNPs) interspersed over five genes of the RAAS. SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Interactions among the SNPs were analyzed by the multifactor dimensionality reduction method (MDR). In single-locus analysis, subjects with AGT -6G, ACE D, and CYP11B2 -344C had increased susceptibility to EH (OR: 1.249; 1.425; 1.201). When subgrouped by sex, males with the t allele of REN Taq I had decreased risk for EH (OR: 0.529), and those with AGT -6G and CYP11B2 -344 C had increased risk for EH (OR: 1.498; 1.449). In females, carrying ACE D increased the risk for EH. (OR: 1.327). In six AGT haplotypes, H1 was protective, while H3 increased susceptibility to EH (OR: 0.683; 2.025). Interaction analysis by MDR showed that there was a strong synergistic effect between ACE I/D and CY11B2 (T-344C) and a moderate interaction between both ACE I/D and CY11B2 T-344C and AGT A-6G. There was a strong synergistic effect between ACE I/D and CY11B2 T-344C and a moderate effect between both ACE I/D and CY11B2 T-344C and AGT A-6G. AGT -6G, ACE D, and CY11B2 -344C increased susceptibility to EH. REN Taq I, AGT -6G, CY11B2 -344 C and ACE D were associated with male and female EH, respectively. H1 and H3 of AGT were protective and risk haplotypes, respectively.

  7. Aldosterone, Parathyroid Hormone, and the Use of Renin-Angiotensin-Aldosterone System Inhibitors: The Multi-Ethnic Study of Atherosclerosis

    PubMed Central

    Brown, Jenifer; de Boer, Ian H.; Robinson-Cohen, Cassianne; Siscovick, David S.; Kestenbaum, Bryan; Allison, Matthew

    2015-01-01

    Context: Aldosterone and PTH are implicated in the pathogenesis of cardiovascular and skeletal diseases. An expanding body of evidence supports a bidirectional and positive physiologic relationship between aldosterone and PTH. Large population-based studies confirming this relationship, and whether it may be targeted as a potential method to mitigate the clinical consequences associated with excess aldosterone and PTH, are needed. Objective: We hypothesized that higher aldosterone levels would associate with higher PTH, and that the use of renin-angiotensin-aldosterone system (RAAS) inhibitors would predict lower PTH in a large, multi-ethnic, community-based cohort. Design, Setting, Participants: We conducted cross-sectional analyses of participants in the Multi-Ethnic Study of Atherosclerosis without apparent primary hyperparathyroidism or chronic kidney disease (n = 5668). We evaluated associations of RAAS inhibitor use with PTH concentration among 1888 treated hypertensive participants. We also tested associations of serum aldosterone concentration with PTH concentration among 1547 participants with these measurements. Outcome: Serum PTH concentration. Results: Higher aldosterone associated with higher PTH (β = 0.19 pg/ml per 1 ng/dl of aldosterone, P < .0001), and this finding was most pronounced among those with a primary hyperaldosteronism-like phenotype. There was a stepwise increment in PTH when comparing untreated normotensives, hypertensives using RAAS inhibitors, untreated hypertensives, and treated hypertensives using non-RAAS inhibitors (40.8, 45.0, 46.2, 47.1 pg/ml, respectively). The use of any RAAS inhibitor independently associated with lower PTH (β = −2.327 pg/ml per use of RAAS inhibitor, P = .006), when compared with the use of any non-RAAS inhibitor medication. Conclusions: Higher serum aldosterone concentration is associated with higher serum PTH concentration, and the use of RAAS inhibitors is associated with lower PTH concentration

  8. The impact of obstructive sleep apnea syndrome on renin and aldosterone.

    PubMed

    Lykouras, D; Theodoropoulos, K; Sampsonas, F; Lagiou, O; Lykouras, M; Spiropoulou, A; Flordellis, C; Alexandrides, T; Karkoulias, K; Spiropoulos, K

    2015-11-01

    Obstructive Sleep Apnoea Syndrome (OSAS) is a respiratory disorder characterized by recurrent airflow obstruction caused by total or partial collapse of the upper airway. OSAS is an established independent factor of cardiovascular risk together with other risk factors such as smoking and increased lipids. The aim of our study was to measure serum levels of aldosterone and renin in OSAS patients that did not suffer from arterial hypertension and compare them to matched healthy subjects in order to reveal the impact of chronic intermittent hypoxia on the renin-angiotensin-aldosterone system. The patients that enrolled in this study were 19 OSAS patients who had undergone overnight polysomnography and had an Apnoea Hypopnoea Index (AHI) greater than 10 events/hour. They were compared to 20 healthy non-OSAS closely matched controls. Serum aldosterone and direct renin concentration were measured by radioimmunoassay. Aldosterone concentration follows a diurnal variation; therefore, all blood samples were obtained at the same time (6 AM). There were no significant differences in serum aldosterone levels between the two studied groups of OSAS patients and the healthy subjects group (140.6 pg/ml ± 25.2 vs. 133.2 pg/ml ± 18.5 with p = 0.223). Similar were the results for the renin levels (25.0 ± 6.9 vs. 24.9 ± 4.4 with p = 0.360). Our study suggests that patients with OSAS, but without existing hypertension have aldosterone and renin levels similar to healthy subjects. According to our findings a direct connection between OSAS and the development of arterial hypertension may not be established via sympathetic system activation.

  9. Nocturnal pituitary hormone and renin profiles during chronic heat exposure.

    PubMed

    Saini, J; Brandenberger, G; Libert, J P; Follenius, M

    1993-07-01

    To establish the principal endocrine systems involved in the initial adaptation to chronic passive heat exposure, responses of the hydromineral and pituitary systems were compared. Nocturnal plasma profiles of growth hormone, prolactin, thyrotropin, and plasma renin activity were determined during a period of prolonged heat exposure designed to simulate a hot climate. Two groups of six male subjects (G1 and G2) were kept for 11 days in a climatically controlled apartment. The G1 group was exposed to 20 degrees C throughout the study, and the G2 group was exposed to 20 degrees C for 5 days and to 35 degrees C for the following 6 days. Blood was collected continuously during the 1st and 10th nights from 2300 to 0700 h and was sampled in 10-min aliquots for hormone analysis. Heat exposure increased the nocturnal mean core temperature (P < 0.02) and stimulated plasma renin activity (P < 0.01) but had little effect on the pituitary hormones except for a small increase in prolactin (P < 0.05). For the G1 group there was no change in hormone profiles. These results demonstrate that the principal initial endocrine system involved in acclimatization to passive heat exposure is the renin-angiotensin system, reflecting counteractive measures against salt and water losses. In contrast, 5 days of continuous heat exposure does not provoke metabolic changes, indicated by the small effect on pituitary hormone profiles.

  10. Prognostic Impact of Loop Diuretics in Patients With Chronic Heart Failure - Effects of Addition of Renin-Angiotensin-Aldosterone System Inhibitors and β-Blockers.

