Science.gov

Sample records for renal renin-angiotensin system

  1. 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…

  2. 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.

  3. Reproduction and the renin-angiotensin system.

    PubMed

    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. Postnatal development of the renal medulla; role of the renin-angiotensin system.

    PubMed

    Madsen, K; Tinning, A R; Marcussen, N; Jensen, B L

    2013-05-01

    Adverse events during foetal development can predispose the individual for cardiovascular disease later in life, a correlation known as foetal programming of adult hypertension. The 'programming' events have been associated with the kidneys due to the significant role in extracellular volume control and long-term blood pressure regulation. Previously, nephron endowment and functional consequences of a low nephron number have been extensively investigated without achieving a full explanation of the underlying pathophysiological mechanisms. In this review, we will focus on mechanisms of postnatal development in the renal medulla with regard to the programming effects. The renin-angiotensin system is critically involved in mammalian kidney development and impaired signalling gives rise to developmental renal lesions that have been associated with hypertension later in life. A consistent finding in both experimental animal models and in human case reports is atrophy of the renal medulla with developmental lesions to both medullary nephron segments and vascular development with concomitant functional disturbances reaching into adulthood. A review of current knowledge of the role of the renin-angiotensin system for renal medullary development will be given.

  5. The Renin-Angiotensin and Renal Dopaminergic Systems Interact in Normotensive Humans

    PubMed Central

    Eisner, Gilbert M.; Armando, Ines; Browning, Shaunagh; Pezzullo, John C.; Rhee, Lauren; Dajani, Mustafa; Carey, Robert M.; Jose, Pedro A.

    2016-01-01

    The renin-angiotensin-aldosterone (RAAS) and renal dopaminergic systems interact to maintain sodium balance. High NaCl intake increases renal synthesis of dopamine and dopaminergic receptor activity, decreasing epithelial sodium transport, whereas sodium deficit activates the RAAS, increasing epithelial sodium transport. We tested the hypothesis that attenuation of the natriuretic effect of dopamine D1-like receptors during salt restriction results in part from increased RAAS activity in seven salt-resistant normotensive adults using a double-blind placebo-controlled balanced crossover design. All subjects attained sodium balance on low (50 mmol Na+/day) and high (300 mmol Na+/day) NaCl diets, administered 4 weeks apart. Sodium, potassium, lithium, para-aminohippurate, and creatinine clearances were measured before, during, and after a 3-hour infusion of fenoldopam, a D1-like receptor agonist, with and without pretreatment with enalapril, an angiotensin converting enzyme inhibitor. On the high NaCl diet, fenoldopam-induced natriuresis was associated with the inhibition of renal proximal and distal tubule sodium transport. On the low NaCl diet, fenoldopam decreased renal distal tubule sodium transport but did not cause natriuresis. The addition of enalapril to fenoldopam restored the natriuretic effect of fenoldopam and its inhibitory effect on proximal tubule sodium transport. Thus, on a high NaCl diet fenoldopam causes natriuresis by inhibiting renal proximal and distal tubule transport, but on a low NaCl diet the increased RAAS activity prevents the D1-like receptor from inhibiting renal proximal tubule sodium transport, neutralizing the natriuretic effect of fenoldopam. These results demonstrate an interaction between the renin-angiotensin and renal dopaminergic systems in humans and highlight the influence of dietary NaCl on these interactions. PMID:25977313

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

    PubMed

    Urushihara, Maki; Kagami, Shoji

    2016-07-05

    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.

  7. 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

  8. Association between the intrarenal renin-angiotensin system and renal injury in chronic kidney disease of dogs and cats.

    PubMed

    Mitani, Sawane; Yabuki, Akira; Taniguchi, Kazuyuki; Yamato, Osamu

    2013-02-01

    The association of renin and angiotensin II, which are potent components of the renin-angiotensin system, with the severity of chronic renal disease was investigated immunohistochemically in dogs and cats. Immunoreactivities of renin and angiotensin II were evaluated quantitatively, and their correlations with the degrees of glomerulosclerosis, glomerular hypertrophy, interstitial cell infiltration and interstitial fibrosis were statistically analyzed. Immunoreactivities for renin were detected in afferent arteries in both dogs and cats. The score of renin-positive signals showed no correlation with plasma creatinine concentration or any of the histopathological parameters, except for the diameter of glomeruli in dogs. Immunoreactivities for angiotensin II were detected in tubules (primarily proximal tubules) and interstitial mononuclear cells in both dogs and cats. The score of tubular angiotensin II correlated with glomerulosclerosis and cell infiltration in cats but not in dogs. The score of interstitial angiotensin II correlated with plasma creatinine concentration, glomerulosclerosis, cell infiltration and fibrosis in dogs and with glomerulosclerosis and cell infiltration in cats. In conclusion, the results of the study suggest that intrarenal renin-angiotensin system is correlated with the severity of kidney disease, with the underlying mechanism differing between dogs and cats.

  9. Nuclear Expression of Renin-Angiotensin System Components in NRK-52E Renal Epithelial Cells

    PubMed Central

    Alzayadneh, Ebaa M.; Chappell, Mark C.

    2014-01-01

    Introduction Isolated nuclei of sheep proximal tubules express angiotensin receptors as well as angiotensinogen (AGT) and renin. The present study characterized the NRK-52E tubular epithelial cell line for the intracellular expression of renin-angiotensin system (RAS) components. Methods RAS components were visualized by immunofluorescent staining in intact cells and protein expression in isolate nuclei. Results An antibody to the Ang I sequence of AGT (AI-AGT) revealed only cytosolic staining, while an antibody to an internal epitope of AGT (Int-AGT) revealed primarily nuclear staining. Immunoblots of nuclear and cytosolic fractions confirmed the differential cell staining of AGT. Immunostaining for renin was present on nuclei of intact cells. Nuclear renin activity averaged 0.77 ± 0.05 nmol/mg protein/hr that was reduced by aliskiren (0.13 ± 0.01 nmol/mg/hr, n=3, p<0.01); trypsin activation increased activity 3-fold. Peptide staining localized Ang II and Ang-(1–7) to the nucleus and peptide content averaged 59 ± 2 and 57 ± 22 fmol/mg (n=4), respectively. Peptide metabolism in isolated nuclei revealed the processing of Ang I to Ang-(1–7) by thimet oligopeptidase. Conclusion We conclude that the NRK-52E cells express an intracellular RAS localized to the nucleus and may be an appropriate cell model to elucidate the functional relevance of this system. PMID:24961503

  10. Oxidative Stress Causes Imbalance of Renal Renin Angiotensin System (RAS) Components and Hypertension in Obese Zucker Rats

    PubMed Central

    Luo, Hao; Wang, Xinquan; Chen, Caiyu; Wang, Jialiang; Zou, Xue; Li, Chuanwei; Xu, Zaicheng; Yang, Xiaoli; Shi, Weibin; Zeng, Chunyu

    2015-01-01

    Background Oxidative stress plays an important role in the pathogenesis of hypertension, especially in obesity‐related hypertension. The natriuretic and antinatriuretic components of the renal renin angiotensin system (RAS) maintain sodium homeostasis and blood pressure. Here, we test the hypothesis that increased oxidative stress leads to the imbalance of RAS components and hypertension in obese Zucker rats. Methods and Results Lean and obese rats received vehicle or tempol, a superoxide dismutase mimetic in the drinking water for 4 weeks. Compared with vehicle‐treated lean rats, vehicle‐treated obese rats exhibited higher blood pressure and increased renal oxidative stress, accompanied by increased diuretic and natriuretic responses to AT1R antagonist (Candesartan) and AT2R agonist (CGP‐42112A) and reduced diuretic and natriuretic response to MasR agonist (Ang‐[1 to 7]). Moreover, obese rats had higher ACE, AT1R and AT2R, lower ACE2 and MasR expressions in the kidney. All of the above‐mentioned abnormalities were reversed to some degree by tempol treatment. In primary cultures of renal proximal tubular (RPT) cells from lean and obese rats, tempol treatment also increased AT2R, ACE2, and MasR expressions but decreased AT1R and ACE expressions in obese rats. Conclusions Taken together, our study indicated that the imbalance of renal RAS components was associated with increased oxidative stress in obese rats. Furthermore, antioxidant treatment with tempol reversed the imbalance of renal RAS components and led to diuresis and natriuresis, which, at least in part, explains the blood pressure‐lowering effect of antioxidant supplementation in obesity‐related hypertension. PMID:25687731

  11. The link between the renin-angiotensin-aldosterone system and renal injury in obesity and the metabolic syndrome.

    PubMed

    Thethi, Tina; Kamiyama, Masumi; Kobori, Hiroyuki

    2012-04-01

    Obesity is a risk factor for type 2 diabetes mellitus (DM) and is associated with chronic kidney disease. Activation of the renin-angiotensin-aldosterone system (RAAS) is common in obesity. The RAAS is an important mediator of hypertension. Mechanisms involved in activation of the RAAS in obesity include sympathetic stimulation, synthesis of adipokines in the RAAS by visceral fat, and hemodynamic alterations. The RAAS is known for its role in regulating blood pressure and fluid and electrolyte homeostasis. The role of local/tissue RAAS in specific tissues has been a focus of research. Urinary angiotensinogen (UAGT) provides a specific index of the intrarenal RAAS. Investigators have demonstrated that sex steroids can modulate the expression and activity of the different components of the intrarenal RAAS and other tissues. Our data suggest that obese women without DM and hypertension have significantly higher levels of UAGT than their male counterparts. These differences existed without any background difference in the ratio of microalbumin to creatinine in the urine or the estimated glomerular filtration rate, raising a question about the importance of baseline gender differences in the endogenous RAAS in the clinical spectrum of cardiovascular diseases and the potential utility of UAGT as a marker of the intrarenal RAAS. Animal studies have demonstrated that modifying the amount of angiotensin, the biologically active component of the RAAS, directly influences body weight and adiposity. This article reviews the role of the RAAS in renal injury seen in obesity and the metabolic syndrome.

  12. Resetting of renal tissular renin-angiotensin and bradykinin-kallikrein systems after unilateral kidney denervation in rats.

    PubMed

    Bohlender, Jürgen M; Nussberger, Jürg; Birkhäuser, Frédéric; Grouzmann, Eric; Thalmann, George N; Imboden, Hans

    2017-02-20

    The renal tissular renin-angiotensin and bradykinin-kallikrein systems control kidney function together with the renal sympathetic innervation but their interaction is still unclear. To further elucidate this relationship, we investigated these systems in rats 6 days after left kidney denervation (DNX, n = 8) compared to sham-operated controls (CTR, n = 8). Plasma renin concentration was unchanged in DNX vs. CTR (p = NS). Kidney bradykinin (BK) and angiotensin (Ang) I and II concentrations decreased bilaterally in DNX vs. CTR rats (~20 to 40%, p < 0.05) together with Ang IV and V concentrations that were extremely low (p = NS). Renin, Ang III and dopamine concentrations decreased by ~25 to 50% and norepinephrine concentrations by 99% in DNX kidneys (p < 0.05) but were unaltered in opposite kidneys. Ang II/I and KA were comparable in DNX, contralateral and CTR kidneys. Ang III/II increased in right vs. DNX or CTR kidneys (40-50%, p < 0.05). Ang II was mainly located in tubular epithelium by immunocytological staining and its cellular distribution was unaffected by DNX. Moreover, the angiotensinergic and catecholaminergic innervation of right kidneys was unchanged vs. CTR. We found an important dependency of tissular Ang and BK levels on the renal innervation that may contribute to the resetting of kidney function after DNX. The DNX-induced peptide changes were not readily explained by kidney KA, renin or plasma Ang I generation. However, tissular peptide metabolism and compartmentalization may have played a central role. The mechanisms behind the concentration changes remain unclear and deserve further clarification.

  13. 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.

  14. 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.

  15. Diuretic-induced renal impairment without volume depletion in cirrhosis: changes in the renin-angiotensin system and the effect of β-adrenergic blockade

    PubMed Central

    Wilkinson, S. P.; Bernardi, M.; Wheeler, P. G.; Smith, I. K.; Williams, R.

    1979-01-01

    In 4 patients with cirrhosis and ascites, diuretic therapy resulted in an impairment of renal function that was associated with a rise in plasma renin activity (PRA). In 3, this occurred in the absence of volume depletion. When diuretics were discontinued, renal function returned to normal. β-adrenergic blocking drugs were then given to suppress renin secretion and diurectics restarted. On this occasion, impairment of renal function did not occur. In 2 further patients, administration of β-adrenergic blockers during a period of diuretic-induced renal impairment resulted in an improvement in renal function. Although these findings may indicate that diuretic-induced renal impairment in cirrhosis is at least partly due to activation of the renin-angiotensin system, in another group of patients a diuretic-induced rise in PRA was not associated with a deterioration in renal function. PMID:44911

  16. Role of renin angiotensin system inhibitors in cardiovascular and renal protection: a lesson from clinical trials.

    PubMed

    Stojiljkovic, Ljuba; Behnia, Rahim

    2007-01-01

    Beneficial effects of angiotensin converting enzyme inhibitors (ACEI) and angiotensin type 1 receptor (AT1) blockers in patients with cardiovascular and renal diseases have been clearly demonstrated in numerous large outcomes studies. In patients with heart failure (HF), ACEI have been shown to reduce overall mortality, mortality from cardiovascular causes, to increase life expectancy, as well as to preserve the renal function (CONSENSUS, SAVE, TRACE, AIRE, AIREX, CATS trials). In addition, in the PROGRESS study ACEI substantially decreased the risk of stroke and transient ischemic attacks in patients with cerebrovascular disorders. The HOPE and EUROPA studies confirmed that long term therapy with ACEI provides significant survival benefit in patients with broad range of atherosclerotic cardiovascular diseases. After these large and well designed clinical studies, ACEI have become standard therapy for routine secondary prevention in all patients with cardiovascular diseases, unless contraindicated. AT1 receptor blockers have been recently added to the cardiovascular therapeutic armamentarium. They are believed to provide additional protection by inhibition of locally synthesized angiotensin II on the level of AT1 receptor. The ELITE II, ValHeFT and CHARM studies have shown that AT1 receptor blockers are equally effective as ACEI in reduction of mortality and morbidity in patients with HF. Importantly, they may be used together with ACEI, or as alternative treatment in ACEI intolerant patients. Renal protection is another important effect of both ACEI and AT1 blockers that has been confirmed in several large clinical trials. The North American Microalbuminemia Study group and EUCLID group demonstrated significant reduction in progression of diabetic nephropathy in patients with insulin dependent diabetes mellitus (IDDM) treated with ACEI. AT1 receptor blockers are mainly studied in the non-insulin dependent diabetes mellitus (NIDDM) nephropathy. Four recent clinical

  17. 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

  18. 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

  19. From preeclampsia to renal disease: a role of angiogenic factors and the renin-angiotensin aldosterone system?

    PubMed

    van der Graaf, Anne Marijn; Toering, Tsjitske J; Faas, Marijke M; Lely, A Titia

    2012-10-01

    Complicating up to 8% of pregnancies, preeclampsia is the most common glomerular disease worldwide and remains a leading cause of infant and maternal morbidity and mortality. Although the exact pathogenesis of this syndrome of hypertension and proteinuria is still incomplete, a consistent line of evidence has identified an imbalance of proangiogenic and anti-angiogenic proteins as a key factor in the development of preeclampsia. Furthermore, more attention has been recently addressed to the renin-angiotensin aldosterone system (RAAS), to provide understanding on the hypertension of preeclampsia. The imbalance of the RAAS and the imbalance between angiogenic and anti-angiogenic factors, which may be both common to preeclampsia and chronic kidney disease (CKD), might explain why a history of preeclampsia predisposes women to develop CKD. In this review, we briefly describe the characteristics of preeclampsia with a focus on the mechanisms of angiogenesis and the RAAS and its role in the pathogenesis of preeclampsia. Our main focus will be on the intriguing association between preeclampsia and the subsequent increased risk of developing CKD and on the potential mechanisms by which the risk of CKD is elevated in women with a history of preeclampsia.