    PubMed

    Miura, Masanobu; Sugimura, Koichiro; Sakata, Yasuhiko; Miyata, Satoshi; Tadaki, Soichiro; Yamauchi, Takeshi; Onose, Takeo; Tsuji, Kanako; Abe, Ruri; Oikawa, Takuya; Kasahara, Shintaro; Nochioka, Kotaro; Takahashi, Jun; Shimokawa, Hiroaki

    2016-05-25

    It remains to be elucidated whether addition of renin-angiotensin-aldosterone system (RAAS) inhibitors and/or β-blockers to loop diuretics has a beneficial prognostic impact on chronic heart failure (CHF) patients. From the Chronic Heart failure Analysis and Registry in the Tohoku district 2 (CHART-2) Study (n=10,219), we enrolled 4,134 consecutive patients with symptomatic stage C/D CHF (mean age, 69.3 years, 67.7% male). We constructed Cox models for composite of death, myocardial infarction, stroke and HF admission. On multivariate inverse probability of treatment weighted (IPTW) Cox modeling, loop diuretics use was associated with worse prognosis with hazard ratio (HR) 1.28 (P<0001). Furthermore, on IPTW multivariate Cox modeling for multiple treatments, both low-dose (<40 mg/day) and high-dose (≥40 mg/day) loop diuretics were associated with worse prognosis with HR 1.32 and 1.56, respectively (both P<0.001). Triple blockade with RAS inhibitor(s), mineral corticoid (aldosterone) receptor antagonist(s) (MRA), and β-blocker(s) was significantly associated with better prognosis in those on low-dose but not on high-dose loop diuretics. Chronic use of loop diuretics is significantly associated with worse prognosis in CHF patients in a dose-dependent manner, whereas the triple combination of RAAS inhibitor(s), MRA, and β-blocker(s) is associated with better prognosis when combined with low-dose loop diuretics. (Circ J 2016; 80: 1396-1403).

  11. Tonic suppression of spontaneous baroreceptor reflex by endogenous angiotensins via AT(2) subtype receptors at nucleus reticularis ventrolateralis in the rat.

    PubMed

    Lin, K; Chan, S H; Chan, J Y

    2001-04-01

    We evaluated the role of endogenous angiotensins at the rostral nucleus reticularis ventrolateralis (NRVL) in the modulation of spontaneous baroreceptor reflex (BRR) response and the subtype of angiotensin receptors involved using rats anesthetized and maintained with pentobarbital sodium. Bilateral microinjection of angiotensin II (ANG II) or its active metabolite angiotensin III (ANG III) (5, 10, or 20 pmol) into the NRVL significantly suppressed the spontaneous BRR response, as represented by the magnitude of transfer function between systemic arterial pressure and heart rate signals. The inhibitory effect of ANG III (20 pmol) was discernibly reversed by coadministration with its peptide antagonist, [Ile(7)]ANG III (1.6 nmol), or the nonpeptide AT(2) receptor antagonist, PD-123319 (1.6 nmol), but not by the nonpeptide AT(1) receptor antagonist, losartan (1.6 nmol). On the other hand, the peptide antagonist, [Sar(1), Ile(8)]ANG II (1.6 nmol) or both non-peptide antagonists appreciably reversed the suppressive action of ANG II (20 pmol). Whereas losartan produced minimal effect, blocking the endogenous activity of the angiotensins by microinjection into the bilateral NRVL of PD-123319, [Sar(1), Ile(8)]ANG II or [Ile(7)]ANG III elicited significant enhancement of the spontaneous BRR response. We conclude that under physiologic conditions both endogenous ANG II and ANG III may exert a tonic inhibitory modulation on the spontaneous BRR response by acting selectively on the AT(2) subtype receptors at the NRVL. Copyright 2001 Wiley-Liss, Inc.

  12. Angiotensin type 1 receptor mediates chronic ethanol consumption-induced hypertension and vascular oxidative stress.

    PubMed

    Passaglia, Patrícia; Ceron, Carla S; Mecawi, André S; Antunes-Rodrigues, José; Coelho, Eduardo B; Tirapelli, Carlos R

    2015-11-01

    We hypothesized that chronic ethanol intake enhances vascular oxidative stress and induces hypertension through renin-angiotensin system (RAS) activation. Male Wistar rats were treated with ethanol (20% v/v). The increase in blood pressure induced by ethanol was prevented by losartan (10mg/kg/day; p.o. gavage), a selective AT1 receptor antagonist. Chronic ethanol intake increased plasma renin activity (PRA), angiotensin converting enzyme (ACE) activity, plasma angiotensin I (ANG I) and angiotensin II (ANG II) levels and serum aldosterone levels. No differences on plasma osmolality and sodium or potassium levels were detected after treatment with ethanol. Ethanol consumption did not alter ACE activity, as well as the levels of ANG I and ANG II in the rat aorta or mesenteric arterial bed (MAB). Ethanol induced systemic and vascular oxidative stress (aorta and MAB) and these effects were prevented by losartan. The decrease on plasma and vascular nitrate/nitrite (NOx) levels induced by ethanol was prevented by losartan. Ethanol intake did not alter protein expression of ACE, AT1 or AT2 receptors in both aorta and MAB. Aortas from ethanol-treated rats displayed decreased ERK1/2 phosphorylation and increased protein expression of SAPK/JNK. These responses were prevented by losartan. MAB from ethanol-treated rats displayed reduced phosphorylation of p38MAPK and ERK1/2 and losartan did not prevent these responses. Our study provides novel evidence that chronic ethanol intake increases blood pressure, induces vascular oxidative stress and decreases nitric oxide (NO) bioavailability through AT1-dependent mechanisms. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Validation of methods to control for immortal time bias in a pharmacoepidemiologic analysis of renin-angiotensin system inhibitors in type 2 diabetes.

    PubMed

    Yang, Xilin; Kong, Alice Ps; Luk, Andrea Oy; Ozaki, Risa; Ko, Gary Tc; Ma, Ronald Cw; Chan, Juliana Cn; So, Wing Yee

    2014-01-01

    Pharmacoepidemiologic analysis can confirm whether drug efficacy in a randomized controlled trial (RCT) translates to effectiveness in real settings. We examined methods used to control for immortal time bias in an analysis of renin-angiotensin system (RAS) inhibitors as the reference cardioprotective drug. We analyzed data from 3928 patients with type 2 diabetes who were recruited into the Hong Kong Diabetes Registry between 1996 and 2005 and followed up to July 30, 2005. Different Cox models were used to obtain hazard ratios (HRs) for cardiovascular disease (CVD) associated with RAS inhibitors. These HRs were then compared to the HR of 0.92 reported in a recent meta-analysis of RCTs. During a median follow-up period of 5.45 years, 7.23% (n = 284) patients developed CVD and 38.7% (n = 1519) were started on RAS inhibitors, with 39.1% of immortal time among the users. In multivariable analysis, time-dependent drug-exposure Cox models and Cox models that moved immortal time from users to nonusers both severely inflated the HR, and time-fixed models that included immortal time deflated the HR. Use of time-fixed Cox models that excluded immortal time resulted in a HR of only 0.89 (95% CI, 0.68-1.17) for CVD associated with RAS inhibitors, which is closer to the values reported in RCTs. In pharmacoepidemiologic analysis, time-dependent drug exposure models and models that move immortal time from users to nonusers may introduce substantial bias in investigations of the effects of RAS inhibitors on CVD in type 2 diabetes.

  14. Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study.