  20. The "his and hers" of the renin-angiotensin system.

    PubMed

    Hilliard, Lucinda M; Sampson, Amanda K; Brown, Russell D; Denton, Kate M

    2013-02-01

    Sex differences exist in the regulation of arterial pressure and renal function by the renin-angiotensin system (RAS). This may in part stem from a differential balance in the pressor and depressor arms of the RAS. In males, the ACE/AngII/AT(1)R pathways are enhanced, whereas, in females, the balance is shifted towards the ACE2/Ang(1-7)/MasR and AT(2)R pathways. Evidence clearly demonstrates that premenopausal women, as compared to aged-matched men, are protected from renal and cardiovascular disease, and this differential balance of the RAS between the sexes likely contributes. With aging, this cardiovascular protection in women is lost and this may be related to loss of estrogen postmenopause but the possible contribution of other sex hormones needs to be further examined. Restoration of these RAS depressor pathways in older women, or up-regulation of these in males, represents a therapeutic target that is worth pursuing.

  1. Renin-angiotensin system activation accelerates atherosclerosis in experimental renal failure by promoting endoplasmic reticulum stress-related inflammation

    PubMed Central

    Yang, Jia; Zhang, Xi; Yu, Xinyi; Tang, Weixue; Gan, Hua

    2017-01-01

    In this study, we investigated the association between the renin-angiotensin system (RAS), endoplasmic reticulum (ER) stress and atherosclerosis (AS) in uremic apolipo-protein E knockout (apoE−/−) mice. Mild uremia was induced by a 5/6 nephrectomy (5/6 Nx) in 10-week-old apoE−/− mice. Four weeks after nephrectomy, the mice received losartan or no treatment for 16 weeks. Sham-operated mice served as the controls. We found that uremia accelerated AS at the aortic root. The activation of ER stress and the significant upregulation of pro-inflammatory cytokines and chemokines were observed in the uremic mice. Phosphorylated inositol-requiring 1α (p-IRE1α), an ER stress marker protein, was mainly expressed in macrophages in the atherosclerotic lesions. Treatment with losartan significantly attenuated aortic AS, inhibited ER stress and reduced aortic inflammation. In in vitro experiments, angiotensin II (Ang II) increased the levels of the common ER stress maker, glucose-regulated protein 78 (GRP78) and the phosphorylation of IRE1α in RAW264.7 macrophages. Treatment with losartan inhibited the activation of ER stress and the upregulation of GRP78, and enhanced the expression of nuclear factor-κB (NF-κB) inhibitor (IκB) in Ang II-stimulated RAW264.7 macrophages. IRE1α-siRNA suppressed inflammation and downregulated IκB expression and IκB kinase (IKK) phosphorylation, which inhibited IκB degradation and NF-κB p65 nuclear translocation in Ang II-treated RAW264.7 macrophages. These findings suggest that RAS activation accelerates AS by promoting ER stress-related inflammation in uremic mice. PMID:28098884

  2. 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)

  3. The Impact of Renin-Angiotensin System Blockade on Renal Outcomes and Mortality in Pre-Dialysis Patients with Advanced Chronic Kidney Disease

    PubMed Central

    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

    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. PMID:28122064

  4. 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

  5. Activation of the Renin-Angiotensin System Promotes Colitis Development

    PubMed Central

    Shi, Yongyan; Liu, Tianjing; He, Lei; Dougherty, Urszula; Chen, Li; Adhikari, Sarbani; Alpert, Lindsay; Zhou, Guolin; Liu, Weicheng; Wang, Jiaolong; Deb, Dilip K.; Hart, John; Liu, Shu Q.; Kwon, John; Pekow, Joel; Rubin, David T.; Zhao, Qun; Bissonnette, Marc; Li, Yan Chun

    2016-01-01

    The renin-angiotensin system (RAS) plays pathogenic roles in renal and cardiovascular disorders, but whether it is involved in colitis is unclear. Here we show that RenTgMK mice that overexpress active renin from the liver developed more severe colitis than wild-type controls. More than 50% RenTgMK mice died whereas all wild-type mice recovered. RenTgMK mice exhibited more robust mucosal TH17 and TH1/TH17 responses and more profound colonic epithelial cell apoptosis compared to wild-type controls. Treatment with aliskiren (a renin inhibitor), but not hydralazine (a smooth muscle relaxant), ameliorated colitis in RenTgMK mice, although both drugs normalized blood pressure. Chronic infusion of angiotensin II into wild-type mice mimicked the severe colitic phenotype of RenTgMK mice, and treatment with losartan [an angiotensin type 1 receptor blocker (ARB)] ameliorated colitis in wild-type mice, confirming a colitogenic role for the endogenous RAS. In human biopsies, pro-inflammatory cytokines were suppressed in patients with inflammatory bowel disease who were on ARB therapy compared to patients not receiving ARB therapy. These observations demonstrate that activation of the RAS promotes colitis in a blood pressure independent manner. Angiotensin II appears to drive colonic mucosal inflammation by promoting intestinal epithelial cell apoptosis and mucosal TH17 responses in colitis development. PMID:27271344

  6. Physiological evolution of the renin-angiotensin system.

    PubMed

    Nishimura, H

    1978-09-01

    The renin-angiotensin system (RAS) in mammals may participate in the controls of blood pressure and aldosterone secretion, and possibly in the regulation of renal function. It has been shown that renin release is controlled by:1) two intrarenal receptors, the renal arteriolar receptor and the macula densa; 2) the sympathetic nervous system; and 3) several humoral agents. Recent studies indicate interrelations between the RAS and renal prostaglandins and the kallikrein-kinin system. Comparative studies have revealed that renal renin and the juxtaglomerular (JG) cells emerged during the early evolution of bony fishes, wherease the macula densa evolved later in the vertebrate phylogney. Exogenously administered angiotensins and renin produce vasopressor actions in representative species of all vertebrate classes from elasmobranchs to mammals, and increase secreations of mineralocorticoids from the adrenal cortex (interrenal) in amphibians, repitles, and possibly in teleosts. Angiotensin causes glomerular diuresis in teleosts and lung-fishes, which may be ascribed to increased dorsal aortic pressure, while angiotensin may have both glomerular and tubular actions in some amphibians. Intracranial injection of angiotensin stimulates drinking in teleosts, repites, and birds, but not in amphibians. Hemorrage and acute hypotension are potent stimuli for causing renin release in an aglomerular teleost and a bird. When we consider this fact together with the anatomical evidence that the evolution of the JG cells precedes that of the macula densa, it appears that the RAS HAS EVOLVED WITH A CLOSE RELATIONSHIP TO BLOOD PRESSURE HOEMOSTASIS. On the other hand, there is no clear evidence that the RAS is activated in depleted teleosts and amphibians. Although the RAS appears to exert several functions in man and other mammals, some of them may be more important in primitive animals, while a similar function remains in mammals as a relic of the primitive system. Comparative

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

    PubMed Central

    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

    2016-01-01

    Background 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. Methods 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. Results 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). Conclusion Dapagliflozin treatment showed

  8. Renin-Angiotensin-aldosterone system in autosomal dominant polycystic kidney disease.

    PubMed

    Tkachenko, Oleksandra; Helal, Imed; Shchekochikhin, Dmitry; Schrier, Robert W

    2013-02-01

    Autosomal dominant polycystic kidney disease is the most frequent life-threatening hereditary disease. Prognostic factors for progressive renal impairment have been identified such as gender, race, age, proteinuria, hematuria, hypertension. Hypertension is the only risk factor for renal dysfunction in autosomal dominant polycystic kidney disease, which is presently treatable. Better understanding of the pathophysiology of hypertension will help in defining appropriate interventions. The renin-angiotensin-aldosterone-system is the pivotal factor in the pathogenesis of hypertension in autosomal dominant polycystic kidney disease. Basic research and clinical studies in autosomal dominant polycystic kidney disease implicated activation of the renin-angiotensin-aldosterone-system. Therapy of hypertension in autosomal dominant polycystic kidney disease with angiotensin-converting enzyme inhibitors or angiotensin receptor blocker has the potential to prevent cardiovascular complications and slow the progression of renal disease. The results of two large multicenter double-blind placebo controlled randomized clinical trials (the HALT-PKD trials) possibly will elucidate the beneficial effects of the renin-angiotensin-aldosterone-system inhibition in autosomal dominant polycystic kidney disease.

  9. Chronic vasodilation increases renal medullary PDE5A and α-ENaC through independent renin-angiotensin-aldosterone system pathways.

    PubMed

    West, Crystal A; Shaw, Stefan; Sasser, Jennifer M; Fekete, Andrea; Alexander, Tyler; Cunningham, Mark W; Masilamani, Shyama M E; Baylis, Chris

    2013-11-15

    We have previously observed that many of the renal and hemodynamic adaptations seen in normal pregnancy can be induced in virgin female rats by chronic systemic vasodilation. Fourteen-day vasodilation with sodium nitrite or nifedipine (NIF) produced plasma volume expansion (PVE), hemodilution, and increased renal medullary phosphodiesterase 5A (PDE5A) protein. The present study examined the role of the renin-angiotensin-aldosterone system (RAAS) in this mechanism. Virgin females were treated for 14 days with NIF (10 mg·kg(-1)·day(-1) via diet), NIF with spironolactone [SPR; mineralocorticoid receptor (MR) blocker, 200-300 mg·kg(-1)·day(-1) via diet], NIF with losartan [LOS; angiotensin type 1 (AT1) receptor blocker, 20 mg·kg(-1)·day(-1) via diet], enalapril (ENAL; angiotensin-converting enzyme inhibitor, 62.5 mg/l via water), or vehicle (CON). Mean arterial pressure (MAP) was reduced 7.4 ± 0.5% with NIF, 6.33 ± 0.5% with NIF + SPR, 13.3 ± 0.9% with NIF + LOS, and 12.0 ± 0.4% with ENAL vs. baseline MAP. Compared with CON (3.6 ± 0.3%), plasma volume factored for body weight was increased by NIF (5.2 ± 0.4%) treatment but not by NIF + SPR (4.3 ± 0.3%), NIF + LOS (3.6 ± 0.1%), or ENAL (4.0 ± 0.3%). NIF increased PDE5A protein abundance in the renal inner medulla, and SPR did not prevent this increase (188 ± 16 and 204 ± 22% of CON, respectively). NIF increased the α-subunit of the epithelial sodium channel (α-ENaC) protein in renal outer (365 ± 44%) and inner (526 ± 83%) medulla, and SPR prevented these changes. There was no change in either PDE5A or α-ENaC abundance vs. CON in rats treated with NIF + LOS or ENAL. These data indicate that the PVE and renal medullary adaptations in response to chronic vasodilation result from RAAS signaling, with increases in PDE5A mediated through AT1 receptor and α-ENaC through the MR.

  10. The growth factor midkine regulates the renin-angiotensin system in mice

    PubMed Central

    Hobo, Akinori; Yuzawa, Yukio; Kosugi, Tomoki; Kato, Noritoshi; Asai, Naoto; Sato, Waichi; Maruyama, Shoichi; Ito, Yasuhiko; Kobori, Hiroyuki; Ikematsu, Shinya; Nishiyama, Akira; Matsuo, Seiichi; Kadomatsu, Kenji

    2009-01-01

    The renin-angiotensin system plays a pivotal role in regulating blood pressure and is involved in the pathogenesis of kidney disorders and other diseases. Here, we report that the growth factor midkine is what we believe to be a novel regulator of the renin-angiotensin system. The hypertension induced in mice by 5/6 nephrectomy was accompanied by renal damage and elevated plasma angiotensin II levels and was ameliorated by an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin receptor blocker. Notably, ACE activity in the lung, midkine expression in the lung, and midkine levels in the plasma were all increased after 5/6 nephrectomy. Exposure to midkine protein enhanced ACE expression in primary cultured human lung microvascular endothelial cells. Furthermore, hypertension was not induced and renal damage was less severe in midkine-deficient mice. Supplemental administration of midkine protein to midkine-deficient mice restored ACE expression in the lung and hypertension after 5/6 nephrectomy. Oxidative stress might be involved in midkine expression, since expression of NADH/NADPH oxidase–1, –2, and –4 was induced in the lung after 5/6 nephrectomy. Indeed, the antioxidative reagent tempol reduced midkine expression and plasma angiotensin II levels and consequently ameliorated hypertension. These results suggest that midkine regulates the renin-angiotensin system and mediates the kidney-lung interaction after 5/6 nephrectomy. PMID:19451697

  11. 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

  12. The renin-angiotensin system meets the hallmarks of cancer.

    PubMed

    Wegman-Ostrosky, Talia; Soto-Reyes, Ernesto; Vidal-Millán, Silvia; Sánchez-Corona, José

    2015-06-01

    The hallmarks of cancer are described as the distinctive and complementary capacities that cells must acquire during the multistep development of becoming a cancer cell that allow them to survive, proliferate and disseminate. The renin-angiotensin system (RAS) was first discovered and extensively studied in the physiological regulation of systemic arterial pressure. RAS signalling increases cell proliferation in malignancy by directly affecting tumour and stromal cells and by indirectly modulating the growth of vascular cells during angiogenesis. We aim to describe and give a general view of how the RAS is involved in several hallmarks of cancer and how this could open a window to several interesting treatments.

  13. 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

  14. African Americans, hypertension and the renin angiotensin system

    PubMed Central

    Williams, Sandra F; Nicholas, Susanne B; Vaziri, Nosratola D; Norris, Keith C

    2014-01-01

    African Americans have exceptionally high rates of hypertension and hypertension related complications. It is commonly reported that the blood pressure lowering efficacy of renin angiotensin system (RAS) inhibitors is attenuated in African Americans due to a greater likelihood of having a low renin profile. Therefore these agents are often not recommended as initial therapy in African Americans with hypertension. However, the high prevalence of comorbid conditions, such as diabetes, cardiovascular and chronic kidney disease makes treatment with RAS inhibitors more compelling. Despite lower circulating renin levels and a less significant fall in blood pressure in response to RAS inhibitors in African Americans, numerous clinical trials support the efficacy of RAS inhibitors to improve clinical outcomes in this population, especially in those with hypertension and risk factors for cardiovascular and related diseases. Here, we discuss the rationale of RAS blockade as part of a comprehensive approach to attenuate the high rates of premature morbidity and mortality associated with hypertension among African Americans. PMID:25276290

  15. REGULATION OF MULTIPLE RENIN-ANGIOTENSIN SYSTEM GENES BY SRY

    PubMed Central

    Milsted, Amy; Underwood, Adam C.; Dunmire, Jeff; DelPuerto, Helen L.; Martins, Almir S.; Ely, Daniel L.; Turner, Monte E.

    2010-01-01

    We demonstrated that the Sry gene complex on the SHR Y chromosome is a candidate locus for hypertension that accounts for the SHR Y chromosome blood pressure effect. All rat strains examined to date share 6 Sry loci, and a seventh Sry locus (Sry3) appears to be unique to SHR males. Previously, we showed that Sry1 increased activity of the tyrosine hydroxylase promoter in transfected PC12 cells, and Sry1 delivered to adrenal gland of WKY rats increased blood pressure and sympathetic nervous system activity. The objective of this study was to determine whether renin-angiotensin system genes participate in Sry-mediated effects. Sry expression vectors were co-transfected into CHO cells with luciferase reporter constructs containing promoters of angiotensinogen (Agt −1430/+22), renin (Ren −1050/−1), ACE (ACE −1677/+21) and ACE2 (ACE2 −1091/+83). Sry1, Sry2 and Sry3 differentially up-regulated activity of the promoters of angiotensinogen, renin and ACE genes, and down-regulated ACE2 promoter activity. The largest effect was seen with Sry3, which increased activity of angiotensinogen promoter by 1.7 fold, renin promoter by 1.3 fold, ACE promoter by 2.6 fold, and decreased activity of ACE2 promoter by 0.5 fold. The effect of Sry1 on promoter activity was significantly less than Sry3. Sry2 activated promoters at a significantly lower level than Sry1. The result of either an additive effect of Sry regulation of multiple genes in the renin-angiotensin system or alterations in expression of a single gene could favor increased levels of Ang II and decreased levels of Ang-(1-7). These actions of Sry could result in increased blood pressure in males and contribute to gender differences in blood pressure. PMID:19809364

  16. Macrophages in neuroinflammation: role of the renin-angiotensin-system.

    PubMed

    Hammer, Anna; Stegbauer, Johannes; Linker, Ralf A

    2017-04-01

    Macrophages are essential players of the innate immune system which are involved in the initiation and progression of various inflammatory and autoimmune diseases including neuroinflammation. In the past few years, it has become increasingly clear that the regulation of macrophage responses by the local tissue milieu is also influenced by mediators which were first discovered as regulators in the nervous or also cardiovascular system. Here, the renin-angiotensin system (RAS) is a major focus of current research. Besides its classical role in blood pressure control, body fluid, and electrolyte homeostasis, the RAS may influence (auto)immune responses, modulate T cells, and particularly act on macrophages via different signaling pathways. Activation of classical RAS pathways including angiotensin (Ang) II and AngII type 1 (AT1R) receptors may drive pro-inflammatory macrophage responses in neuroinflammation via regulation of chemokines. More recently, alternative RAS pathways were described, such as binding of Ang-(1-7) to its receptor Mas. Signaling via Mas pathways may counteract some of the AngII/AT1R-mediated effects. In macrophages, the Ang-(1-7)/Mas exerts beneficial effects on neuroinflammation via modulating macrophage polarization, migration, and T cell activation in vitro and in vivo. These data delineate a pivotal role of the RAS in inflammation of the nervous system and identify RAS modulation as a potential new target for immunotherapy with a special focus on macrophages.

  17. Contribution of genetic polymorphism in the renin-angiotensin system to the development of renal complications in insulin-dependent diabetes: Genetique de la Nephropathie Diabetique (GENEDIAB) study group.

    PubMed Central

    Marre, M; Jeunemaitre, X; Gallois, Y; Rodier, M; Chatellier, G; Sert, C; Dusselier, L; Kahal, Z; Chaillous, L; Halimi, S; Muller, A; Sackmann, H; Bauduceau, B; Bled, F; Passa, P; Alhenc-Gelas, F

    1997-01-01

    Diabetic nephropathy is a glomerular disease due to uncontrolled diabetes and genetic factors. It can be caused by glomerular hypertension produced by capillary vasodilation, due to diabetes, against constitutional glomerular resistance. As angiotensin II increases glomerular pressure, we studied the relationship between genetic polymorphisms in the renin-angiotensin system-angiotensin I converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II, subtype 1, receptor-and the renal involvement of insulin-dependent diabetic subjects with proliferative retinopathy: those exposed to the risk of nephropathy due to diabetes. Of 494 subjects recruited in 17 centers in France and Belgium (GENEDIAB Study), 157 (32%) had no nephropathy, 104 (21%) incipient (microalbuminuria), 126 (25 %) established (proteinuria), and 107 (22%) advanced (plasma creatinine > or = 150 micromol/liter or renal replacement therapy) nephropathy. The severity of renal involvement was associated with ACE insertion/deletion (I/D) polymorphism: chi2 for trend 5.135, P = 0.023; adjusted odds ratio attributable to the D allele 1.889 (95% CI 1.209-2.952, P = 0.0052). Renal involvement was not directly linked to other polymorphisms. However, ACE I-D and AGT M235T polymorphisms interacted significantly (P = 0.0166): in subjects with ACE ID and DD genotypes, renal involvement increased from the AGT MM to TT genotypes. Thus, genetic determinants that affect renal angiotensin II and kinin productions are risk factors for the progression of glomerular disease in uncontrolled insulin-dependent diabetic patients. PMID:9120002

  18. 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 adipositymore » and 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

  19. Therapeutic potential of the renin angiotensin system in ischaemic stroke.

    PubMed

    Arroja, Mariana Moreira Coutinho; Reid, Emma; McCabe, Christopher

    2016-01-01

    The renin angiotensin system (RAS) consists of the systemic hormone system, critically involved in regulation and homeostasis of normal physiological functions [i.e. blood pressure (BP), blood volume regulation], and an independent brain RAS, which is involved in the regulation of many functions such as memory, central control of BP and metabolic functions. In general terms, the RAS consists of two opposing axes; the 'classical axis' mediated primarily by Angiotensin II (Ang II), and the 'alternative axis' mediated mainly by Angiotensin-(1-7) (Ang-(1-7)). An imbalance of these two opposing axes is thought to exist between genders and is thought to contribute to the pathology of cardiovascular conditions such as hypertension, a stroke co-morbidity. Ischaemic stroke pathophysiology has been shown to be influenced by components of the RAS with specific RAS receptor antagonists and agonists improving outcome in experimental models of stroke. Manipulation of the two opposing axes following acute ischaemic stroke may provide an opportunity for protection of the neurovascular unit, particularly in the presence of pre-existing co-morbidities where the balance may be shifted. In the present review we will give an overview of the experimental stroke studies that have investigated pharmacological interventions of the RAS.

  20. The renin-angiotensin system and the central nervous system.

    PubMed

    Ganong, W F

    1977-04-01

    One of several factors affecting the secretion of renin by the kidneys is the sympathetic nervous system. The sympathetic input is excitatory and is mediated by beta-adrenergic receptors, which are probably located on the membranes of the juxtaglomerular cells. Stimulation of sympathetic areas in the medulla, midbrain and hypothalamus raises blood pressure and increases renin secretion, whereas stimulation of other parts of the hypothalamus decreases blood pressure and renin output. The centrally active alpha-adrenergic agonist clonidine decreases renin secretion, lowers blood pressure, inhibits ACTH and vasopressin secretion, and increases growth hormone secretion in dogs. The effects on ACTH and growth hormone are abolished by administration of phenoxybenzamine into the third ventricle, whereas the effect on blood pressure is abolished by administration of phenoxybenzamine in the fourth ventricle without any effect on the ACTH and growth hormone responses. Fourth ventricular phenoxybenzamine decreases but does not abolish the inhibitory effect of clonidine on renin secretion. Circulating angiotensin II acts on the brain via the area postrema to raise blood pressure and via the subfornical organ to increase water intake. Its effect on vasopressin secretion is debated. The brain contains a renin-like enzyme, converting enzyme, renin substrate, and angiotensin. There is debate about the nature and physiological significance of the angiotensin II-generating enzyme in the brain, and about the nature of the angiotensin I and angiotensin II that have been reported to be present in the central nervous system. However, injection of angiotensin II into the cerebral ventricles produces drinking, increased secretion of vasopressin and ACTH, and increased blood pressure. The same responses are produced by intraventricular renin. Angiotensin II also facilitates sympathetic discharge in the periphery, and the possibility that it exerts a similar action on the adrenergic neurons

  1. Emergence and evolution of the renin-angiotensin-aldosterone system.

    PubMed

    Fournier, David; Luft, Friedrich C; Bader, Michael; Ganten, Detlev; Andrade-Navarro, Miguel A

    2012-05-01

    The renin-angiotensin-aldosterone system (RAAS) is not the sole, but perhaps the most important volume regulator in vertebrates. To gain insights into the function and evolution of its components, we conducted a phylogenetic analysis of its main related genes. We found that important parts of the system began to appear with primitive chordates and tunicates and that all major components were present at the divergence of bony fish, with the exception of the Mas receptor. The Mas receptor first appears after the bony-fish/tetrapod divergence. This phase of evolutionary innovation happened about 400 million years ago. We found solid evidence that angiotensinogen made its appearance in cartilage fish. The presence of several RAAS genes in organisms that lack all the components shows that these genes have had other ancestral functions outside of their current role. Our analysis underscores the utility of sequence comparisons in the study of evolution. Such analyses may provide new hypotheses as to how and why in today's population an increased activity of the RAAS frequently leads to faulty salt and volume regulation, hypertension, and cardiovascular diseases, opening up new and clinically important research areas for evolutionary medicine.

  2. Prorenin receptor regulates more than the renin-angiotensin system.

    PubMed

    Müller, Dominik N; Binger, Katrina J; Riediger, Fabian

    2012-06-01

    The (pro)renin receptor (PRR) was initially believed to be a contributor to the pathogenesis of cardiovascular diseases via the amplification of renin- or prorenin-induced angiotensin (Ang) formation. However, a recent paradigm shift suggests a new role for PRR, separate from the renin-angiotensin system (RAS), in contributing to cellular homeostasis. Specifically, PRR is thought to be essential for vacuolar H(+) -ATPase (V-ATPase) activity and acts as an adaptor between the V-ATPase and the Wnt signalling pathway. Recent PRR conditional knock-out studies have confirmed this link between V-ATPase and PRR, with deletion resulting in the accumulation of autophagic vacuoles and animal lethality. The molecular mechanism by which PRR contributes to V-ATPase activity, and whether multiple signalling pathways are affected by PRR loss, is currently unknown. Additionally, cleavage by furin at a single site within full-length PRR results in the production of a soluble form of the receptor, which is detectable in plasma. Soluble PRR is hypothesized to bind to specific ligands and receptors and mediate signal transduction pathways. Understanding the physiological function of full-length and soluble PRR will be important for establishing its role in pathology.

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

    SciTech Connect

    Kim, Suyeon; Soltani-Bejnood, Morvarid; Quignard-Boulange, Annie; Massiera, Florence; Teboul, Michele; Ailhaud, Gerard; Kim, Jung; Moustaid-Moussa, Naima; Voy, Brynn H

    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), 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.

  4. Brain renin-angiotensin system and dopaminergic cell vulnerability

    PubMed Central

    Labandeira-García, Jose L.; Garrido-Gil, Pablo; Rodriguez-Pallares, Jannette; Valenzuela, Rita; Borrajo, Ana; Rodríguez-Perez, Ana I.

    2014-01-01

    Although the renin-angiotensin system (RAS) was classically considered as a circulating system that regulates blood pressure, many tissues are now known to have a local RAS. Angiotensin, via type 1 receptors, is a major activator of the NADPH-oxidase complex, which mediates several key events in oxidative stress (OS) and inflammatory processes involved in the pathogenesis of major aging-related diseases. Several studies have demonstrated the presence of RAS components in the basal ganglia, and particularly in the nigrostriatal system. In the nigrostriatal system, RAS hyperactivation, via NADPH-oxidase complex activation, exacerbates OS and the microglial inflammatory response and contributes to progression of dopaminergic degeneration, which is inhibited by angiotensin receptor blockers and angiotensin converting enzyme (ACE) inhibitors. Several factors may induce an increase in RAS activity in the dopaminergic system. A decrease in dopaminergic activity induces compensatory upregulation of local RAS function in both dopaminergic neurons and glia. In addition to its role as an essential neurotransmitter, dopamine may also modulate microglial inflammatory responses and neuronal OS via RAS. Important counterregulatory interactions between angiotensin and dopamine have also been observed in several peripheral tissues. Neurotoxins and proinflammatory factors may also act on astrocytes to induce an increase in RAS activity, either independently of or before the loss of dopamine. Consistent with a major role of RAS in dopaminergic vulnerability, increased RAS activity has been observed in the nigra of animal models of aging, menopause and chronic cerebral hypoperfusion, which also showed higher dopaminergic vulnerability. Manipulation of the brain RAS may constitute an effective neuroprotective strategy against dopaminergic vulnerability and progression of Parkinson’s disease. PMID:25071471

  5. Brain Renin-Angiotensin System: Does It Exist?

    PubMed

    van Thiel, Bibi S; Góes Martini, Alexandre; Te Riet, Luuk; Severs, David; Uijl, Estrellita; Garrelds, Ingrid M; Leijten, Frank P J; van der Pluijm, Ingrid; Essers, Jeroen; Qadri, Fatimunnisa; Alenina, Natalia; Bader, Michael; Paulis, Ludovit; Rajkovicova, Romana; Domenig, Oliver; Poglitsch, Marko; Danser, A H Jan

    2017-04-10

    Because of the presence of the blood-brain barrier, brain renin-angiotensin system activity should depend on local (pro)renin synthesis. Indeed, an intracellular form of renin has been described in the brain, but whether it displays angiotensin (Ang) I-generating activity (AGA) is unknown. Here, we quantified brain (pro)renin, before and after buffer perfusion of the brain, in wild-type mice, renin knockout mice, deoxycorticosterone acetate salt-treated mice, and Ang II-infused mice. Brain regions were homogenized and incubated with excess angiotensinogen to detect AGA, before and after prorenin activation, using a renin inhibitor to correct for nonrenin-mediated AGA. Renin-dependent AGA was readily detectable in brain regions, the highest AGA being present in brain stem (>thalamus=cerebellum=striatum=midbrain>hippocampus=cortex). Brain AGA increased marginally after prorenin activation, suggesting that brain prorenin is low. Buffer perfusion reduced AGA in all brain areas by >60%. Plasma renin (per mL) was 40× to 800× higher than brain renin (per gram). Renin was undetectable in plasma and brain of renin knockout mice. Deoxycorticosterone acetate salt and Ang II suppressed plasma renin and brain renin in parallel, without upregulating brain prorenin. Finally, Ang I was undetectable in brains of spontaneously hypertensive rats, while their brain/plasma Ang II concentration ratio decreased by 80% after Ang II type 1 receptor blockade. In conclusion, brain renin levels (per gram) correspond with the amount of renin present in 1 to 20 μL of plasma. Brain renin disappears after buffer perfusion and varies in association with plasma renin. This indicates that brain renin represents trapped plasma renin. Brain Ang II represents Ang II taken up from blood rather than locally synthesized Ang II.

  6. Inhibition of the renin-angiotensin system for lowering coronary artery disease risk.

    PubMed

    Sheppard, Richard J; Schiffrin, Ernesto L

    2013-04-01

    The renin-angiotensin system when activated exerts proliferative and pro-inflammatory actions and thereby contributes to progression of atherosclerosis, including that occurring in the coronary arteries. It thus contributes as well to coronary artery disease (CAD). Several clinical trials have examined effects of renin-angiotensin system inhibition for primary and secondary prevention of coronary heart disease. These include important trials such as HOPE, EUROPA and PEACE using angiotensin converting enzyme inhibitors, VALIANT, OPTIMAAL and TRANSCEND using angiotensin receptor blockers, and the ongoing TOPCAT study in patients with preserved ejection fraction heart failure, many of who also have coronary artery disease. Data are unavailable as yet of effects of either direct renin inhibitors or the new angiotensin receptor/neprilysin inhibitor agents. Today, inhibition of the renin-angiotensin system is standard-of-care therapy for lowering cardiovascular risk in secondary prevention in high cardiovascular risk subjects.

  7. Secretin is involved in sodium conservation through the renin-angiotensin-aldosterone system.

    PubMed

    Bai, Juan; Chow, Billy K C

    2017-04-01

    Secretin (SCT) and its receptor (SCTR) are important in fluid regulation at multiple levels via the modulation of expression and translocation of renal aquaporin 2 and functions of central angiotensin II (ANGII). The functional interaction of SCT with peripheral ANGII, however, remains unknown. As the ANGII-aldosterone axis dominates the regulation of renal epithelial sodium channel (ENaC) function, we therefore tested whether SCT/SCTR can regulate sodium homeostasis via the renin-angiotensin-aldosterone system. SCTR-knockout (SCTR(-/-)) mice showed impaired aldosterone synthase (CYP11B2) expression and, consequently, aldosterone release upon intraperitoneal injection of ANGII. Endogenous ANGII production induced by dietary sodium restriction was higher in SCTR(-/-) than in C57BL/6N [wild-type (WT)] mice, but CYP11B2 and aldosterone synthesis were not elevated. Reduced accumulation of cholesteryl ester-the precursor of aldosterone-was observed in adrenal glands of SCTR(-/-) mice that were fed a low-sodium diet. Absence of SCTR resulted in elevated basal transcript levels of adrenal CYP11B2 and renal ENaCs. Although transcript and protein levels of ENaCs were similar in WT and SCTR(-/-) mice under sodium restriction, ENaCs in SCTR(-/-) mice were less sensitive to amiloride hydrochloride. In summary, the SCT/SCTR axis is involved in aldosterone precursor uptake, and the knockout of SCTR results in defective aldosterone biosynthesis/release and altered sensitivity of ENaCs to amiloride.-Bai, J., Chow, B. K. C. Secretin is involved in sodium conservation through the renin-angiotensin-aldosterone system.

  8. Mammary renin-angiotensin system-regulating aminopeptidase activities are modified in rats with breast cancer.

    PubMed

    del Pilar Carrera, Maria; Ramírez-Expósito, Maria Jesus; Mayas, Maria Dolores; García, Maria Jesus; Martínez-Martos, Jose Manuel

    2010-12-01

    Angiotensin II in particular and/or the local renin-angiotensin system in general could have an important role in epithelial tissue growth and modelling; therefore, it is possible that it may be involved in breast cancer. In this sense, previous works of our group showed a predominating role of angiotensin II in tumoral tissue obtained from women with breast cancer. However, although classically angiotensin II has been considered the main effector peptide of the renin-angiotensin system cascade, several of its catabolism products such as angiotensin III and angiotensin IV also possess biological functions. These peptides are formed through the activity of several proteolytic regulatory enzymes of the aminopeptidase type, also called angiotensinases. The aim of this work was to analyse several specific angiotensinase activities involved in the renin-angiotensin system cascade in mammary tissue from control rats and from rats with mammary tumours induced by N-methyl-nitrosourea (NMU), which may reflect the functional status of their target peptides under the specific conditions brought about by the tumoural process. The results show that soluble and membrane-bound specific aspartyl aminopeptidase activities and membrane-bound glutamyl aminopeptidase activity increased in mammary tissue from NMU-treated animals and soluble aminopeptidase N and aminopeptidase B activities significantly decreased in mammary tissue from NMU-treated rats. These changes support the existence of a local mammary renin-angiotensin system and that this system and its putative functions in breast tissue could be altered by the tumour process, in which we suggest a predominant role of angiotensin III. All described data about the renin-angiotensin system in mammary tissue support the idea that it must be involved in normal breast tissue functions, and its disruption could be involved in one or more steps of the carcinogenesis process.