    PubMed

    Schmidt, Morten; Mansfield, Kathryn E; Bhaskaran, Krishnan; Nitsch, Dorothea; Sørensen, Henrik Toft; Smeeth, Liam; Tomlinson, Laurie A

    2017-03-09

    Objective  To examine long term cardiorenal outcomes associated with increased concentrations of creatinine after the start of angiotensin converting enzyme inhibitor/angiotensin receptor blocker treatment. Design  Population based cohort study using electronic health records from the Clinical Practice Research Datalink and Hospital Episode Statistics. Setting  UK primary care, 1997-2014. Participants  Patients starting treatment with angiotensin converting enzyme inhibitors or angiotensin receptor blockers (n=122 363). Main outcome measures  Poisson regression was used to compare rates of end stage renal disease, myocardial infarction, heart failure, and death among patients with creatinine increases of 30% or more after starting treatment against those without such increases, and for each 10% increase in creatinine. Analyses were adjusted for age, sex, calendar period, socioeconomic status, lifestyle factors, chronic kidney disease, diabetes, cardiovascular comorbidities, and use of other antihypertensive drugs and non-steroidal anti-inflammatory drugs. Results  Among the 2078 (1.7%) patients with creatinine increases of 30% or more, a higher proportion were female, were elderly, had cardiorenal comorbidity, and used non-steroidal anti-inflammatory drugs, loop diuretics, or potassium sparing diuretics. Creatinine increases of 30% or more were associated with an increased adjusted incidence rate ratio for all outcomes, compared with increases of less than 30%: 3.43 (95% confidence interval 2.40 to 4.91) for end stage renal disease, 1.46 (1.16 to 1.84) for myocardial infarction, 1.37 (1.14 to 1.65) for heart failure, and 1.84 (1.65 to 2.05) for death. The detailed categorisation of increases in creatinine concentrations (<10%, 10-19%, 20-29%, 30-39%, and ≥40%) showed a graduated relation for all outcomes (all P values for trends <0.001). Notably, creatinine increases of less than 30% were also associated with increased incidence rate ratios for all

  15. Effect of Renin-Angiotensin Blockers on Left Ventricular Remodeling in Severe Aortic Stenosis.

    PubMed

    Goh, Serene Si-Ning; Sia, Ching-Hui; Ngiam, Nicholas Jinghao; Tan, Benjamin Yong-Qiang; Lee, Poay Sian; Tay, Edgar Lik-Wui; Kong, William Kok-Fai; Yeo, Tiong Cheng; Poh, Kian-Keong

    2017-06-01

    Studies have shown that medical therapy with renin-angiotensin blockers (RABs) may benefit patients with aortic stenosis (AS). However, its use and efficacy remains controversial, including in patients with low flow (LF) with preserved left ventricular ejection fraction (LVEF). We examined the effects of RAB use on LV remodeling in patients with severe AS with preserved LVEF, analyzing the differential effects in patients with LF compared with normal flow (NF). This is a retrospective study of 428 consecutive subjects from 2005 to 2014 with echocardiographic diagnosis of severe AS and preserved LVEF. Clinical and echocardiographic parameters were systematically collected and analyzed. Two hundred forty-two (57%) patients had LF. Sixty-four LF patients (26%) were treated with RAB. Patients on RAB treatment had a higher incidence of hyperlipidemia (69% vs 44%) and diabetes mellitus (53% vs 34%). Severity of AS in terms of valve area, transvalvular mean pressure gradient, and aortic valve resistance were similar between both groups as was the degree of LV diastolic function. The RAB group demonstrated significantly lower LV mass index with a correspondingly lower incidence of concentric LV hypertrophy. Regardless of the duration of RAB therapy, patients had increased odds of having a preserved LV mass index compared with those without RAB therapy. In conclusion, RAB therapy may be associated with less LV pathological remodeling and have a role in delaying patients from developing cardiovascular complications of AS. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Angiotensin converting enzyme 2 amplification limited to the circulation does not protect mice from development of diabetic nephropathy

    PubMed Central

    Wysocki, Jan; Ye, Minghao; Khattab, Ahmed M.; Fogo, Agnes; Martin, Aline; David, Nicolae Valentin; Kanwar, Yashpal; Osborn, Mark; Batlle, Daniel

    2016-01-01

    Blockers of the renin-angiotensin system are effective in the treatment of experimental and clinical diabetic nephropathy. An approach different from blocking the formation or action of angiotensin II(1-8) that could also be effective involves fostering its degradation. Angiotensin converting enzyme 2 (ACE2) is a monocarboxypeptidase than cleaves angiotensin II (1-8) to form angiotensin (1-7). Therefore, we examined the renal effects of murine recombinant ACE2 in mice with streptozotocin-induced diabetic nephropathy as well as that of amplification of circulating ACE2 using minicircle DNA delivery prior to induction of experimental diabetes. This delivery resulted in a long-term sustained and profound increase in serum ACE2 activity and enhanced ability to metabolize an acute angiotensin II (1-8) load. In mice with streptozotocin-induced diabetes pretreated with minicircle ACE2, ACE2 protein in plasma increased markedly and this was associated with a more than 100-fold increase in serum ACE2 activity. However, minicircle ACE2 did not result in changes in urinary ACE2 activity as compared to untreated diabetic mice. In both diabetic groups, glomerular filtration rate increased significantly and to the same extent as compared to non-diabetic controls. Albuminuria, glomerular mesangial expansion, glomerular cellularity and glomerular size, were all increased to a similar extent in minicircle ACE2-treated and untreated diabetic mice, as compared to non-diabetic controls. Recombinant mouse ACE2 given for 4 weeks by intraperitoneal daily injections in mice with streptozotocin-induced diabetic nephropathy also failed to improve albuminuria or kidney pathology. Thus, a profound augmentation of ACE2 confined to the circulation failed to ameliorate the glomerular lesions and hyperfiltration characteristic of early diabetic nephropathy. These findings emphasize the importance of targeting the kidney rather than the circulatory renin angiotensin system to combat diabetic

  17. Differentiation in the effects of the angiotensin II receptor blocker class on autonomic function.

    PubMed

    Esler, Murray

    2002-06-01

    Measurement of regional sympathetic activity with nerve recording and noradrenaline spillover isotope dilution techniques demonstrates activation of the sympathetic nerves of the heart, kidneys and skeletal muscle vasculature in younger patients with essential hypertension. Sympathetic overactivity in the renal sympathetic outflow is a prominent pathophysiological feature in obesity-related hypertensives of any age. This increase in sympathetic activity is thought to both initiate and sustain the blood pressure elevation, and, in addition, contributes to adverse cardiovascular events. Sympathetic overactivity seems to particularly influence systolic pressure, by increasing the rate of left ventricular ejection, by reducing arterial compliance through increasing neural arterial tone, and via arteriolar vasoconstriction, by promoting rebound of the reflected arterial wave from the periphery. Inhibition of the renin-angiotensin system in certain circumstances appears to be able to reduce sympathetic nervous activity. Claims have been made for such an action at virtually every site in the sympathetic neuraxis. In reality, renin-angiotensin actions on the sympathetic nervous system are probably much more circumscribed than this, with the case perhaps being strongest for a presynaptic action of angiotensin on sympathetic nerves, to augment noradrenaline release. The ability of angiotensin receptor blockers to antagonize neural presynaptic angiotensin AT1 receptors appears to differ markedly between the individual agents in this drug class. In experimental models, such as the pithed rat, neural presynaptic actions are particularly evident with eprosartan. In a blinded study of crossover design, the effects of eprosartan and losartan on sympathetic nerve firing, measured by microneurography, and whole body noradrenaline spillover to plasma is currently being measured in patients with essential hypertension. A reduction in noradrenaline spillover disproportionate to any

  18. Sodium intake influences hemodynamic and neural responses to angiotensin receptor blockade in rostral ventrolateral medulla.