  9. Renin-angiotensin system in ureteric bud branching morphogenesis: implications for kidney disease.

    PubMed

    Yosypiv, Ihor V

    2014-04-01

    Failure of normal branching morphogenesis of the ureteric bud (UB), a key ontogenic process that controls organogenesis of the metanephric kidney, leads to congenital anomalies of the kidney and urinary tract (CAKUT), the leading cause of end-stage kidney disease in children. Recent studies have revealed a central role of the renin-angiotensin system (RAS), the cardinal regulator of blood pressure and fluid/electrolyte homeostasis, in the control of normal kidney development. Mice or humans with mutations in the RAS genes exhibit a spectrum of CAKUT which includes renal medullary hypoplasia, hydronephrosis, renal hypodysplasia, duplicated renal collecting system and renal tubular dysgenesis. Emerging evidence indicates that severe hypoplasia of the inner medulla and papilla observed in angiotensinogen (Agt)- or angiotensin (Ang) II AT 1 receptor (AT 1 R)-deficient mice is due to aberrant UB branching morphogenesis resulting from disrupted RAS signaling. Lack of the prorenin receptor (PRR) in the UB in mice causes reduced UB branching, resulting in decreased nephron endowment, marked kidney hypoplasia, urinary concentrating and acidification defects. This review provides a mechanistic rational supporting the hypothesis that aberrant signaling of the intrarenal RAS during distinct stages of metanephric kidney development contributes to the pathogenesis of the broad phenotypic spectrum of CAKUT. As aberrant RAS signaling impairs normal renal development, these findings advocate caution for the use of RAS inhibitors in early infancy and further underscore a need to avoid their use during pregnancy and to identify the types of molecular processes that can be targeted for clinical intervention.

  10. 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

  11. Klotho Ameliorates Kidney Injury and Fibrosis and Normalizes Blood Pressure by Targeting the Renin-Angiotensin System.

    PubMed

    Zhou, Lili; Mo, Hongyan; Miao, Jinhua; Zhou, Dong; Tan, Roderick J; Hou, Fan Fan; Liu, Youhua

    2015-12-01

    Loss of Klotho and activation of the renin-angiotensin system (RAS) are common pathological findings in chronic kidney diseases. However, whether these two events are intricately connected is poorly understood. We hypothesized that Klotho might protect kidneys by targeted inhibition of RAS activation in diseased kidneys. To test this hypothesis, mouse models of remnant kidney, as well as adriamycin nephropathy and unilateral ureteral obstruction, were utilized. At 6 weeks after 5/6 nephrectomy, kidney injury was evident, characterized by elevated albuminuria and serum creatinine levels, and excessive deposition of interstitial matrix proteins. These lesions were accompanied by loss of renal Klotho expression, up-regulation of RAS components, and development of hypertension. In vivo expression of exogenous Klotho through hydrodynamic-based gene delivery abolished the induction of multiple RAS proteins, including angiotensinogen, renin, angiotensin-converting enzyme, and angiotensin II type 1 receptor, and normalized blood pressure. Klotho also inhibited β-catenin activation and ameliorated renal fibrotic lesions. Similar results were obtained in mouse models of adriamycin and obstructive nephropathy. In cultured kidney tubular epithelial cells, Klotho dose-dependently blocked Wnt1-triggered RAS activation. Taken together, these results demonstrate that Klotho exerts its renal protection by targeted inhibition of RAS, a pathogenic pathway known to play a key role in the evolution and progression of hypertension and chronic kidney disorders.

  12. Improvement of sodium status to optimize the efficacy of Renin-Angiotensin system blockade.

    PubMed

    Laverman, Gozewijn D; Navis, Gerjan

    2011-12-01

    Blockade of the renin-angiotensin-aldosterone system (RAAS) offers superior renoprotection in the treatment of patients with hypertension, but the efficacy of RAAS inhibition strongly depends on sodium status, presumably in relation to extracellular volume status. Because assessing volume status by physical examination is challenging, 24-hour urine collection and NT-proBNP levels are useful tools for guiding volume management and achieving sodium status targets.

  13. Epochs in the depressor/pressor balance of the renin-angiotensin system.

    PubMed

    Colafella, Katrina M Mirabito; Hilliard, Lucinda M; Denton, Kate M

    2016-05-01

    The renin-angiotensin system (RAS) plays a commanding role in the regulation of extracellular fluid homoeostasis. Tigerstadt and Bergman first identified the RAS more than two centuries ago. By the 1980s a voyage of research and discovery into the mechanisms and actions of this system led to the development of drugs that block the RAS, which have become the mainstay for the treatment of cardiovascular and renal disease. In the last 25 years new components of the RAS have come to light, including the angiotensin type 2 receptor (AT2R) and the angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) [Ang(1-7)]/Mas receptor (MasR) axis. These have been shown to counter the classical actions of angiotensin II (AngII) at the predominant angiotensin type 1 receptor (AT1R). Our studies, and those of others, have demonstrated that targeting these depressor RAS pathways may be therapeutically beneficial. It is apparent that the evolution of both the pressor and depressor RAS pathways is distinct throughout life and that the depressor/pressor balance of the RAS vary between the sexes. These temporal patterns of expression suggest that therapies targeting the RAS could be optimized for discrete epochs in life.

  14. 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.

  15. The role of local renin-angiotensin system in arterial chemoreceptors in sleep-breathing disorders

    PubMed Central

    Fung, Man Lung

    2014-01-01

    The renin-angiotensin system (RAS) plays pivotal roles in the regulation of cardiovascular and renal functions to maintain the fluid and electrolyte homeostasis. Experimental studies have demonstrated a locally expressed RAS in the carotid body, which is functional significant in the effect of angiotensin peptides on the regulation of the activity of peripheral chemoreceptors and the chemoreflex. The physiological and pathophysiological implications of the RAS in the carotid body have been proposed upon recent studies showing a significant upregulation of the RAS expression under hypoxic conditions relevant to altitude acclimation and sleep apnea and also in animal model of heart failure. Specifically, the increased expression of angiotensinogen, angiotensin-converting enzyme and angiotensin AT1 receptors plays significant roles in the augmented carotid chemoreceptor activity and inflammation of the carotid body. This review aims to summarize these results with highlights on the pathophysiological function of the RAS under hypoxic conditions. It is concluded that the maladaptive changes of the RAS in the carotid body plays a pathogenic role in sleep apnea and heart failure, which could potentially be a therapeutic target for the treatment of the pathophysiological consequence of sleep apnea. PMID:25249981

  16. Immunohistochemical expression of intrarenal renin angiotensin system components in response to tempol in rats fed a high salt diet

    PubMed Central

    Cao, Gabriel; Della Penna, Silvana Lorena; Kouyoumdzian, Nicolás Martín; Choi, Marcelo Roberto; Gorzalczany, Susana; Fernández, Belisario Enrique; Toblli, Jorge Eduardo; Rosón, María Inés

    2017-01-01

    AIM To determine the effect of tempol in normal rats fed high salt on arterial pressure and the balance between antagonist components of the renal renin-angiotensin system. METHODS Sprague-Dawley rats were fed with 8% NaCl high-salt (HS) or 0.4% NaCl (normal-salt, NS) diet for 3 wk, with or without tempol (T) (1 mmol/L, administered in drinking water). Mean arterial pressure (MAP), glomerular filtration rate (GFR), and urinary sodium excretion (UVNa) were measured. We evaluated angiotensin II (Ang II), angiotensin 1-7 (Ang 1-7), angiotensin converting enzyme 2 (ACE2), mas receptor (MasR), angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptor (AT2R) in renal tissues by immunohistochemistry. RESULTS The intake of high sodium produced a slight but significant increase in MAP and differentially regulated components of the renal renin-angiotensin system (RAS). This included an increase in Ang II and AT1R, and decrease in ACE-2 staining intensity using immunohistochemistry. Antioxidant supplementation with tempol increased natriuresis and GFR, prevented changes in blood pressure and reversed the imbalance of renal RAS components. This includes a decrease in Ang II and AT1R, as increase in AT2, ACE2, Ang (1-7) and MasR staining intensity using immunohistochemistry. In addition, the natriuretic effects of tempol were observed in NS-T group, which showed an increased staining intensity of AT2, ACE2, Ang (1-7) and MasR. CONCLUSION These findings suggest that a high salt diet leads to changes in the homeostasis and balance between opposing components of the renal RAS in hypertension to favour an increase in Ang II. Chronic antioxidant supplementation can modulate the balance between the natriuretic and antinatriuretic components of the renal RAS. PMID:28101449

  17. Combination of drugs acting on the natriuretic system and the renin-angiotensin system in heart failure.

    PubMed

    Chee, Kok H; Amudha, Kadirvelu; Hussain, Nik A; Haizal, Haron K; Choy, Anna-Maria J; Lang, Chim C

    2003-09-01

    Conventional diuretic agents are very effective agents in relieving volume overload and congestive symptoms in chronic heart failure (CHF). However, they are associated with activation of the renin-angiotensin system (RAS) and the sympathetic nervous system and a reduction in glomerular filtration rate, all of which have been associated with adverse outcomes in CHF. Therefore, there is an increasing interest in drugs that target the natriuretic system without neurohormonal activation and deterioration of renal function. In this review, we will discuss the underlying rationale and evidence behind currently pursued strategies that target the natriuretic system. This includes the administration of natriuretic peptides (NPs) and strategies that potentiate the NP system, such as neutral endopeptidase inhibition. We will also highlight some potentially important interactions of these strategies with drugs that target the RAS.

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

    PubMed

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

    2016-12-01

    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.Hypertension Research advance online publication, 1 December 2016; doi:10.1038/hr.2016.166.

  19. 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.

  20. Angiotensin-(1-7): an active member of the renin-angiotensin system.

    PubMed

    Kucharewicz, I; Pawlak, R; Matys, T; Chabielska, E; Buczko, W

    2002-12-01

    Angiotensin-(1-7) [Ang-(1-7)] is an active member of renin-angiotensin system (RAS). It counterbalances vasoconstriction, mitogenic, arrhythmogenic and prothrombotic actions of Ang II. Inducing natiuresis and diuresis opposes also the water and sodium retention produced by Ang II. Till now the specific receptor side for Ang-(1-7) has been not cloned, but the current data strongly suggest that an interaction (cross-talk) between angiotensin receptors may play a role in the effects of Ang-(1-7).

  1. 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.

  2. Circulating renin-angiotensin system and catecholamines in childhood: is there a role for birthweight?

    PubMed

    Franco, Maria C P; Casarini, Dulce E; Carneiro-Ramos, Marcela S; Sawaya, Ana L; Barreto-Chaves, Maria L M; Sesso, Ricardo

    2008-03-01

    There have been only a few reports on the sympathoadrenal and renin-angiotensin systems in children of small gestational age. The purpose of the present study was to investigate plasma levels of ACE (angiotensin-converting enzyme) activity, angiotensin and catecholamines in 8- to 13-year-old children and to determine whether there are correlations between the components of these systems with both birthweight and BP (blood pressure) levels. This clinical study included 66 children (35 boys and 31 girls) in two groups: those born at term with an appropriate birthweight [AGA (appropriate-for-gestational age) group, n=31] and those born at term but with a small birthweight for gestational age [SGA (small-for-gestational age) group, n=35]. Concentrations of angiotensin, catecholamines and ACE activity were determined in plasma. Circulating noradrenaline levels were significantly elevated in SGA girls compared with AGA girls (P=0.036). In addition, angiotensin II and ACE activity were higher in SGA boys (P=0.024 and P=0.050 respectively). There was a significant association of the circulating levels of both angiotensin II and ACE activity with BP levels in our study population. Although the underlying mechanisms that link restricted fetal growth with later cardiovascular events are not fully understood, the findings in the present study support the link between low birthweight and overactivity of both sympathoadrenal and renin-angiotensin systems into later childhood.

  3. From rat to human: regulation of Renin-Angiotensin system genes by sry.

    PubMed

    Prokop, Jeremy W; Watanabe, Ingrid Kazue Mizuno; Turner, Monte E; Underwood, Adam C; Martins, Almir S; Milsted, Amy

    2012-01-01

    The testis determining protein, Sry, has functions outside of testis determination. Multiple Sry loci are found on the Y-chromosome. Proteins from these loci have differential activity on promoters of renin-angiotensin system genes, possibly contributing to elevation of blood pressure. Variation at amino acid 76 accounts for the majority of differential effects by rat proteins Sry1 and Sry3. Human SRY regulated rat promoters in the same manner as rat Sry, elevating Agt, Ren, and Ace promoter activity while downregulating Ace 2. Human SRY significantly regulated human promoters of AGT, REN, ACE2, AT2, and MAS compared to control levels, elevating AGT and REN promoter activity while decreasing ACE2, AT2, and MAS. While the effect of human SRY on individual genes is often modest, we show that many different genes participating in the renin-angiotensin system can be affected by SRY, apparently in coordinated fashion, to produce more Ang II and less Ang-(1-7).

  4. The Ovarian Renin-Angiotensin System (OVRAS): A Major Factor in Ovarian Function and Disease.

    PubMed

    Palumbo, Angela; Ávila, Julio; Naftolin, Frederick

    2016-12-01

    This contribution summarizes the pivotal role of the ovarian renin-angiotensin system (OVRAS) in ovarian physiology and disease, with particular emphasis on human clinical implications and established translational applications. The presence of a complete OVRAS in all studied species has been known for decades. The OVRAS has major effects on follicle development/atresia and ovulation and steroid hormone secretion, that is, it is necessary for normal reproduction. It is well established that OVRAS activity is regulated by gonadotropins and depends on activation of proteases in the area of growing follicles. Angiotensin and angiotensin receptors are widely distributed in the ovarian follicle, preovulatory theca and granulosa cells, and postovulatory mural granulosa-lutein cells and regulate steroidogenesis. Molecular blockade of the OVRAS inhibits oocyte maturation and ovulation. Pathologically abnormal OVRAS function has been associated with infertility, polycystic ovarian syndrome (PCOS), ovarian hyperstimulation syndrome (OHSS), and ovarian cancer. Both hyperandrogenism in PCOS and third space fluid accumulation in OHSS have been convincingly linked to overexpression of renin and angiotensin. Blockade of angiotensin receptors is under study for the treatment of gynecologic cancer, OHSS, and PCOS. However, a full understanding of the OVRAS and translational applications is lacking. In part, this is due to the discovery in recent years of previously unknown renin-angiotensin system (RAS) components and novel functions of "classical" RAS components that remain to be integrated into translational studies; newer, more specific agents to block RAS components are available only now for such research and treatment. The need for further studies is evident.

  5. Involvement of the renin-angiotensin system in endogenous central histamine-induced reversal of critical haemorrhagic hypotension in rats.

    PubMed

    Jochem, J

    2004-03-01

    The study was undertaken to examine the involvement of the renin-angiotensin system in the reversal by endogenous central histamine of critical haemorrhagic hypotension in anaesthetised Wistar rats. Histamine N-methyltransferase inhibitor metoprine (20 microg) administered intracerebroventricularly at 5 min of critical hypotension 20-25 mmHg produced increases in histamine concentrations as measured 20 min after treatment in the hypothalamus (581.33 +/- 63.23 vs. 488.26 +/- 56.34 ng/g of wet tissue; P < 0.01) and medulla oblongata (53.42 +/- 14.65 vs. 34.68 +/- 13.52 ng/g of wet tissue; P < 0.05). That was accompanied by 34.7% higher plasma angiotensin II concentration in comparison to the control group. Metoprine produced dose-dependent (5-20 microg) rises in mean arterial pressure (MAP) and heart rate, which were significantly higher than those in normotensive animals. The resuscitating action of metoprine (20 microg) was associated with rises in renal, mesenteric and hindquarters blood flows, and a 100% survival at 2 h after treatment, while in the saline-treated group, all the animals died within 30 min. Angiotensin type 1 (AT(1)) receptor antagonist ZD 7155 (0.5 mg/kg; iv) decreased regional vascular resistance and inhibited metoprine-induced increase in MAP, whereas AT(2) receptor blocker PD 123319 (10 mg/kg; i.v.) had no effect. Angiotensin-converting enzyme inhibitor captopril (30 mg/kg; i.v.) reduced the increase in plasma angiotensin II level and the haemodynamic effects of metoprine. Neither capropril, nor angiotensin receptor antagonists influence the survival at 2 h after treatment. In conclusion, the renin-angiotensin system is involved in central histamine-induced resuscitating action in rats.

  6. [Insulin, renin-angiotensin system, aldosterone and endothelial dysfunction].

    PubMed

    Rubio-Guerra, Alberto Francisco; Durán-Salgado, Montserrat Berenice

    2011-01-01

    Beyond its metabolic effects, insulin has several actions on the vasculature. Under normal conditions, insulin maintains normal endothelial function, but in the presence of insulin resistance, insulin leads to endothelial dysfunction. Insulin releases nitric oxide, which promotes an antiatherosclerotic, antiinflamatory and vasodilated state. However, in presence of high levels of angiotensin II, insulin activates pathways that lead to atherosclerosis, vasoconstriction and inflammation. We will review the actions of insulin on the vascular system, and its interactions with other vasoactive mediators, such as angiotensin II and endothelin-1.

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

    PubMed Central

    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

    2017-01-01

    Background 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. Methods 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. Results 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. Conclusion 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. PMID:28321294

  8. Physiology and Pathophysiology of the Intrarenal Renin-Angiotensin System: An Update.

    PubMed

    Yang, Tianxin; Xu, Chuanming

    2017-04-01

    The renin-angiotensin system (RAS) has a pivotal role in the maintenance of extracellular volume homeostasis and blood pressure through complex mechanisms. Apart from the well known systemic RAS, occurrence of a local RAS has been documented in multiple tissues, including the kidney. A large body of recent evidence from pharmacologic and genetic studies, particularly those using various transgenic approaches to manipulate intrarenal levels of RAS components, has established the important role of intrarenal RAS in hypertension. Recent studies have also begun to unravel the molecular mechanisms that govern intrarenal RAS activity. This local system is under the control of complex regulatory networks consisting of positive regulators of (pro)renin receptor, Wnt/β-catenin signaling, and PGE2/PGE2 receptor EP4 subtype, and negative regulators of Klotho, vitamin D receptor, and liver X receptors. This review highlights recent advances in defining the regulation and function of intrarenal RAS as a unique entity separate from systemic angiotensin II generation.

  9. 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

  10. The role of renin-angiotensin aldosterone system related micro-ribonucleic acids in hypertension

    PubMed Central

    Wang, Hui-Bo; Yang, Jun

    2015-01-01

    Micro-ribonucleic acids (miRNAs) are small (21-25 nucleotide) single-stranded, evolutionarily conserved non-protein-coding RNAs, which control diverse cellular functions by interacting with the 3’ untranslated region of specific target messenger RNAs at the post-transcriptional level. Research shows that an aberrant expression profile of miRNAs has been linked to a series of diseases, including hypertension. In the past few decades, it has been demonstrated that excessive activation of the renin-angiotensin aldosterone system (RAAS) involves in the pathogenesis of hypertension. This article reviews the latest insights in the identification of RAAS-correlative miRNAs and the potential mechanisms for their roles in hypertension. PMID:26446323

  11. Diet-induced hypercholesterolemia impaired testicular steroidogenesis in mice through the renin-angiotensin system.

    PubMed

    Martínez-Martos, José M; Arrazola, Marce; Mayas, María D; Carrera-González, María P; García, María J; Ramírez-Expósito, María J

    2011-08-01

    Hypercholesterolemia and low testosterone concentrations in men are associated with a high risk factor for atherosclerosis. It is known that cholesterol serves as the major precursor for the synthesis of the sex hormones. The bioactive peptides of the renin-angiotensin-system localized in the gonads play a key role in the relation between cholesterol and testosterone by modulating steroidogenesis and inhibiting testosterone production. In the present work, we evaluated the effects of diet-induced hypercholesterolemia on circulating testosterone levels and its relationship with the testicular RAS-regulating specific aminopeptidase activities in male mouse. A significant decrease in serum circulating levels of testosterone was observed after induced hypercholesterolemia. The changes found in aminopeptidase activities suggest a role of Ang III and Ang IV in the regulation of steroidogenesis.

  12. [Alzheimer disease--contribution of renin-angiotensin system to Alzheimer disease progression].

    PubMed

    Ohrui, Takashi

    2012-09-01

    There is increasing evidence that certain components of the renin-angiotensin system (RAS) may have a crucial role in learning and memory processes. We have previously shown that brain-penetrating ACE inhibitors can reduce the incidence of Alzheimer diseases (AD) in elderly hypertensive patients and that hypertension treatment with brain penetrating ACE inhibitors slowed the rate of cognitive decline in mild-to-moderate AD patients with hypertension. We speculate that the favorable effects might be due to the direct effects of brain-penetrating ACE inhibitors on RAS in the brain, since no significant differences were found in the levels of blood pressure among the groups treated with several antihypertensive drugs. Brain penetrating ACE inhibitors might have benefits not only for the prevention but also for the treatment of mild to moderate AD with hypertension.

  13. 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

  14. 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.

  15. Increased Methylglyoxal Formation with Upregulation of Renin Angiotensin System in Fructose Fed Sprague Dawley Rats

    PubMed Central

    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. PMID:24040205

  16. 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.

  17. Renin-Angiotensin System Blockade Associated with Statin Improves Endothelial Function in Diabetics

    PubMed Central

    Gismondi, Ronaldo Altenburg; Bedirian, Ricardo; Pozzobon, Cesar Romaro; Ladeira, Márcia Cristina; Oigman, Wille; Neves, Mário Fritsch

    2015-01-01

    Background Studies suggest that statins have pleiotropic effects, such as reduction in blood pressure, and improvement in endothelial function and vascular stiffness. Objective To analyze if prior statin use influences the effect of renin-angiotensin-aldosterone system inhibitors on blood pressure, endothelial function, and vascular stiffness. Methods Patients with diabetes and hypertension with office systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 80 mmHg had their antihypertensive medications replaced by amlodipine during 6 weeks. They were then randomized to either benazepril or losartan for 12 additional weeks while continuing on amlodipine. Blood pressure (assessed with ambulatory blood pressure monitoring), endothelial function (brachial artery flow-mediated dilation), and vascular stiffness (pulse wave velocity) were evaluated before and after the combined treatment. In this study, a post hoc analysis was performed to compare patients who were or were not on statins (SU and NSU groups, respectively). Results The SU group presented a greater reduction in the 24-hour systolic blood pressure (from 134 to 122 mmHg, p = 0.007), and in the brachial artery flow-mediated dilation (from 6.5 to 10.9%, p = 0.003) when compared with the NSU group (from 137 to 128 mmHg, p = 0.362, and from 7.5 to 8.3%, p = 0.820). There was no statistically significant difference in pulse wave velocity (SU group: from 9.95 to 9.90 m/s, p = 0.650; NSU group: from 10.65 to 11.05 m/s, p = 0.586). Conclusion Combined use of statins, amlodipine, and renin-angiotensin-aldosterone system inhibitors improves the antihypertensive response and endothelial function in patients with hypertension and diabetes. PMID:26465872

  18. 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.

  19. 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

    Total sleep deprivation leads to decrements in neurobehavioral performance and changes in electroencephalographic (EEG) oscillations as well as the incidence of slow eye movements ad detected in the electro-oculogram (EOG) during wakefulness. Although total sleep deprivation is a powerful tool to investigate the association of EEG/EOG and neurobehavioral decrements, sleep loss during space flight is usual only partial. Furthermore exposure to the microgravity environment leads to changes in sodium and volume homeostasis and associated renal and cardio-endocrine responses. Some of these changes can be induced in head down tilt bedrest studies. We integrate research tools and research projects to enhance the fidelity of the simulated conditions of space flight which are characterized by complexity and mutual interactions. The effectiveness of countermeasures and physiologic mechanisms underlying neurobehavioral changes and renal-cardio endocrine changes are investigated in Project 3 of the Human Performance Team and Project 3 of the Cardiovascular Alterations Team respectively. Although the. specific aims of these two projects are very different, they employ very similar research protocols. Thus, both projects investigate the effects of posture/bedrest and sleep deprivation (total or partial) on outcome measures relevant to their specific aims. The main aim of this enhancement grant is to exploit the similarities in research protocols by including the assessment of outcome variables relevant to the Renal-Cardio project in the research protocol of Project 3 of the Human Performance Team and by including the assessment of outcome variables relevant to the Quantitative EEG and Sleep Deprivation Project in the research protocols of Project 3 of the Cardiovascular Alterations team. In particular we will assess Neurobehavioral Function and Waking EEG in the research protocols of the renal-cardio endocrine project and renin-angiotensin and cardiac function in the research

  20. Local Fetal Lung Renin-Angiotensin System as a Target to Treat Congenital Diaphragmatic Hernia

    PubMed Central

    Nogueira-Silva, Cristina; Carvalho-Dias, Emanuel; Piairo, Paulina; Nunes, Susana; Baptista, Maria J; Moura, Rute S; Correia-Pinto, Jorge

    2012-01-01

    Antenatal stimulation of lung growth is a reasonable approach to treat congenital diaphragmatic hernia (CDH), a disease characterized by pulmonary hypoplasia and hypertension. Several evidences from the literature demonstrated a possible involvement of renin-angiotensin system (RAS) during fetal lung development. Thus, the expression pattern of renin, angiotensin-converting enzyme, angiotensinogen, type 1 (AT1) and type 2 (AT2) receptors of angiotensin II (ANGII) was assessed by immunohisto-chemistry throughout gestation, whereas the function of RAS in the fetal lung was evaluated using fetal rat lung explants. These were morphometrically analyzed and intracellular pathway alterations assessed by Western blot. In nitrofen-induced CDH model, pregnant rats were treated with saline or PD-123319. In pups, lung growth, protein/DNA ratio, radial saccular count, epithelial differentiation and lung maturation, vascular morphometry, right ventricular hypertrophy and overload molecular markers, gasometry and survival time were evaluated. Results demonstrated that all RAS components were constitutively expressed in the lung during gestation and that ANGII had a stimulatory effect on lung branching, mediated by AT1 receptor, through p44/42 and Akt phosphorylation. This stimulatory effect on lung growth was mimicked by AT2-antagonist (PD-123319) treatment. In vivo antenatal PD-123319 treatment increased lung growth, ameliorated indirect parameters of pulmonary hypertension, improved lung function and survival time in nonventilated CDH pups, without maternal or fetal deleterious effects. Therefore, this study demonstrated a local and physiologically active RAS during lung morphogenesis. Moreover, selective inhibition of AT2 receptor is presented as a putative antenatal therapy for CDH. PMID:22113494

  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. Blood, pituitary, and brain renin-angiotensin systems and regulation of secretion of anterior pituitary gland.

    PubMed

    Ganong, W F

    1993-07-01

    In addition to increasing blood pressure, stimulating aldosterone and vasopressin secretion, and increasing water intake, angiotensin II affects the secretion of anterior pituitary hormones. Some of these effects are direct. There are angiotensin II receptors on lactotropes and corticotropes in rats, and there may be receptors on thyrotropes and other secretory cells. Circulating angiotensin II reaches these receptors, but angiotensin II is almost certainly generated locally by the pituitary renin-angiotensin system as well. There are also indirect effects produced by the effects of brain angiotensin II on the secretion of hypophyseotropic hormones. In the anterior pituitary of the rat, the gonadotropes contain renin, angiotensin II, and some angiotensin-converting enzyme. There is debate about whether these cells also contain small amounts of angiotensinogen, but most of the angiotensinogen is produced by a separate population of cells and appears to pass in a paracrine fashion to the gonadotropes. An analogous situation exists in the brain. Neurons contain angiotensin II and probably renin, but most angiotensin-converting enzyme is located elsewhere and angiotensinogen is primarily if not solely produced by astrocytes. Angiotensin II causes secretion of prolactin and adrenocorticotropic hormone (ACTH) when added to pituitary cells in vitro. Paracrine regulation of prolactin secretion by angiotensin II from the gonadotropes may occur in vitro under certain circumstances, but the effects of peripheral angiotensin II on ACTH secretion appear to be mediated via the brain and corticotropin-releasing hormone (CRH). In the brain, there is good evidence that locally generated angiotensin II causes release of norepinephrine that in turn stimulates gonadotropin-releasing hormone-secreting neurons, increasing circulating luteinizing hormone. In addition, there is evidence that angiotensin II acts in the arcuate nuclei to increase the secretion of dopamine into the portal

  3. Neprilysin is a Mediator of Alternative Renin-Angiotensin-System Activation in the Murine and Human Kidney

    PubMed Central

    Domenig, Oliver; Manzel, Arndt; Grobe, Nadja; Königshausen, Eva; Kaltenecker, Christopher C.; Kovarik, Johannes J.; Stegbauer, Johannes; Gurley, Susan B.; van Oyen, Dunja; Antlanger, Marlies; Bader, Michael; Motta-Santos, Daisy; Santos, Robson A.; Elased, Khalid M.; Säemann, Marcus D.; Linker, Ralf A.; Poglitsch, Marko

    2016-01-01

    Cardiovascular and renal pathologies are frequently associated with an activated renin-angiotensin-system (RAS) and increased levels of its main effector and vasoconstrictor hormone angiotensin II (Ang II). Angiotensin-converting-enzyme-2 (ACE2) has been described as a crucial enzymatic player in shifting the RAS towards its so-called alternative vasodilative and reno-protective axis by enzymatically converting Ang II to angiotensin-(1-7) (Ang-(1-7)). Yet, the relative contribution of ACE2 to Ang-(1-7) formation in vivo has not been elucidated. Mass spectrometry based quantification of angiotensin metabolites in the kidney and plasma of ACE2 KO mice surprisingly revealed an increase in Ang-(1-7), suggesting additional pathways to be responsible for alternative RAS activation in vivo. Following assessment of angiotensin metabolism in kidney homogenates, we identified neprilysin (NEP) to be a major source of renal Ang-(1-7) in mice and humans. These findings were supported by MALDI imaging, showing NEP mediated Ang-(1-7) formation in whole kidney cryo-sections in mice. Finally, pharmacologic inhibition of NEP resulted in strongly decreased Ang-(1-7) levels in murine kidneys. This unexpected new role of NEP may have implications for the combination therapy with NEP-inhibitors and angiotensin-receptor-blockade, which has been shown being a promising therapeutic approach for heart failure therapy. PMID:27649628

  4. The role of the renin-angiotensin-aldosterone system in the pathobiology of pulmonary arterial hypertension (2013 Grover Conference series).

    PubMed

    Maron, Bradley A; Leopold, Jane A

    2014-06-01

    Pulmonary arterial hypertension (PAH) is associated with aberrant pulmonary vascular remodeling that leads to increased pulmonary artery pressure, pulmonary vascular resistance, and right ventricular dysfunction. There is now accumulating evidence that the renin-angiotensin-aldosterone system is activated and contributes to cardiopulmonary remodeling that occurs in PAH. Increased plasma and lung tissue levels of angiotensin and aldosterone have been detected in experimental models of PAH and shown to correlate with cardiopulmonary hemodynamics and pulmonary vascular remodeling. These processes are abrogated by treatment with angiotensin receptor or mineralocorticoid receptor antagonists. At a cellular level, angiotensin and aldosterone activate oxidant stress signaling pathways that decrease levels of bioavailable nitric oxide, increase inflammation, and promote cell proliferation, migration, extracellular matrix remodeling, and fibrosis. Clinically, enhanced renin-angiotensin activity and elevated levels of aldosterone have been detected in patients with PAH, which suggests a role for angiotensin and mineralocorticoid receptor antagonists in the treatment of PAH. This review will examine the current evidence linking renin-angiotensin-aldosterone system activation to PAH with an emphasis on the cellular and molecular mechanisms that are modulated by aldosterone and may be of importance for the pathobiology of PAH.

  5. 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.

  6. Comparative Analysis of Renin-Angiotensin System (RAS)-Related Gene Expression Between Hypertensive and Normotensive Rats

    PubMed Central

    Williamson, Chad R.; Khurana, Sandhya; Nguyen, Phong; Byrne, Collin J.; Tai, T.C.