    PubMed

    DiBona, G F; Jones, S Y

    2001-04-01

    To determine the effects of physiological alterations in endogenous angiotensin II activity on basal renal sympathetic nerve activity (RSNA) and its arterial baroreflex regulation, angiotensin II type 1 receptor antagonists were microinjected into the rostral ventrolateral medulla of anesthetized rats consuming a low, normal, or high sodium diet that were instrumented for simultaneous measurement of arterial pressure and RSNA. Plasma renin activity was increased in rats fed a low sodium diet and decreased in those fed a high sodium diet. Losartan (50, 100, and 200 pmol) decreased heart rate and RSNA (but not mean arterial pressure) dose-dependently; the responses were significantly greater in rats fed a low sodium diet than in those fed a high sodium diet. Candesartan (1, 2, and 10 pmol) decreased mean arterial pressure, heart rate, and RSNA dose-dependently; the responses were significantly greater in rats fed a low sodium diet than in those fed a normal or high sodium diet. [D-Ala(7)]Angiotensin-(1-7) (100, 200, and 1000 pmol) did not affect mean arterial pressure, heart rate, or RSNA in rats fed either a low or a high sodium diet. In rats fed a low sodium diet, candesartan reset the arterial baroreflex control of RSNA to a lower level of arterial pressure, and in rats with congestive heart failure, candesartan increased the arterial baroreflex gain of RSNA. Physiological alterations in the endogenous activity of the renin-angiotensin system influence the bradycardic, vasodepressor, and renal sympathoinhibitory responses to rostral ventrolateral medulla injection of antagonists to angiotensin II type 1 receptors but not to angiotensin-(1-7) receptors.

  19. Circadian Differences in the Contribution of the Brain Renin-Angiotensin System in Genetically Hypertensive Mice

    PubMed Central

    Jackson, Kristy L.; Marques, Francine Z.; Lim, Kyungjoon; Davern, Pamela J.; Head, Geoffrey A.

    2018-01-01

    Objective: Genetically hypertensive BPH/2J mice are recognized as a neurogenic model of hypertension, primarily based on sympathetic overactivity and greater neuronal activity in cardiovascular regulatory brain regions. Greater activity of the central renin angiotensin system (RAS) and reactive oxygen species (ROS) reportedly contribute to other models of hypertension. Importantly the peripheral RAS contributes to the hypertension in BPH/2J mice, predominantly during the dark period of the 24 h light cycle. The aim of the present study was to determine whether central AT1 receptor stimulation and the associated ROS signaling contribute to hypertension in BPH/2J mice in a circadian dependent manner. Methods: Blood pressure (BP) was measured in BPH/2J and normotensive BPN/3J mice (n = 7–8) via pre-implanted telemetry devices. Acute intracerebroventricular (ICV) microinjections of AT1 receptor antagonist, candesartan, and the superoxide dismutase (SOD) mimetic, tempol, were administered during the dark and light period of the 24 h light cycle via a pre-implanted ICV guide cannula. In separate mice, the BP effect of ICV infusion of the AT1 receptor antagonist losartan for 7 days was compared with subcutaneous infusion to determine the contribution of the central RAS to hypertension in BPH/2J mice. Results: Candesartan administered ICV during the dark period induced depressor responses which were 40% smaller in BPH/2J than BPN/3J mice (Pstrain < 0.05), suggesting AT1 receptor stimulation may contribute less to BP maintenance in BPH/2J mice. During the light period candesartan had minimal effect on BP in either strain. ICV tempol had comparable effects on BP between strains during the light and dark period (Pstrain > 0.08), suggesting ROS signaling is also not contributing to the hypertension in BPH/2J mice. Chronic ICV administration of losartan (22 nmol/h) had minimal effect on BPN/3J mice. By contrast in BPH/2J mice, both ICV and subcutaneously administered losartan

  20. On the Mechanism of Serotonin-Induced Dipsogenesis in the Rat

    NASA Technical Reports Server (NTRS)

    Kikta, Dianne C.; Barney, Christopher C.; Threatte, Rose M.; Fregly, Melvin J.; Rowland, Neil E.; Greenleaf, John E.

    1983-01-01

    Subcutaneous administration of 1-5-hydroxytryptophan (5-HTP), the precursor of serotonin, to female rats induces copious drinking accompanied by activation of the renin-angiotensin system. Neither a reduction in blood pressure nor body temperature accompanied administration of 5-HTP. The objective of the present study was to determine whether serotonin-induced dipsogenesis, like that of 5-HTP, is mediated via the renin-angiotensin system. Serotonin (2 mg/kg, SC)-induced drinking was inhibited by the dopaminergic antagonist, haloperidol (150 /micro g/kg, IP), which also inhibits angiotensin II-induced drinking, Both captopril (35 mg/kg, IP), an angiotensin converting enzyme inhibitor, and propranolol (6 micro g/kg, IP), a beta-adrenergic antagonist, blocked serotonin-induced dipsogenesis. The alpha(sub a),-adrenergic agonist, clonidine (6.25 micro g/kg, SC), which suppresses renin release from the kidney, attenuated serotonin-induced water intake. The dipsogenic responses to submaximal concentrations of both serotonin (1 mg/kg, SC) and isoproterenol (8 micro g/kg, SC) were additive rather than interactive suggesting that similar pathways mediate both responses. The serotonergic receptor antagonist, methysergide (3 mg/kg, IP), inhibited serotonin-induced drinking but had no effect on isoproterenol (25micro g/kg, SC)-induced dipsogenesis. However, neither serotonin (2 mg/kg, SC) nor isoproterenol (25 micro g/kg, SC)-induced drinking was inhibited by cinansefin (25 micro g/kg, IP). These data indicate that serotonin induces drinking in rats via the renin-angiotensin system. However, the results of the studies using methysergide suggest that scrotonin appears to act at a point prior to activation of beta-adrenoceptors in the pathway leading to release of renin from the kidneys.

  1. The granulocyte-angiotensin system. Angiotensin I-converting activity of cathepsin G.

    PubMed

    Klickstein, L B; Kaempfer, C E; Wintroub, B U

    1982-12-25

    Cathepsin G, an Mr = 26,000-29,000 cationic human neutrophil lysosomal serine protease, releases angiotensin II from angiotensinogen and was, therefore, examined for angiotensin I-converting activity. Cathepsin G-dependent angiotensin I conversion was detected by a high performance liquid chromatography assay which permitted independent quantitation of angiotensin I and angiotensin II and detection of angiotensin degradation products. 1.8-5.0 X 10(-9) M cathepsin G converted angiotensin I (3.3 X 10(-4) M) to angiotensin II without further degradation of angiotensin II. The pH optimum for cathepsin G-catalyzed angiotensin I conversion was pH 7.0-7.5, and the Km and Kcat were 2.2 X 10(-4) M and 3.4 s-1, respectively. In contrast to dipeptidyl hydrolase-converting enzyme, cathepsin G did not inactivate bradykinin, did not cleave hippuryl-His-Leu, and was not inhibited by 10(-4) M Captopril or SQ 20881. Purified human neutrophils stimulated with 2.5 X 10(-6) M-10(-10) M fMet-Leu-Phe released angiotensin-converting activity with a Km of 3.3 X 10(-4) M. That the angiotensin-converting activity released from neutrophils was attributable to cathepsin G was indicated by similar susceptibility to inhibitors and adsorption by goat antibody to cathepsin G. The granulocyte-angiotensin system provides a mechanism for the local generation of angiotensin II at sites of neutrophil accumulation and may be of significance in regulation of blood flow in tissue microvasculature.