    2017-01-01

    Background The renal renin-angiotensin system (RAS) is physiologically important for blood pressure regulation. Altered regulation of RAS-related genes has been observed in an animal model of hypertension (spontaneously hypertensive rats – SHRs). The current understanding of certain RAS-related gene expression differences between Wistar-Kyoto rats (WKYs) and SHRs is either limited or has not been compared. The purpose of this study was to compare the regulation of key RAS-related genes in the kidneys of adult WKYs and SHRs. Material/Methods Coronal sections were dissected through the hilus of kidneys from 16-week-old male WKYs and SHRs. RT-PCR analysis was performed for Ace, Ace2, Agt, Agtr1a, Agtr1b, Agtr2, Atp6ap2 (PRR), Mas1, Ren, Rnls, and Slc12a3 (NCC). Results Increased mRNA expression was observed for Ace, Ace2, Agt, Agtr1a, Agtr1b, and Atp6ap2 in SHRs compared to WKYs. Mas1, Ren, Slc12a3, and Rnls showed no difference in expression between animal types. Conclusions This study shows that the upregulation of several key RAS-related genes in the kidney may account for the increased blood pressure of adult SHRs. PMID:28138124

  7. Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute?

    PubMed Central

    2015-01-01

    The renin-angiotensin system (RAS) constitutes a key hormonal system in the physiological regulation of blood pressure through peripheral and central mechanisms. Indeed, dysregulation of the RAS is considered a major factor in the development of cardiovascular pathologies, and pharmacological blockade of this system by the inhibition of angiotensin-converting enzyme (ACE) or antagonism of the angiotensin type 1 receptor (AT1R) offers an effective therapeutic regimen. The RAS is now defined as a system composed of different angiotensin peptides with diverse biological actions mediated by distinct receptor subtypes. The classic RAS comprises the ACE-ANG II-AT1R axis that promotes vasoconstriction; water intake; sodium retention; and increased oxidative stress, fibrosis, cellular growth, and inflammation. In contrast, the nonclassical RAS composed primarily of the ANG II/ANG III-AT2R and the ACE2-ANG-(1–7)-AT7R pathways generally opposes the actions of a stimulated ANG II-AT1R axis. In lieu of the complex and multifunctional aspects of this system, as well as increased concerns on the reproducibility among laboratories, a critical assessment is provided on the current biochemical approaches to characterize and define the various components that ultimately reflect the status of the RAS. PMID:26475588

  8. 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.

  9. 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

  10. 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.

  11. Atlas of tissue renin-angiotensin-aldosterone system in human: A transcriptomic meta-analysis

    PubMed Central

    Nehme, Ali; Cerutti, Catherine; Dhaouadi, Nedra; Gustin, Marie Paule; Courand, Pierre-Yves; Zibara, Kazem; Bricca, Giampiero

    2015-01-01

    Tissue renin-angiotensin-aldosterone system (RAAS) has attracted much attention because of its physiological and pharmacological implications; however, a clear definition of tissue RAAS is still missing. We aimed to establish a preliminary atlas for the organization of RAAS across 23 different normal human tissues. A set of 37 genes encoding classical and novel RAAS participants including gluco- and mineralo-corticoids were defined as extended RAAS (extRAAS) system. Microarray data sets containing more than 10 normal tissues were downloaded from the GEO database. R software was used to extract expression levels and construct dendrograms of extRAAS genes within each data set. Tissue co-expression modules were then extracted from reproducible gene clusters across data sets. An atlas of the maps of tissue-specific organization of extRAAS was constructed from gene expression and coordination data. Our analysis included 143 data sets containing 4933 samples representing 23 different tissues. Expression data provided an insight on the favored pathways in a given tissue. Gene coordination indicated the existence of tissue-specific modules organized or not around conserved core groups of transcripts. The atlas of tissue-specific organization of extRAAS will help better understand tissue-specific effects of RAAS. This will provide a frame for developing more effective and selective pharmaceuticals targeting extRAAS. PMID:25992767

  12. Chronic ethanol intake modifies renin-angiotensin system-regulating aminopeptidase activities in mouse cerebellum.

    PubMed

    Mayas, M D; Ramírez-Expósito, M J; García, M J; Carrera, M P; Cobo, M; Camacho, B; Martínez Martos, J M

    2005-04-01

    In developing cerebellum, where critical periods of vulnerability have been established for several basic substances, it has been extensively studied the wide array of abnormalities induced by exposure to ethanol (EtOH). However, little is known about the effects of EtOH consumption on cerebellar functions in adult individuals. Several studies show participation in cognitive activities to be concentrated in the lateral cerebellum (hemispheres), whereas basic motor functions such as balance and coordination are represented in the medial parts of the cerebellum (vermis and paravermis). In addition to the circulating renin angiotensin system (RAS), a local system has been postulated in brain. The effector peptides of the RAS are formed via the activity of several aminopeptidases (AP). The present work analyses the effect of chronic EtOH intake on the RAS-regulating AP activities in the soluble and membrane-bound fractions of two cerebellar locations: the hemispheres and the vermis. We hypothesize that cerebellar RAS is involved in basic motor functions rather than in cognitive activities.

  13. Therapeutic potential of targeting the renin angiotensin system in portal hypertension

    PubMed Central

    Herath, Chandana B; Grace, Josephine A; Angus, Peter W

    2013-01-01

    Portal hypertension is responsible for the bulk of the morbidity and mortality in patients with cirrhosis. Drug therapy to reduce portal pressure involves targeting two vascular beds. The first approach is to reduce intra hepatic vascular tone induced by the activity of powerful vasocontrictors such as angiotensin II, endothelin-1 and the sympathetic system and mediated via contraction of perisinusoidal myofibroblasts and pervascular smooth muscle cells. The second approach is to reduce mesenteric and portal blood flow. Non-selective β-blockers are widely used and have been shown to prolong patient survival and reduce oesophageal variceal bleeding in advanced cirrhosis. However many patients are unable to tolerate these drugs and they are ineffective in a significant proportion of patients. Unfortunately there are no other drug therapies that have proven efficacy in the treatment of portal hypertension and prevention of variceal bleeding. This review briefly outlines current therapeutic approaches to the management of portal hypertension, and the evidence supporting the role of the renin angiotensin system (RAS) and the use of RAS blockers in this condition. It will also outline recent advances in RAS research that could lead to the development of new treatments focusing in particular on the recently discovered “alternate axis” of the RAS. PMID:23596549

  14. The renin-angiotensin-aldosterone system and the eye in diabetes.

    PubMed

    Strain, W David; Chaturvedi, Nish

    2002-12-01

    Diabetic retinopathy is the leading cause of blindness in the under 65s, and with the burden of disease case load expected to exceed 200 million worldwide within 10 years, much effort is being spent on prophylactic interventions. Early work focused on improving glycaemic control; however, with the publication of EURODIAB Controlled trial of Lisinopril in Insulin-dependent Diabetes (EUCLID) and United Kingdom Prospective Diabetes Study (UKPDS), the focus has recently moved to control of blood pressure and specifically the renin-angiotensin system (RAS). There is a large body of evidence for a local RAS within the eye that is activated in diabetes. This appears to be directly responsible, as well as indirectly through other mediators, for an increase in concentration of vascular endothelial growth factor (VEGF), a selective angiogenic and vasopermeability factor that is implicated in the pathogenesis of diabetic retinopathy. Inhibition of angiotensin-converting enzyme appears to reduce concentrations of VEGF, with a concurrent anti-proliferative effect independent of systemic VEGF levels or blood pressure. Angiotensin II (Ang II) Type 1 (AT(1)) receptor blockade has been shown to reduce neovascularisation independent of VEGF levels in animal models. This may be due to antagonism of activation of mitogen-activated protein kinase, which is a potent cellular proliferation stimulator, by Ang II, although this needs further evaluation.

  15. Renin-angiotensin system inhibitor and statins combination therapeutics - what have we learnt?

    PubMed

    Koh, Kwang Kon; Sakuma, Ichiro; Hayashi, Toshio; Kim, Sang Hyun; Chung, Wook-Jin

    2015-05-01

    Hypercholesterolemia and hypertension are the most common risk factors for cardiovascular disease (CVD). Updated guidelines emphasize target reduction of overall cardiovascular risks. Hypercholesterolemia and hypertension have a synergistic deleterious effect on insulin resistance and endothelial dysfunction. Unregulated renin-angiotensin system (RAS) is important in the pathogenesis of atherosclerosis. Statins are the most important in patients with hypercholesterolemia to prevent CVD by lowering low-density lipoprotein-cholesterol, improving endothelial dysfunction, and other anti-atherosclerotic effects. Unfortunately, statin therapy dose-dependently causes insulin resistance and increases the risk of type 2 diabetes mellitus. RAS inhibitors improve both endothelial dysfunction and insulin resistance in addition to blood pressure lowering. Further, cross-talk between hypercholesterolemia and RAS exists at multiple steps of insulin resistance and endothelial dysfunction. In this regard, combined therapy with statins and RAS inhibitors demonstrates additive/synergistic beneficial effects on endothelial dysfunction and insulin resistance in addition to lowering both cholesterol levels and blood pressure and it did reduce cardiovascular events when compared with either monotherapy in patients. This is mediated by both distinct and interrelated mechanisms. Therefore, combined therapy with statins and RAS inhibitors may be important in developing optimal management strategies in patients with hypertension, hypercholesterolemia, diabetes, metabolic syndrome or obesity to prevent or treat CVD.

  16. New Concepts in Malaria Pathogenesis: The Role of the Renin-Angiotensin System

    PubMed Central

    Silva, Leandro S.; Silva-Filho, João Luiz; Caruso-Neves, Celso; Pinheiro, Ana Acacia S.

    2016-01-01

    Malaria is a worldwide health problem leading the death of millions of people. The disease is induced by different species of protozoa parasites from the genus Plasmodium. In humans, Plasmodium falciparum is the most dangerous species responsible for severe disease. Despite all efforts to establish the pathogenesis of malaria, it is far from being fully understood. In addition, resistance to existing drugs has developed in several strains and the development of new effective compounds to fight these parasites is a major issue. Recent discoveries indicate the potential role of the renin-angiotensin system (RAS) in malaria infection. Angiotensin receptors have not been described in the parasite genome, however several reports in the literature suggest a direct effect of angiotensin-derived peptides on different aspects of the host-parasite interaction. The aim of this review is to highlight new findings on the involvement of the RAS in parasite development and in the regulation of the host immune response in an attempt to expand our knowledge of the pathogenesis of this disease. PMID:26779452

  17. 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

  18. Renin-angiotensin system genes polymorphism in Egyptians with premature coronary artery disease.

    PubMed

    Abd El-Aziz, Tarek A; Hussein, Yousri M; Mohamed, Randa H; Shalaby, Sally M

    2012-05-01

    Genetics polymorphism of the renin-angiotensin system (RAS) affects the pathogenesis of atherosclerosis and associated with coronary artery disease (CAD). We aimed to investigate the association between the RAS genes and premature CAD (PCAD) in Egyptians. 116 patients with PCAD, 114 patients with late onset CAD and 119 controls were included in the study. Angiotensin converting enzyme (ACE), angiotensin II receptor type 1 (ATR1) and angiotensinogen (AGT) genes polymorphisms were analyzed by polymerase chain reaction (PCR). We found that ACE DD, AGT TT and ATR1 CC increased the risk of PCAD by 2.7, 2.8 and 2.86 respectively). Smoking, hypertension, diabetes, total cholesterol, triglycerides and LDL cholesterol were independent risk factors for the development of PCAD. We conclude that the ACE DD, AGT TT and ATR1 CC genotypes may increase the susceptibility of an individual to have PCAD. The coexistence of CAD risk factors with these risky RAS genotypes may lead to the development of PCAD in Egyptian patients.

  19. 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

  20. 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.

  1. Impact of the renin-angiotensin system on cardiac energy metabolism in heart failure.

    PubMed

    Mori, Jun; Zhang, Liyan; Oudit, Gavin Y; Lopaschuk, Gary D

    2013-10-01

    The renin-angiotensin system (RAS) plays a key pathogenic role in heart failure. The adverse effects of angiotensin II (Ang II), a major player of the RAS, contributes to the development of heart failure. Heart failure is accompanied by significant perturbations in cardiac energy metabolism that can both decrease cardiac energy supply and decrease cardiac efficiency. Recent evidence suggests that Ang II might be involved in these perturbations in cardiac energy metabolism. Furthermore, new components of the RAS, such as angiotensin converting enzyme 2 and Ang1-7, have been reported to exert beneficial effects on cardiac energy metabolism. As a result, a further understanding of the relationship between the RAS and cardiac energy metabolism has the potential to improve the control of heart failure, and may lead to the development of new therapies to treat heart failure. This review summarizes what effects the RAS has on cardiac energy metabolism, highlighting how Ang II can induce cardiac insulin resistance and mitochondrial damage, and what role reactive oxygen species and sirtuins have on these processes.

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

    PubMed

    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.

  3. Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure.

    PubMed

    Vardeny, Orly; Miller, Ryan; Solomon, Scott D

    2014-12-01

    Neprilysin is an enzyme that contributes to the breakdown of the biologically active natriuretic peptides and several other vasoactive compounds. Inhibiting neprilysin has been a therapeutic target for several compounds that have been tested in cardiovascular disease, including ecadotril, candoxatril, omapatrilat, and LCZ696. Although ecadotril, candoxatril, and omapatrilat were initially tested in hypertension and/or heart failure, lack of efficacy and side effects led to discontinuation of their development. LCZ696 (sacubitril valsartan) is a first-in-class angiotensin receptor neprilysin inhibitor that has been developed for use in heart failure. This compound is composed of 2 molecular moieties in a single crystalline complex-the angiotensin receptor blocker valsartan and a neprilysin inhibitor prodrug-and has now been tested in hypertension, in a phase 2 trial in heart failure with preserved ejection fraction, and has demonstrated greater efficacy than enalapril in a phase 3 trial in heart failure with reduced ejection fraction. Its ability to inhibit the renin-angiotensin-aldosterone axis and augment the endogenous natriuretic peptide system provides a distinctive mechanism of action in cardiovascular disease.

  4. G-protein coupled receptors of the renin-angiotensin system: new targets against breast cancer?

    PubMed Central

    Rodrigues-Ferreira, Sylvie; Nahmias, Clara

    2015-01-01

    G-protein coupled receptors (GPCRs) constitute the largest family of membrane receptors, with high potential for drug discovery. These receptors can be activated by a panel of different ligands including ions, hormones, small molecules, and vasoactive peptides. Among those, angiotensins [angiotensin II (AngII) and angiotensin 1–7] are the major biologically active products of the classical and alternative renin-angiotensin system (RAS). These peptides bind and activate three different subtypes of GPCRs, namely AT1, AT2, and Mas receptors, to regulate cardiovascular functions. Over the past decade, the contribution of several RAS components in tumorigenesis has emerged as a novel important concept, AngII being considered as harmful and Ang1–7 as protective against cancer. Development of selective ligands targeting each RAS receptor may provide novel and efficient targeted therapeutic strategies against cancer. In this review, we focus on breast cancer to summarize current knowledge on angiotensin receptors (AT1, AT2, and Mas), and discuss the potential use of angiotensin receptor agonists and antagonists in clinics. PMID:25741281

  5. G-protein coupled receptors of the renin-angiotensin system: new targets against breast cancer?

    PubMed

    Rodrigues-Ferreira, Sylvie; Nahmias, Clara

    2015-01-01

    G-protein coupled receptors (GPCRs) constitute the largest family of membrane receptors, with high potential for drug discovery. These receptors can be activated by a panel of different ligands including ions, hormones, small molecules, and vasoactive peptides. Among those, angiotensins [angiotensin II (AngII) and angiotensin 1-7] are the major biologically active products of the classical and alternative renin-angiotensin system (RAS). These peptides bind and activate three different subtypes of GPCRs, namely AT1, AT2, and Mas receptors, to regulate cardiovascular functions. Over the past decade, the contribution of several RAS components in tumorigenesis has emerged as a novel important concept, AngII being considered as harmful and Ang1-7 as protective against cancer. Development of selective ligands targeting each RAS receptor may provide novel and efficient targeted therapeutic strategies against cancer. In this review, we focus on breast cancer to summarize current knowledge on angiotensin receptors (AT1, AT2, and Mas), and discuss the potential use of angiotensin receptor agonists and antagonists in clinics.