  2. Brain angiotensin-(1-7)/Mas axis: A new target to reduce the cardiovascular risk to emotional stress.

    PubMed

    Fontes, Marco Antônio Peliky; Martins Lima, Augusto; Santos, Robson Augusto Souza dos

    2016-04-01

    Emotional stress is now considered a risk factor for several diseases including cardiac arrhythmias and hypertension. It is well known that the activation of neuroendocrine and autonomic mechanisms features the response to emotional stress. However, its link to cardiovascular diseases and the regulatory mechanisms involved remain to be further comprehended. The renin-angiotensin system (RAS) plays an important role in homeostasis on all body systems. Specifically in the brain, the RAS regulates a number of physiological aspects. Recent data indicate that the activation of angiotensin-converting enzyme/angiotensin II/AT1 receptor axis facilitates the emotional stress responses. On the other hand, growing evidence indicates that its counterregulatory axis, the angiotensin-converting enzyme 2 (ACE2)/(Ang)iotensin-(1-7)/Mas axis, reduces anxiety and attenuates the physiological responses to emotional stress. The present review focuses on angiotensin-(1-7)/Mas axis as a promising target to attenuate the physiological response to emotional stress reducing the risk of cardiovascular diseases. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Angiotensin-I-converting enzyme and its relatives

    PubMed Central

    Riordan, James F

    2003-01-01

    Angiotensin-I-converting enzyme (ACE) is a monomeric, membrane-bound, zinc- and chloride-dependent peptidyl dipeptidase that catalyzes the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II, by removing a carboxy-terminal dipeptide. ACE has long been known to be a key part of the renin angiotensin system that regulates blood pressure, and ACE inhibitors are important for the treatment of hypertension. There are two forms of the enzyme in humans, the ubiquitous somatic ACE and the sperm-specific germinal ACE, both encoded by the same gene through transcription from alternative promoters. Somatic ACE has two tandem active sites with distinct catalytic properties, whereas germinal ACE, the function of which is largely unknown, has just a single active site. Recently, an ACE homolog, ACE2, has been identified in humans that differs from ACE in being a carboxypeptidase that preferentially removes carboxy-terminal hydrophobic or basic amino acids; it appears to be important in cardiac function. ACE homologs (also known as members of the M2 gluzincin family) have been found in a wide variety of species, even in those that neither have a cardiovascular system nor synthesize angiotensin. X-ray structures of a truncated, deglycosylated form of germinal ACE and a related enzyme from Drosophila have been reported, and these show that the active site is deep within a central cavity. Structure-based drug design targeting the individual active sites of somatic ACE may lead to a new generation of ACE inhibitors, with fewer side-effects than currently available inhibitors. PMID:12914653

  4. Improvement in Renal Hemodynamics following Combined Angiotensin II Infusion and AT1R Blockade in Aged Female Sheep following Fetal Unilateral Nephrectomy

    PubMed Central

    Singh, Reetu R.; Lankadeva, Yugeesh R.

    2013-01-01

    Renin-angiotensin system (RAS) is a powerful modulator of renal hemodynamic and fluid homeostasis. Up-regulation in components of intra-renal RAS occurs with ageing. Recently we reported that 2 year old uninephrectomised (uni-x) female sheep have low renin hypertension and reduced renal function. By 5 years of age, these uni-x sheep had augmented decrease in renal blood flow (RBF) compared to sham. We hypothesised that this decrease in RBF in 5 year old uni-x sheep was due to an up-regulation in components of the intra-renal RAS. In this study, renal responses to angiotensin II (AngII) infusion and AngII type 1 receptor (AT1R) blockade were examined in the same 5 year old sheep. We also administered AngII in the presence of losartan to increase AngII bioavailability to the AT2R in order to understand AT2R contribution to renal function in this model. Uni-x animals had significantly lower renal cortical content of renin, AngII (∼40%) and Ang 1–7 (∼60%) and reduced cortical expression of AT1R gene than sham animals. In response to both AngII infusion and AT1R blockade via losartan, renal hemodynamic responses and tubular sodium excretion were significantly attenuated in uni-x animals compared to sham. However, AngII infusion in the presence of losartan caused ∼33% increase in RBF in uni-x sheep compared to ∼14% in sham (P<0.05). This was associated with a significant decrease in renal vascular resistance in the uni-x animals (22% vs 15%, P<0.05) without any changes in systemic blood pressure. The present study shows that majority of the intra-renal RAS components are suppressed in this model of low renin hypertension. However, increasing the availability of AngII to AT2R by AT1R blockade improved renal blood flow in uni-x sheep. This suggests that manipulation of the AT2R maybe a potential therapeutic target for treatment of renal dysfunction associated with a congenital nephron deficit. PMID:23840884

  5. Prenatal exposure to angiotensin II increases blood pressure and decreases salt sensitivity in rats.

    PubMed

    Svitok, Pavel; Senko, Tomas; Panakova, Zuzana; Olexova, Lucia; Krskova, Lucia; Okuliarova, Monika; Zeman, Michal

    2017-01-01

    Renin angiotensin aldosterone system (RAAS) plays an essential role in the homeostatic control of arterial blood pressure, perfusion of tissues, and control of extracellular fluid. Its components are highly expressed in the developing kidney, general vasculature, brain, and heart. A modified intrauterine environment alters mechanisms controlling blood pressure (BP) and can lead to hypertension in the adult offspring and developmentally programmed RAAS can be involved in this process. There are very little data about the effects of increased angiotensin II (Ang II) concentrations during pregnancy on in utero development of the fetus. In our study, we administered Ang II to pregnant female rats via osmotic mini-pumps and evaluated the postnatal development and BP control in the offspring. To estimate possible developmental changes in sensitivity to salt, we exposed the offspring to a diet with increased salt content and measured plasma aldosterone levels and plasma renin activity. Increased Ang II during pregnancy raised BP in the offspring; however, salt sensitivity was decreased in comparison to controls. Relative weight of the left ventricle was decreased in the offspring prenatally exposed to Ang II, while relative kidney weight was reduced only in female offspring. Prenatal treatment led to increased aldosterone levels and decreased plasma renin activity, suggesting a complex physiological response. Our results suggest that conditions leading to upregulation of RAAS during pregnancy can influence the cardiovascular system of the fetus and have a long-term impact on the offspring's health.

  6. Factors Influencing Renal Vasculature during Anesthesia, Trauma, and Oliguric Renal Failure States in Man

    DTIC Science & Technology

    1980-03-01

    striking influence of prior sodium intake on the pathogenesis of acute renal failure, raising the possibility that the renin - angiotensin system was...the product of the renin - angiotensin system , is the most powerful renal vasoconstrictor agent yet identified. These observations, viewed in the light of... angiotensin and, when they became available, to a detailed study of agents suitable for pharmacologic interruption of the renin - angiotensin system . We showed

  7. Possible contribution of (pro)renin receptor to development of gestational diabetes mellitus.

    PubMed

    Bokuda, Kanako; Ichihara, Atsuhiro

    2014-12-15

    (Pro)renin receptor [(P)RR], a receptor for renin and prorenin, was first cloned in 2002. Since then, the pathophysiological roles of (P)RR have been growing concerns. (P)RR binds renin and prorenin, with two important consequences, nonproteolytic activation of prorenin, leading to the tissue renin-angiotensin system activation and the intracellular signalings. It is now also known to play an important role as vacuolar H(+)-ATPase associated protein, involving in Wnt signaling, main component of embryonic development. Extracellular domain of full-length (P)RR is cleaved in golgi-complex forming soluble (P)RR [s(P)RR]. The s(P)RR is now possible to be measured in human blood and urine. It is now measured in different pathophysiological states, and recent study showed that elevated plasma s(P)RR levels in the early stage of pregnancies are associated with higher incidence of gestational diabetes mellitus later in the pregnancies. Plasma s(P)RR levels of neonates are known to be higher than that of adults. It was also shown that, increased s(P)RR concentrations in cord blood, associated with a lower small for gestational age birth likelihood. These data suggests the involvement of (P)RR in embryo's growth. In this review article, we attempt to figure out the possible pathophysiological roles of the (P)RR in maternal glucose intolerance and embryo's growth, through reviewing previous studies.

  8. [Blockers of renin-angiotensin-aldosterone system in the treatment of arterial hypertension: classics versus the modern].

    PubMed

    Kanorskiĭ, S G

    2013-01-01

    According to results of large clinical studies angiotensin II receptor blockers (ARB) and aliskiren do not lower risk of cardiovascular complications and mortality in wide spectrum of clinical conditions and are able to worsen renal outcomes. It is expedient to prefer inhibitors of angiotensin converting enzyme in particular perindopril over ARB in the treatment of patients with arterial hypertension taking into consideration differences in effect on mortality. Fixed perindopril/indapamide combination provides achievement of target arterial pressure in many patients with uncontrolled hypertension, has good tolerability, is metabolically neutral, and possesses high organoprotective properties.

  9. Angiotensin II Reduces Food Intake by Altering Orexigenic Neuropeptide Expression in the Mouse Hypothalamus

    PubMed Central

    Yoshida, Tadashi; Semprun-Prieto, Laura; Wainford, Richard D.; Sukhanov, Sergiy; Kapusta, Daniel R.

    2012-01-01

    Angiotensin II (Ang II), which is elevated in many chronic disease states such as end-stage renal disease and congestive heart failure, induces cachexia and skeletal muscle wasting by increasing muscle protein breakdown and reducing food intake. Neurohormonal mechanisms that mediate Ang II-induced appetite suppression are unknown. Consequently, we examined the effect of Ang II on expression of genes regulating appetite. Systemic Ang II (1 μg/kg · min) infusion in FVB mice rapidly reduced hypothalamic expression of neuropeptide Y (Npy) and orexin and decreased food intake at 6 h compared with sham-infused controls but did not change peripheral leptin, ghrelin, adiponectin, glucagon-like peptide, peptide YY, or cholecystokinin levels. These effects were completely blocked by the Ang II type I receptor antagonist candesartan or deletion of Ang II type 1a receptor. Ang II markedly reduced phosphorylation of AMP-activated protein kinase (AMPK), an enzyme that is known to regulate Npy expression. Intracerebroventricular Ang II infusion (50 ng/kg · min) caused a reduction of food intake, and Ang II dose dependently reduced Npy and orexin expression in the hypothalamus cultured ex vivo. The reduction of Npy and orexin in hypothalamic cultures was completely prevented by candesartan or the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside. Thus, Ang II type 1a receptor-dependent Ang II signaling reduces food intake by suppressing the hypothalamic expression of Npy and orexin, likely via AMPK dephosphorylation. These findings have major implications for understanding mechanisms of cachexia in chronic disease states such as congestive heart failure and end-stage renal disease, in which the renin-angiotensin system is activated. PMID:22234465

  10. The unique response of renin and aldosterone to dietary sodium intervention in sodium sensitivity.

    PubMed

    Shin, Sung Joon; Lim, ChiYeon; Oh, Sang Woo; Rhee, Moo-Yong

    2014-06-01

    Sodium sensitivity (SS) is a phenomenon in which significant changes in blood pressure (BP) are observed based on sodium intake. The renin-angiotensin-aldosterone system plays a critical role in sodium handling and hypertension. We identified the specific responses of renin and aldosterone based on dietary sodium intake and revealed the relationship between these hormonal changes and dietary sodium intake in patients with SS. In total, 61 subjects were available to analyze full data including plasma renin activity (PRA) and aldosterone. Participants were given a low-sodium DASH diet (LSD) for 7 days and a high-sodium DASH diet (HSD) for the following 7 days. SS was found in five (14.71%) in normotensives, and 14 (51.85%) in hypertensives. In sodium-resistant (SR) subjects, both PRA and aldosterone decreased significantly after consuming HSD. Moreover, a significant correlation was observed between PRA and aldosterone in SR subjects. In contrast, only hypertensive subjects showed a marked fall in PRA after consuming HSD (1.299 ± 0.904 vs. 0.593 ± 0.479) among SS subjects. This study demonstrated the different responses of renin and aldosterone in SS and SR subjects based on dietary sodium intake whether or not they had hypertension. © The Author(s) 2014.

  11. Dual Angiotensin Receptor and Neprilysin Inhibition with Sacubitril/Valsartan in Chronic Systolic Heart Failure: Understanding the New PARADIGM.

    PubMed

    Lillyblad, Matthew P

    2015-11-01

    To evaluate the clinical role of sacubitril/valsartan, a novel angiotensin-neprilysin inhibitor, for the treatment of chronic heart failure with a reduced ejection fraction (HFrEF). A search of PubMed was conducted using a combination of the search terms sacubitril, valsartan, LCZ696, neprilysin inhibition, natriuretic peptide system, renin-angiotensin system, and heart failure with reduced ejection fraction. Bibliographies of all retrieved articles were reviewed for relevant literature. All references included were published between 1980 and May 2015. All studies and review articles that contained data describing the use of sacubitril/valsartan in HFrEF were reviewed. HFrEF remains a disease of high morbidity and mortality. Natriuretic peptide (NP) augmentation has emerged as a most promising neurohormonal target in HFrEF. NPs provide vasodilatory, natriuretic, diuretic, and antiproliferative actions to help support the failing heart. Neprilysin, a neutral endopeptidase, is a primary pathway for NP metabolism. Combined inhibition of the renin angiotensin aldosterone system and neprilysin augments the beneficial natriuretic peptide pathway while providing direct antagonism to increases in angiotensin II. In the landmark PARADIGM HF trial, the neprilysin inhibitor sacubitril added to valsartan significantly improved morbidity and mortality over enalapril, a standard of care in HFrEF. Application of these results to clinical practice requires careful considerations of trial design, study patient population, and clinical monitoring. Sacubitril/valsartan significantly improved morbidity and mortality in patients with chronic HFrEF but will require careful application to "real-world" populations of HFrEF. © The Author(s) 2015.

  12. Worsening renal function during renin-angiotensin-aldosterone system inhibitor initiation and long-term outcomes in patients with left ventricular systolic dysfunction.

    PubMed

    Clark, Hannah; Krum, Henry; Hopper, Ingrid

    2014-01-01

    Impaired renal function is associated with worse clinical outcomes in patients with LV systolic dysfunction (LVSD) and heart failure. Renin-angiotensin-aldosterone system (RAAS) inhibitors provide clinical benefit in these settings and often worsen renal function. It is not clear whether worsening renal function (WRF) in patients exposed to these agents predicts a worse prognosis or merely reflects the pharmacological action of the drug on the kidney. We performed a meta-analysis of all RAAS inhibitor LVSD trials reporting on outcomes according to WRF (as per individual study definition) in both active intervention and placebo groups. Five major studies (SOLVD, SAVE, RALES, Val-HeFT and EPHESUS) contributed, with 20 573 patients. Compared with placebo, RAAS inhibitors reduced all-cause mortality overall [n = 20 573, relative risk ratio (RR) 0.91, 95% confidence interval (CI) 0.86-0.95, P = 0.0003], in the group with no WRF (n = 18 209, RR 0.91, 95% CI 0.83-0.99, P = 0.04), and in the WRF group (n = 2364, RR 0.72, 95% CI 0.62-0.84, P < 0.0001). Compared with no WRF, WRF was associated with increased all-cause mortality; however, this was less in the RAAS inhibitor group (n = 8905, RR 1.22, 95% CI 1.10-1.36, P = 0.0003) than in the placebo group (n = 9304, RR 1.52, 95% CI 1.37-1.69, P < 0.00001). WRF shortly after randomization is associated with worsened outcomes compared with no WRF; however, the reduction in all-cause mortality associated with the use of RAAS inhibitors was significantly greater in the presence of WRF than in the no WRF group. Clinicians should not be deterred from using RAAS inhibitors in the setting of WRF. © 2013 The Authors. European Journal of Heart Failure © 2013 European Society of Cardiology.