  6. Involvement of Renin-Angiotensin System in Retinopathy of Prematurity - A Possible Target for Therapeutic Intervention

    PubMed Central

    Nath, Madhu; Chandra, Parijat; Halder, Nabanita; Singh, Baskar; Deorari, Ashok Kumar; Kumar, Atul; Azad, Rajvardhan; Velpandian, Thirumurthy

    2016-01-01

    Objective Examining the Retinal Renin Angiotensin System (RRAS) in the ROP neonates and analyzing the possibility of modulating the RRAS to prevent the progression in Oxygen Induced Retinopathy (OIR) model. Method Vitreous of ROP patients (n = 44, median age 5.5 months) was quantified for RRAS components, VEGF, HIF-1α and compared with age matched control. The involvement of RRAS in ROP was tested in the rat model of OIR and compared with normoxia. Expressions of RAS components, VEGF and HIF-1α in retina were analyzed using qPCR and retinal structure and function was also analyzed. Effect of Angiotensin Converting Enzyme Inhibitor (ACEI) and Angiotensin Receptor Blocker (ARB) was evaluated and compared with Bevacizumab which served as a positive control. Drug penetration into retina was confirmed by liquid chromatography coupled ESI-tandem mass spectroscopy (LC-MS/MS). Results Multifold increase in the expression of RAS components in human vitreous and rat retina showed their involvement in ROP. ERG & fundus studies in OIR revealed the altered function of retina and were successfully prevented by ARB (telmisartan), ACEI (lisinopril) and bevacizumab. Retinal analysis revealed the presence of ACEI and ARB in their therapeutic levels. Conclusion This study for the first time demonstrates the upregulated level of RAS components in human ROP vitreous and further that the pharmacological intervention in RRAS can functionally and structurally preserve retina against the progression of ROP in the OIR model. PMID:28033392

  7. 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.

  8. Local bone interaction between renin-angiotensin system and kallikrein-kinin system in diabetic rat

    PubMed Central

    Li, Yong; Shen, Guang-Si; Yu, Chen; Li, Guang-Fei; Shen, Jun-Kang; Xu, You-Jia; Gong, Jian-Ping

    2015-01-01

    Objective: This study was performed to investigate bone deteriorations and the involvement of skeletal renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) of male rat in response to the hyperglycemia. Methods: The biomarkers in serum and urine were measured by ELISA kit, and tibias were taken for the measurement on gene, protein expression and histological analysis, feumrs were taken for the measurement on biomechanical parameters and micro-CT. Results: The DM1 showed the decreased level of osteocalcin, testosterone and FGF-23, and the increased level of serum CTX as compared to those of vehicle group. The H&E staining showed remarkable bone deteriorations, including increased disconnections and separation of trabecular bone among growth plate and joint cartilage in DM1 group. Biomechanically, the maximum load, maximum stress, and strain parameter of DM1 group was significantly lower than control group. Type 1 diabetic mice displayed bone loss shown the reduction of bone volume/total volume, trabecular number, trabecular thickness and bone mineral density. The STZ injection significantly up-regulated mRNA expression of AT1R, AGT, renin, renin-receptor, and ACE, and the expression of AT2R, B1R and B2R were down-regulated in tibia of rat in hyperglycemia group. The protein expression of renin, ACE and Ang II were significantly up-regulated, and AT2R, B1R and B2R were down-regulated in DM1 group. Conclusions: The treatment of hyperglycemia was detrimental to bone as compared to the vehicle group, and the underlying mechanism was mediated, at least partially, through down-regulation of KSS activity and up-regulation of RAS activity in local bone. PMID:25973045

  9. 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.

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

    PubMed

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

    2015-08-01

    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.

  11. The brain renin-angiotensin system: a diversity of functions and implications for CNS diseases.

    PubMed

    Wright, John W; Harding, Joseph W

    2013-01-01

    The classic renin-angiotensin system (RAS) was initially described as a hormone system designed to mediate cardiovascular and body water regulation, with angiotensin II as its major effector. The discovery of an independent local brain RAS composed of the necessary functional components (angiotensinogen, peptidases, angiotensins, and specific receptor proteins) significantly expanded the possible physiological and pharmacological functions of this system. This review first describes the enzymatic pathways resulting in active angiotensin ligands and their interaction with AT(1), AT(2), and AT(4) receptor subtypes. Next, we discuss the classic physiologies and behaviors controlled by the RAS including cardiovascular, thirst, and sodium appetite. A final section summarizes non-classic functions and clinical conditions mediated by the brain RAS with focus on memory and Alzheimer's disease. There is no doubt that the brain RAS is an important component in the development of dementia. It also appears to play a role in normal memory consolidation and retrieval. The presently available anti-dementia drugs are proving to be reasonably ineffective, thus alternative treatment approaches must be developed. At the same time, presently available drugs must be tested for their efficacy to treat newly identified syndromes and diseases connected with the RAS. The list of non-classic physiologies and behaviors is ever increasing in both number and scope, attesting to the multidimensional influences of the RAS. Such diversity in function presents a dilemma for both researchers and clinicians. Namely, the blunting of RAS subsystems in the hopes of combating one constellation of underlying causes and disease symptoms may be counter-balanced by unanticipated and unwanted consequences to another RAS subsystem. For example, the use of angiotensin-converting enzyme inhibitors and AT(1) and/or AT(2) receptor blockers have shown great promise in the treatment of cardiovascular related

  12. Functional Local Renin-Angiotensin System in Human and Rat Periodontal Tissue

    PubMed Central

    Santos, Carlos F.; Morandini, Ana C.; Dionísio, Thiago J.; Faria, Flávio A.; Lima, Marta C.; Figueiredo, Caio M.; Colombini-Ishikiriama, Bella L.; Sipert, Carla R.; Maciel, Rubens P.; Akashi, Ana P.; Souza, Gabriela P.; Garlet, Gustavo P.; Rodini, Camila O.; Amaral, Sandra L.; Becari, Christiane; Salgado, Maria C.; Oliveira, Eduardo B.; Matus, Isaac; Didier, Daniela N.; Greene, Andrew S.

    2015-01-01

    The initiation or progression of periodontitis might involve a local renin-angiotensin system (RAS) in periodontal tissue. The aim of this study was to further characterize the local RAS in human and rat periodontal tissues between healthy and periodontally-affected tissue. Components of the RAS were investigated using in vitro, ex vivo and in vivo experiments involving both human and Wistar rat periodontium. Although not upregulated when challenged with P. gingivalis-lipopolysaccharide, human gingival and periodontal ligament fibroblasts expressed RAS components. Likewise, healthy and inflamed human gingiva expressed RAS components, some of which were shown to be functional, yet no differences in expression were found between healthy and diseased gingiva. However, in inflamed tissue the immunoreactivity was greater for the AT1R compared to AT2R in fibroblasts. When compared to healthy tissue, ACE activity was increased in human gingiva from volunteers with gingivitis. Human-gingiva homogenates generated Ang II, Ang 1-9 and Ang 1-7 when incubated with precursors. In gingiva homogenates, Ang II formation from Ang I was nearly abolished only when captopril and chymostatin were combined. Ang 1-7 formation was significantly greater when human gingiva homogenates were incubated with chymostatin alone compared to incubation without any inhibitor, only captopril, or captopril and chymostatin. In rat gingiva, RAS components were also found; their expression was not different between healthy and experimentally induced periodontitis (EP) groups. However, renin inhibition (aliskiren) and an AT1R antagonist (losartan) significantly blocked EP-alveolar-bone loss in rats. Collectively, these data are consistent with the hypothesis that a local RAS system is not only present but is also functional in both human and rat periodontal tissue. Furthermore, blocking AT1R and renin can significantly prevent periodontal bone loss induced by EP in rats. PMID:26244896

  13. Renin-angiotensin system in vertebrates: phylogenetic view of structure and function.

    PubMed

    Nishimura, Hiroko

    2017-03-01

    Renin substrate, biological renin activity, and/or renin-secreting cells in kidneys evolved at an early stage of vertebrate phylogeny. Angiotensin (Ang) I and II molecules have been identified biochemically in representative species of all vertebrate classes, although variation occurs in amino acids at positions 1, 5, and 9 of Ang I. Variations have also evolved in amino acid positions 3 and 4 in some cartilaginous fish. Angiotensin receptors, AT1 and AT2 homologues, have been identified molecularly or characterized pharmacologically in nonmammalian vertebrates. Also, various forms of angiotensins that bypass the traditional renin-angiotensin system (RAS) cascades or those from large peptide substrates, particularly in tissues, are present. Nonetheless, the phylogenetically important functions of RAS are to maintain blood pressure/blood volume homeostasis and ion-fluid balance via the kidney and central mechanisms. Stimulation of cell growth and vascularization, possibly via paracrine action of angiotensins, and the molecular biology of RAS and its receptors have been intensive research foci. This review provides an overview of: (1) the phylogenetic appearance, structure, and biochemistry of the RAS cascade; (2) the properties of angiotensin receptors from comparative viewpoints; and (3) the functions and regulation of the RAS in nonmammalian vertebrates. Discussions focus on the most fundamental functions of the RAS that have been conserved throughout phylogenetic advancement, as well as on their physiological implications and significance. Examining the biological history of RAS will help us analyze the complex RAS systems of mammals. Furthermore, suitable models for answering specific questions are often found in more primitive animals.

  14. Novel and effective gene transfer technique for study of vascular renin angiotensin system.

    PubMed Central

    Morishita, R; Gibbons, G H; Kaneda, Y; Ogihara, T; Dzau, V J

    1993-01-01

    Vascular renin angiotensin system (RAS) has been reported to exist in vascular wall. However, there is no direct evidence whether the vascular RAS per se can modulate growth of vascular smooth muscle cells (VSMC), because there is no suitable method to investigate the effect of endogenously produced vasoactive substances on growth of these cells. In this study, we transferred angiotensin-converting enzyme (ACE) and/or renin cDNAs into cultured VSMC using the efficient Sendai virus (hemagglutinating virus of Japan) liposome-mediated gene transfer method, to examine their relative roles in VSMC growth in vitro. Within 35 min or 6 h, the transfection of ACE cDNA into VSMC by hemagglutinating virus of Japan method resulted in a twofold higher ACE activity than control vector, whereas a cationic liposome (Lipofectin)-mediated method failed to show any effect. This in vitro system provided us with the opportunity to investigate the influence of endogenous vascular RAS on VSMC growth. Transfection of ACE or renin cDNA resulted in increased DNA and RNA synthesis, which was inhibited with the specific angiotensin II receptor antagonist (DuP 753: 10(-6) M). Angiotensin I added to ACE-transfected VSMC increased RNA synthesis in a dose-dependent manner. Cotransfection of renin and ACE cDNAs stimulated further RNA synthesis as compared to ACE or renin cDNA alone. These results showed that transfected components of RAS can modulate VSMC growth through the endogenous production of vascular angiotensin II, and that ACE as well as renin are rate limiting in determining the VSMC RAS activity. We conclude that the hemagglutinating virus of Japan liposome-mediated gene transfer technique provides a new and useful tool for study of endogenous vascular modulators such as vascular RAS. Images PMID:8390484

  15. 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.; Dalton, Bonnie P. (Technical Monitor)

    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.

  16. A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system in cardiomyocytes.

    PubMed

    Lyu, Linmao; Wang, Hui; Li, Bin; Qin, Qingyun; Qi, Lei; Nagarkatti, Mitzi; Nagarkatti, Prakash; Janicki, Joseph S; Wang, Xing Li; Cui, Taixing

    2015-12-01

    Chronic activation of the myocardial renin angiotensin system (RAS) elevates the local level of angiotensin II (Ang II) thereby inducing pathological cardiac hypertrophy, which contributes to heart failure. However, the precise underlying mechanisms have not been fully delineated. Herein we report a novel paracrine mechanism between cardiac fibroblasts (CF)s and cardiomyocytes whereby Ang II induces pathological cardiac hypertrophy. In cultured CFs, Ang II treatment enhanced exosome release via the activation of Ang II receptor types 1 (AT1R) and 2 (AT2R), whereas lipopolysaccharide, insulin, endothelin (ET)-1, transforming growth factor beta (TGFβ)1 or hydrogen peroxide did not. The CF-derived exosomes upregulated the expression of renin, angiotensinogen, AT1R, and AT2R, downregulated angiotensin-converting enzyme 2, and enhanced Ang II production in cultured cardiomyocytes. In addition, the CF exosome-induced cardiomyocyte hypertrophy was blocked by both AT1R and AT2R antagonists. Exosome inhibitors, GW4869 and dimethyl amiloride (DMA), inhibited CF-induced cardiomyocyte hypertrophy with little effect on Ang II-induced cardiomyocyte hypertrophy. Mechanistically, CF exosomes upregulated RAS in cardiomyocytes via the activation of mitogen-activated protein kinases (MAPKs) and Akt. Finally, Ang II-induced exosome release from cardiac fibroblasts and pathological cardiac hypertrophy were dramatically inhibited by GW4869 and DMA in mice. These findings demonstrate that Ang II stimulates CFs to release exosomes, which in turn increase Ang II production and its receptor expression in cardiomyocytes, thereby intensifying Ang II-induced pathological cardiac hypertrophy. Accordingly, specific targeting of Ang II-induced exosome release from CFs may serve as a novel therapeutic approach to treat cardiac pathological hypertrophy and heart failure.

  17. 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

  18. Acute Lead Exposure Increases Arterial Pressure: Role of the Renin-Angiotensin System

    PubMed Central

    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

    2011-01-01

    Background 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. Methodology/Principal Findings 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, AT1 and AT2. Pre-treatment with an AT1 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. Conclusion 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. PMID:21494558

  19. Expression of renin-angiotensin system components in the early bovine embryo.

    PubMed

    Pijacka, Wioletta; Hunter, Morag G; Broughton Pipkin, Fiona; Luck, Martin R

    2012-07-01

    The renin-angiotensin system (RAS), mainly associated with the regulation of blood pressure, has been recently investigated in female reproductive organs and the developing foetus. Angiotensin II (Ang II) influences oviductal gamete movements and foetal development, but there is no information about RAS in the early embryo. The aim of this study was to determine whether RAS components are present in the pre-implantation embryo, to determine how early they are expressed and to investigate their putative role at this stage of development. Bovine embryos produced in vitro were used for analysis of RAS transcripts (RT-PCR) and localisation of the receptors AGTR1 and AGTR2 (immunofluorescent labelling). We also investigated the effects of Ang II, Olmesartan (AGTR1 antagonist) and PD123319 (AGTR2 antagonist) on oocyte cleavage, embryo expansion and hatching. Pre-implanted embryos possessed AGTR1 and AGTR2 but not the other RAS components. Both receptors were present in the trophectoderm and in the inner cell mass of the blastocyst. AGTR1 was mainly localised in granular-like structures in the cytoplasm, suggesting its internalisation into clathrin-coated vesicles, and AGTR2 was found mainly in the nuclear membrane and in the mitotic spindle of dividing trophoblastic cells. Treating embryos with PD123319 increased the proportion of hatched embryos compared with the control. These results, the first on RAS in the early embryo, suggest that the pre-implanted embryo responds to Ang II from the mother rather than from the embryo itself. This may be a route by which the maternal RAS influences blastocyst hatching and early embryonic development.

  20. Renin-angiotensin system inhibitors and troponin elevation in spinal surgery.

    PubMed

    McClendon, Jamal; Smith, Timothy R; Thompson, Sara E; Sugrue, Patrick A; Sauer, Andrew J; O'Shaughnessy, Brian A; Carabini, Louanne; Koski, Tyler R

    2014-07-01

    Renin-angiotensin system (RAS) inhibition by angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) has been shown to reduce cardiovascular mortality and non-fatal myocardial infarction (MI) in high-risk surgical patients. However, their effect in spinal surgery has not been explored. Our objective was to determine the effect of RAS inhibitors on postoperative troponin elevation in spinal fusions, and to examine their correlation with hospital stay. We retrospectively analyzed 208 consecutive patients receiving spinal fusions ⩾5 levels between 2007-2010 with a mean follow-up of 1.7 years. Inclusion criteria were age ⩾18 years, elective fusions for kyphoscoliosis, and semi-elective fusions for tumor or infection. Exclusion criteria were trauma and follow-up <1 year. Descriptives, frequencies, and logistic and linear regression were used to analyze troponin elevation (⩾0.04 ng/mL), peak troponin level, and hospital stay. The results featured 208 patients with a mean body mass index (BMI) 28.5 kg/m(2) who underwent 345 spinal fusions. ACEI/ARB were withheld the day prior to surgery in 121 patients with 11 patients noteworthy for intra-operative electrocardiogram changes, 126 patients with troponin elevation, and 14 MI identified prior to discharge. Multivariate logistic regression identified BMI (p=0.04), estimated blood loss (p=0.015), and preoperative ACEI/ARB (p=0.015, odds ratio=2.7) as significant independent predictors for postoperative troponin elevation. Multivariate linear regression showed preoperative Oswestry Disability Index (p=0.002), unplanned return to operating room (p=0.007), pneumonia prior to hospital discharge (p<0.01), and preoperative ACEI/ARB to be associated with hospital stay. In patients with spinal fusions ⩾5 levels, ACEI/ARB are independently associated with postoperative troponin elevation and increased hospital stay.