  13. Impaired endogenous nighttime melatonin secretion relates to intrarenal renin-angiotensin system activation and renal damage in patients with chronic kidney disease.

    PubMed

    Ishigaki, Sayaka; Ohashi, Naro; Isobe, Shinsuke; Tsuji, Naoko; Iwakura, Takamasa; Ono, Masafumi; Sakao, Yukitoshi; Tsuji, Takayuki; Kato, Akihiko; Miyajima, Hiroaki; Yasuda, Hideo

    2016-12-01

    Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. The circadian rhythm of intrarenal RAS activation leads to renal damage and hypertension, which are associated with diurnal blood pressure (BP) variation. The activation of intrarenal RAS following reactive oxygen species (ROS) activation, sympathetic hyperactivity and nitric oxide (NO) inhibition leads to the development of renal damage. Melatonin is a hormone regulating the circadian rhythm, and has multiple functions such as anti-oxidant and anti-adrenergic effects and enhancement of NO bioavailability. Nocturnal melatonin concentrations are lower in CKD patients. However, it is not known if impaired endogenous melatonin secretion is related to BP, intrarenal RAS, or renal damage in CKD patients. We recruited 53 CKD patients and conducted 24-h ambulatory BP monitoring. urine was collected during the daytime and nighttime. We investigated the relationship among the melatonin metabolite urinary 6-sulphatoxymelatonin (U-aMT6s), BP, renal function, urinary angiotensinogen (U-AGT), and urinary albumin (U-Alb). Patients' U-aMT6s levels were significantly and negatively correlated with clinical parameters such as renal function, systolic BP, U-AGT, and U-Alb, during both day and night. Multiple regression analyses for U-aMT6s levels were performed using age, gender, renal function, and each parameter (BPs, U-AGT or U-Alb), at daytime and nighttime. U-aMT6s levels were significantly associated with U-AGT (β = -0.31, p = 0.044) and U-Alb (β = -0.25, p = 0.025) only at night. Impaired nighttime melatonin secretion may be associated with nighttime intrarenal RAS activation and renal damage in CKD patients.

  14. Effects of renin-angiotensin-aldosterone system inhibitors on mortality, hospitalization, and diastolic function in patients with HFpEF. A meta-analysis of 13 randomized controlled trials.

    PubMed

    Zhang, Q; Chen, Y; Liu, Q; Shan, Q

    2016-02-01

    The purpose of this meta-analysis was to evaluate the effects of renin-angiotensin-aldosterone system (RAAS) inhibitors on mortality, hospitalization, diastolic function, and exercise capacity in heart failure with preserved ejection fraction (HFpEF). Thirteen randomized controlled trials (RCTs), totaling 12,532 patients with HFpEF, were selected. All-cause and cardiovascular mortality, all-cause and heart failure-related hospitalization, diastolic function, and the 6-min walk distance were assessed. The risk ratios (RR) of the dichotomous data, weighted mean difference (WMD) of continuous data, and 95 % confidence intervals (CI) were calculated to assess the effects of RAAS inhibitors. RAAS inhibitors significantly decreased heart failure-related hospitalization (RR 0.89; 95 % CI 0.82-0.97; p = 0.01) and improved the diastolic function, as reflected in a reduced E/e' index (MD -1.38; 95 % CI -2.01 to -0.74; p < 0.0001). However, there were no beneficial effects on all-cause cardiovascular mortality and all-cause hospitalization. Other diastolic parameters had few changes compared with the controls. The 6-min walk distance was not improved by the use of RAAS inhibitors. In patients with HFpEF, RAAS inhibitors decreased heart-failure hospitalization and the E/e' index without affecting mortality, all-cause hospitalization, other diastolic function parameters, and the 6-min walk distance.

  15. Additive effects of cilnidipine, an L-/N-type calcium channel blocker, and an angiotensin II receptor blocker on reducing cardiorenal damage in Otsuka Long-Evans Tokushima Fatty rats with type 2 diabetes mellitus.

    PubMed

    Mori, Yutaka; Aritomi, Shizuka; Niinuma, Kazumi; Nakamura, Tarou; Matsuura, Kenichi; Yokoyama, Junichi; Utsunomiya, Kazunori

    2014-01-01

    Cilnidipine (Cil), which is an L-/N-type calcium channel blocker (CCB), has been known to provide renal protection by decreasing the activity of the sympathetic nervous system (SNS) and the renin-angiotensin system. In this study, we compared the effects of the combination of Cil and amlodipine (Aml), which is an L-type CCB, with an angiotensin (Ang) II receptor blocker on diabetic cardiorenal damage in spontaneously type 2 diabetic rats. Seventeen-week-old Otsuka Long-Evans Tokushima Fatty rats were randomly assigned to receive Cil, Aml, valsartan (Val), Cil + Val, Aml + Val, or a vehicle (eight rats per group) for 22 weeks. Antihypertensive potencies were nearly equal among the CCB monotherapy groups and the combination therapy groups. The lowering of blood pressure by either treatment did not significantly affect the glycemic variables. However, exacerbations of renal and heart failure were significantly suppressed in rats administered Cil or Val, and additional suppression was observed in those administered Cil + Val. Although Val increased the renin-Ang system, Aml + Val treatment resulted in additional increases in these parameters, while Cil + Val did not show such effects. Furthermore, Cil increased the ratio of Ang-(1-7) to Ang-I, despite the fact that Val and Aml + Val decreased the Ang-(1-7) levels. These actions of Cil + Val might be due to their synergistic inhibitory effect on the activity of the SNS, and on aldosterone secretion through N-type calcium channel antagonism and Ang II receptor type 1 antagonism. Thus, Cil may inhibit the progression of cardiorenal disease in type 2 diabetes patients by acting as an N-type CCB and inhibiting the aldosterone secretion and SNS activation when these drugs were administered in combination with an Ang II receptor blocker.

  16. TRPV4 participates in pressure-induced inhibition of renin secretion by juxtaglomerular cells.

    PubMed

    Seghers, François; Yerna, Xavier; Zanou, Nadège; Devuyst, Olivier; Vennekens, Rudi; Nilius, Bernd; Gailly, Philippe

    2016-12-15

    Increase in blood pressure in the renal afferent arteriole is known to induce an increase in cytosolic calcium concentration ([Ca 2+ ] i ) of juxtaglomerular (JG) cells and to result in a decreased secretion of renin. Mechanical stimulation of As4.1 JG cells induces an increase in [Ca 2+ ] i that is inhibited by HC067047 and RN1734, two inhibitors of TRPV4, or by siRNA-mediated repression of TRPV4. Inhibition of TRPV4 impairs pressure-induced decrease in renin secretion. Compared to wild-type mice, Trpv4 -/- mice present increased resting plasma levels of renin and aldosterone and present a significantly altered pressure-renin relationship. We suggest that TRPV4 channel participates in mechanosensation at the juxtaglomerular apparatus. The renin-angiotensin system is a crucial blood pressure regulation system. It consists of a hormonal cascade where the rate-limiting enzyme is renin, which is secreted into the blood flow by renal juxtaglomerular (JG) cells in response to low pressure in the renal afferent arteriole. In contrast, an increase in blood pressure results in a decreased renin secretion. This is accompanied by a transitory increase in [Ca 2+ ] i of JG cells. The inverse relationship between [Ca 2+ ] i and renin secretion has been called the 'calcium paradox' of renin release. How increased pressure induces a [Ca 2+ ] i transient in JG cells, is however, unknown. We observed that [Ca 2+ ] i transients induced by mechanical stimuli in JG As4.1 cells were completely abolished by HC067047 and RN1734, two inhibitors of TRPV4. They were also reduced by half by siRNA-mediated repression of TRPV4 but not after repression or inhibition of TRPV2 or Piezo1 ion channels. Interestingly, the stimulation of renin secretion by the adenylate cyclase activator forskolin was totally inhibited by cyclic stretching of the cells. This effect was mimicked by stimulation with GSK1016790A and 4αPDD, two activators of TRPV4 and inhibited in the presence of HC067047. Moreover, in

  17. Heterogeneous Downregulation of Angiotensin II AT1-A and AT1-B Receptors in Arterioles in STZ-Induced Diabetic Rat Kidneys

    PubMed Central

    Razga, Zsolt; Talapka, Petra; Nyengaard, Jens Randel

    2014-01-01

    Introduction. The renin granulation of kidney arterioles is enhanced in diabetes despite the fact that the level of angiotensin II in the diabetic kidney is elevated. Therefore, the number of angiotensin II AT1-A and AT1-B receptors in afferent and efferent arteriole's renin-positive and renin-negative smooth muscle cells (SMC) was estimated. Method. Immunohistochemistry at the electron microscopic level was combined with 3D stereological sampling techniques. Results. In diabetes the enhanced downregulation of AT1-B receptors in the renin-positive than in the renin-negative SMCs in both arterioles was resulted: the significant difference in the number of AT1 (AT1-A + AT1-B) receptors between the two types of SMCs in the normal rats was further increased in diabetes and in contrast with the significant difference observed between the afferent and efferent arterioles in the normal animals, there was no such difference in diabetes. Conclusions. The enhanced downregulation of the AT1-B receptors in the renin-negative SMCs in the efferent arterioles demonstrates that the regulation of the glomerular filtration rate by the pre- and postglomerular arterioles is changed in diabetes. The enhanced downregulation of the AT1-B receptors in the renin-positive SMCs in the arterioles may result in an enhanced level of renin granulation in the arterioles. PMID:24587998

  18. Effect of paricalcitol on renin and albuminuria in non-diabetic stage III-IV chronic kidney disease: a randomized placebo-controlled trial

    PubMed Central

    2013-01-01

    Background Vitamin D receptor activators reduce albuminuria, and may improve survival in chronic kidney disease (CKD). Animal studies suggest that these pleiotropic effects of vitamin D may be mediated by suppression of renin. However, randomized trials in humans have yet to establish this relationship. Methods In a randomized, placebo-controlled, double-blinded crossover study, the effect of oral paricalcitol (2 μg/day) was investigated in 26 patients with non-diabetic, albuminuric stage III-IV CKD. After treatment, plasma concentrations of renin (PRC), angiotensin II (AngII) and aldosterone (Aldo) were measured. GFR was determined by 51Cr-EDTA clearance. Assessment of renal NO dependency was performed by infusion of NG-monomethyl-L-arginine (L-NMMA). Albumin excretion rate (AER) was analyzed in 24-h urine and during 51Cr-EDTA clearance. Results Paricalcitol did not alter plasma levels of renin, AngII, Aldo, or urinary excretion of sodium and potassium. A modest reduction of borderline significance was observed in AER, and paricalcitol abrogated the albuminuric response to L-NMMA. Conclusions In this randomized, placebo-controlled trial paricalcitol only marginally decreased AER and did not alter circulating levels of renin, AngII or Aldo. The abrogation of the rise in albumin excretion by paricalcitol during NOS blockade may indicate that favourable modulation of renal NO dependency could be involved in mediating reno-protection and survival benefits in CKD. Trial registration ClinicalTrials.gov identifier: NCT01136564 PMID:23889806

  19. Hyperkalemia After Initiating Renin-Angiotensin System Blockade: The Stockholm Creatinine Measurements (SCREAM) Project.

    PubMed

    Bandak, Ghassan; Sang, Yingying; Gasparini, Alessandro; Chang, Alex R; Ballew, Shoshana H; Evans, Marie; Arnlov, Johan; Lund, Lars H; Inker, Lesley A; Coresh, Josef; Carrero, Juan-Jesus; Grams, Morgan E

    2017-07-19

    Concerns about hyperkalemia limit the use of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs), but guidelines conflict regarding potassium-monitoring protocols. We quantified hyperkalemia monitoring and risks after ACE-I/ARB initiation and developed and validated a hyperkalemia susceptibility score. We evaluated 69 426 new users of ACE-I/ARB therapy in the Stockholm Creatinine Measurements (SCREAM) project with medication initiation from January 1, 2007 to December 31, 2010, and follow-up for 1 year thereafter. Three fourths (76%) of SCREAM patients had potassium checked within the first year. Potassium >5 and >5.5 mmol/L occurred in 5.6% and 1.7%, respectively. As a comparison, we propensity-matched new ACE-I/ARB users to 20 186 new β-blocker users in SCREAM: 64% had potassium checked. The occurrence of elevated potassium levels was similar between new β-blocker and ACE-I/ARB users without kidney disease; only at estimated glomerular filtration rate <60 mL/min per 1.73 m 2 were risks higher among ACE-I/ARB users. We developed a hyperkalemia susceptibility score that incorporated estimated glomerular filtration rate, baseline potassium level, sex, diabetes mellitus, heart failure, and the concomitant use of potassium-sparing diuretics in new ACE-I/ARB users; this score accurately predicted 1-year hyperkalemia risk in the SCREAM cohort (area under the curve, 0.845, 95% CI: 0.840-0.869) and in a validation cohort from the US-based Geisinger Health System (N=19 524; area under the curve, 0.818, 95% CI: 0.794-0.841), with good calibration. Hyperkalemia within the first year of ACE-I/ARB therapy was relatively uncommon among people with estimated glomerular filtration rate >60 mL/min per 1.73 m 2 , but rates were much higher with lower estimated glomerular filtration rate. Use of the hyperkalemia susceptibility score may help guide laboratory monitoring and prescribing strategies. © 2017 The Authors. Published on

  20. The effect of renin-angiotensin system inhibitors on mortality and heart failure hospitalization in patients with heart failure and preserved ejection fraction: a systematic review and meta-analysis.

    PubMed

    Shah, Ravi V; Desai, Akshay S; Givertz, Michael M

    2010-03-01

    Although renin-angiotensin system (RAS) inhibitors have little demonstrable effect on mortality in patients with heart failure and preserved ejection fraction (HF-PEF), some trials have suggested a benefit with regard to reduction in HF hospitalization. Here, we systematically review and evaluate prospective clinical studies of RAS inhibitors enrolling patients with HF-PEF, including the 3 major trials of RAS inhibition (Candesartan in Patients with Chronic Heart Failure and Preserved Left Ventricular Ejection Fraction [CHARM-Preserved], Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction [I-PRESERVE], and Perindopril in Elderly People with Chronic Heart Failure [PEP-CHF]). We also conducted a pooled analysis of 8021 patients in the 3 major randomized trials of RAS inhibition in HF-PEF (CHARM-Preserved, I-PRESERVE, and PEP-CHF) in fixed-effect models, finding no clear benefit with regard to all-cause mortality (odds ratio [OR] 1.03, 95% confidence interval [CI], 0.92-1.15; P=.62), or HF hospitalization (OR 0.90, 95% CI 0.80-1.02; P=.09). Although RAS inhibition may be valuable in the management of comorbidities related to HF-PEF, RAS inhibition in HF-PEF is not associated with consistent reduction in HF hospitalization or mortality in this emerging cohort. Copyright (c) 2010 Elsevier Inc. All rights reserved.