  1. Targeting cardiac mast cells: pharmacological modulation of the local renin-angiotensin system.

    PubMed

    Reid, Alicia C; Brazin, Jacqueline A; Morrey, Christopher; Silver, Randi B; Levi, Roberto

    2011-11-01

    Enhanced production of angiotensin II and excessive release of norepinephrine in the ischemic heart are major causes of arrhythmias and sudden cardiac death. Mast cell-dependent mechanisms are pivotal in the local formation of angiotensin II and modulation of norepinephrine release in cardiac pathophysiology. Cardiac mast cells increase in number in myocardial ischemia and are located in close proximity to sympathetic neurons expressing angiotensin AT1- and histamine H3-receptors. Once activated, cardiac mast cells release a host of potent pro-inflammatory and pro-fibrotic cytokines, chemokines, preformed mediators (e.g., histamine) and proteases (e.g., renin). In myocardial ischemia, angiotensin II (formed locally from mast cell-derived renin) and histamine (also released from local mast cells) respectively activate AT1- and H3-receptors on sympathetic nerve endings. Stimulation of angiotensin AT1-receptors is arrhythmogenic whereas H3-receptor activation is cardioprotective. It is likely that in ischemia/reperfusion the balance may be tipped toward the deleterious effects of mast cell renin, as demonstrated in mast cell-deficient mice, lacking mast cell renin and histamine in the heart. In these mice, no ventricular fibrillation occurs at reperfusion following ischemia, as opposed to wild-type hearts which all fibrillate. Preventing mast cell degranulation in the heart and inhibiting the activation of a local renin-angiotensin system, hence abolishing its detrimental effects on cardiac rhythmicity, appears to be more significant than the loss of histamine-induced cardioprotection. This suggests that therapeutic targets in the treatment of myocardial ischemia, and potentially congestive heart failure and hypertension, should include prevention of mast cell degranulation, mast cell renin inhibition, local ACE inhibition, ANG II antagonism and H3-receptor activation.

  2. Age-Associated Changes in the Vascular Renin-Angiotensin System in Mice

    PubMed Central

    Yoon, Hye Eun; Kim, Eun Nim; Kim, Min Young; Lim, Ji Hee; Jang, In-Ae; Ban, Tae Hyun; Shin, Seok Joon; Park, Cheol Whee; Chang, Yoon Sik; Choi, Bum Soon

    2016-01-01

    Background. This study evaluated whether the change in the renin-angiotensin system (RAS) is associated with arterial aging in mice. Methods. Histologic changes and expressions of transforming growth factor-β (TGF-β), collagen IV, fibronectin, angiotensin II (Ang II), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), angiotensin II type 1 receptor (AT1R), angiotensin II type 2 receptor (AT2R), prorenin receptor (PRR), Mas receptor (MasR), endothelial nitric oxide synthase (eNOS), NADPH oxidase 2 and oxidase 4 (Nox2 and Nox4), 8-hydroxy-2′-deoxyguanosine (8-OHdG), 3-nitrotyrosine, and superoxide dismutase 1 and dismutase 2 (SOD1 and SOD2) were measured in the thoracic aortas from 2-month-old, 12-month-old, and 24-month-old C57/BL6 mice. Results. Twenty-four-month-old mice showed significantly increased aortic media thickness and expressions of TGF-β, collagen IV, and fibronectin, compared to 2-month-old and 12-month-old mice. The expressions of PRR, ACE, and Ang II, and AT1R-positive area significantly increased, whereas expressions of ACE2 and MasR and AT2R-positive area decreased with age. The expressions of phosphorylated serine1177-eNOS, SOD1, and SOD2 decreased, and the 8-OHdG-positive area and the 3-nitrotyrosine-positive area increased with age. The expression of Nox2 significantly increased with age, but that of Nox4 did not change. Conclusions. The enhanced PRR-ACE-Ang II-AT1R axis and reduced ACE2-MasR axis were associated with arterial aging in mice. PMID:27200147

  3. Age-Associated Changes in the Vascular Renin-Angiotensin System in Mice.

    PubMed

    Yoon, Hye Eun; Kim, Eun Nim; Kim, Min Young; Lim, Ji Hee; Jang, In-Ae; Ban, Tae Hyun; Shin, Seok Joon; Park, Cheol Whee; Chang, Yoon Sik; Choi, Bum Soon

    2016-01-01

    Background. This study evaluated whether the change in the renin-angiotensin system (RAS) is associated with arterial aging in mice. Methods. Histologic changes and expressions of transforming growth factor-β (TGF-β), collagen IV, fibronectin, angiotensin II (Ang II), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), angiotensin II type 1 receptor (AT1R), angiotensin II type 2 receptor (AT2R), prorenin receptor (PRR), Mas receptor (MasR), endothelial nitric oxide synthase (eNOS), NADPH oxidase 2 and oxidase 4 (Nox2 and Nox4), 8-hydroxy-2'-deoxyguanosine (8-OHdG), 3-nitrotyrosine, and superoxide dismutase 1 and dismutase 2 (SOD1 and SOD2) were measured in the thoracic aortas from 2-month-old, 12-month-old, and 24-month-old C57/BL6 mice. Results. Twenty-four-month-old mice showed significantly increased aortic media thickness and expressions of TGF-β, collagen IV, and fibronectin, compared to 2-month-old and 12-month-old mice. The expressions of PRR, ACE, and Ang II, and AT1R-positive area significantly increased, whereas expressions of ACE2 and MasR and AT2R-positive area decreased with age. The expressions of phosphorylated serine(1177)-eNOS, SOD1, and SOD2 decreased, and the 8-OHdG-positive area and the 3-nitrotyrosine-positive area increased with age. The expression of Nox2 significantly increased with age, but that of Nox4 did not change. Conclusions. The enhanced PRR-ACE-Ang II-AT1R axis and reduced ACE2-MasR axis were associated with arterial aging in mice.

  4. Blockade of the renin-angiotensin system increases adiponectin concentrations in patients with essential hypertension.

    PubMed

    Furuhashi, Masato; Ura, Nobuyuki; Higashiura, Katsuhiro; Murakami, Hideyuki; Tanaka, Marenao; Moniwa, Norihito; Yoshida, Daisuke; Shimamoto, Kazuaki

    2003-07-01

    Adiponectin, an adipocyte-derived protein, has been suggested to play an important role in insulin sensitivity. We examined the association between insulin sensitivity (M value) evaluated by the euglycemic-hyperinsulinemic glucose clamp and adiponectin concentrations in 30 essential hypertensives (EHT) and 20 normotensives (NT) and investigated the effect of blockade of the renin-angiotensin system (RAS) on adiponectin concentrations. EHT were divided into 12 insulin-resistant EHT (EHT-R) and 18 non-insulin-resistant EHT (EHT-N) using mean-1 SD of the M value in NT. There were no intergroup differences in age, gender, and body mass index (BMI). EHT-R had significantly higher levels of insulin and triglyceride and lower levels of adiponectin than did NT and EHT-N. EHT-R had higher levels of free fatty acid and lower levels of high-density lipoprotein (HDL) cholesterol than did EHT-N. Adiponectin concentrations were positively correlated with M value and HDL cholesterol and negatively correlated with BMI, insulin, free fatty acid, and triglyceride but not with blood pressure. M value, BMI, and HDL cholesterol were independent determinants of adiponectin concentrations in multiple and stepwise regression analyses. Sixteen EHT were treated with an angiotensin-converting enzyme inhibitor (temocapril, 4 mg/d; n=9) or an angiotensin II receptor blocker (candesartan, 8 mg/d; n=7) for 2 weeks. Treatment with temocapril or candesartan significantly decreased blood pressure and increased M value and adiponectin concentrations but did not affect BMI and HDL cholesterol. These results suggest that hypoadiponectinemia is related to insulin resistance in essential hypertension and that RAS blockade increases adiponectin concentrations with improvement in insulin sensitivity.

  5. HUMAN INTERVENTIONS TO CHARACTERIZE NOVEL RELATIONSHIPS BETWEEN THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM AND PARATHYROID HORMONE

    PubMed Central

    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

    2014-01-01

    Observational studies in primary hyperaldosteronism (PA) suggest a positive relationship between aldosterone and parathyroid hormone (PTH); however, interventions to better characterize the physiologic 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 PA. PTH was measured before and after: Study 1) low-dose angiotensin II [AngII] infusion (1 ng/kg/min) and captopril administration (25 mg × 1); Study 2) high-dose AngII infusion (3 ng/kg/min); Study 3) blinded crossover randomization to aldosterone infusion (0.7 µg/kg/hr) and vehicle; and Study 4) blinded randomization to spironolactone (50mg/daily) or placebo for 6 weeks. Infusion of AngII at 1 ng/kg/min acutely increased aldosterone (+148%) and PTH (+10.3%), while AngII at 3 ng/kg/min 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 over 6 weeks modestly lowered PTH when compared to placebo (P<0.05). In vitro studies revealed the presence of AngII 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 PA: the acute modulation of PTH by the RAAS appears to be mediated by AngII, 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. PMID:24191286

  6. The vascular renin-angiotensin system contributes to blunted vasodilation induced by transient high pressure in human adipose microvessels.

    PubMed

    Durand, Matthew J; Phillips, Shane A; Widlansky, Michael E; Otterson, Mary F; Gutterman, David D

    2014-07-01

    Increased intraluminal pressure can reduce endothelial function in resistance arterioles; however, the mechanism of this impairment is unknown. The purpose of this study was to determine the effect of local renin-angiotensin system inhibition on the pressure-induced blunting of endothelium-dependent vasodilation in human adipose arterioles. Arterioles (100-200 μm) were dissected from fresh adipose surgical specimens, cannulated onto glass micropipettes, pressurized to an intraluminal pressure of 60 mmHg, and constricted with endothelin-1. Vasodilation to ACh was assessed at 60 mmHg and again after a 30-min exposure to an intraluminal pressure of 150 mmHg. The vasodilator response to ACh was significantly reduced in vessels exposed to 150 mmHg. Exposure of the vessels to the superoxide scavenger polyethylene glycol-SOD (100 U/ml), the ANG II type 1 receptor antagonist losartan (10(-6) mol/l), or the angiotensin-converting enzyme inhibitor captopril (10(-5) mol/l) prevented the pressure-induced reduction in ACh-dependent vasodilation observed in untreated vessels. High intraluminal pressure had no effect on papaverine-induced vasodilation or ANG II sensitivity. Increased intraluminal pressure increased dihydroethidium fluorescence in cannulated vessels, which could be prevented by polyethylene glycol-SOD or losartan treatment and endothelial denudation. These data indicate that high intraluminal pressure can increase vascular superoxide and reduce nitric oxide-mediated vasodilation via activation of the vascular renin-angiotensin system. This study provides evidence showing that the local renin-angiotensin system in the human microvasculature may be pressure sensitive and contribute to endothelial dysfunction after acute bouts of hypertension.

  7. Effect of contrasted sodium diets on the pharmacokinetics and pharmacodynamic effects of renin-angiotensin system blockers.

    PubMed

    Azizi, Michel; Blanchard, Anne; Charbit, Beny; Wuerzner, Grégoire; Peyrard, Séverine; Ezan, Eric; Funck-Brentano, Christian; Ménard, Joël

    2013-06-01

    Dietary sodium, the main determinant of the pharmacodynamic response to renin-angiotensin system blockade, influences the pharmacokinetics of various cardiovascular drugs. We compared the effect of contrasted sodium diets on the pharmacokinetics of single oral doses of 8 mg candesartan cilexetil, 160 mg valsartan, 10 mg ramipril, and 50 mg atenolol administered to 64 (16 per group) normotensive male subjects randomly assigned to sodium depletion (SD) or sodium repletion (SR) in a crossover study. Pharmacodynamic response was assessed as the increase in plasma renin concentration for renin-angiotensin system blockers and electrocardiographic changes in PR interval duration for atenolol. The area under the curve (AUC) for plasma candesartan and atenolol concentrations was significantly lower for SR than for SD (respective ratios of AUC0-∞: 0.74; [90% CI, 0.66-0.82] and 0.69 [90% CI, 0.54-0.88], respectively), indicating a lack of bioequivalence between SR and SD. SR did not affect the pharmacokinetics of valsartan or ramipril. The increase in plasma renin concentration with the 3 renin-angiotensin system blockers was 10 times lower during the SR than the SD period. In the multiple regression analysis, the AUC0-24 of plasma drug concentration explained <1% and 21% of the variance of the AUC0-24 of delta plasma renin concentration for candesartan (P=0.8882/P=0.0368) during the SR and SD periods, respectively. The atenolol-induced lengthening of PR interval was fully reversed by SR. Thus, sodium balance modulates the pharmacokinetics of candesartan cilexetil and atenolol, with measurable effects on the selected pharmacodynamic end points.

  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. Functional vascular renin-angiotensin system in hypertensive transgenic rats for the mouse renin gene Ren-2.

    PubMed

    Arribas, S; Sánchez-Ferrer, C F; Peiró, C; Ponte, A; Salaices, M; Marín, J

    1994-10-01

    1. Isolated aortic segments from transgenic rats for the mouse renin gene Ren-2 were more sensitive than those from control Sprague-Dawley ones to the vasoconstrictions induced by angiotensin II and to the potentiation of norepinephrine contractions by this peptide. 2. In transgenic, but not in control aorta, pretreatment with angiotensinogen potentiated norepinephrine-induced vasoconstrictions, this effect being abolished by captopril. 3. These results suggest that in the aorta of transgenic rats there is a higher functional tissue renin-angiotensin system that potentiates the vascular reactivity to norepinephrine.

  10. Water metabolism dysfunction via renin-angiotensin system activation caused by liver damage in mice treated with microcystin-RR.

    PubMed

    Zhong, Qing; Sun, Feng; Wang, Weiguang; Xiao, Wenqing; Zhao, Xiaoni; Gu, Kangding

    2017-03-19

    Microcystins (MCs) are a group of monocyclic heptapeptide toxins that have been shown to act as potent hepatotoxins. However, the observed symptoms of water metabolism disruption induced by microcystin-RR (MC-RR) or MCs have rarely been reported, and a relatively clear mechanism has not been identified. In the present study, male mice were divided into 4 groups (A: 140μg/kg, B: 70μg/kg,C: 35μg/kg, and D: 0μg/kg) and administered MC-RR daily for a month. On day 8 of treatment, an increase in water intake and urine output was observed in the high-dose group compared with the control, and the symptoms worsened with the repeated administration of the toxin until day 30. In addition, the urine specific gravity decreased and serum enzymes that can reflect hepatic damage increased in the high-dose group compared with the control (P<0.05). The mRNA level of angiotensinogen (AGT) in hepatocytes was upregulated to approximately 150% of the control (P<0.05), and the serum renin-angiotensin system (RAS) was activated in the high-dose group; however, signs of renal injury were not observed throughout the experiment. After the toxin treatment was completed, the high levels of the RAS and vasopressin in group A returned to normal levels within 1 week. As expected, the symptoms of polyuria and polydipsia also disappeared. Therefore, we propose that water metabolism dysfunction occurs via RAS activation caused by liver damage because the increased serum RAS levels in the experiment were consistent with the increased urine output and water intake in the mice during the observation period. In addition, we found for the first time that a RAS blocker could alleviate the observed polyuria and polydipsia and inactivate the high level of the RAS induced by MC-RR in a dose-dependent manner, which further supported our hypothesis.

  11. 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.

  12. Sequential activation of the intrarenal renin-angiotensin system in the progression of hypertensive nephropathy in Goldblatt rats.

    PubMed

    Kim, Yang Gyun; Lee, Sang Ho; Kim, Se-Yun; Lee, Arah; Moon, Ju Young; Jeong, Kyung-Hwan; Lee, Tae Won; Lim, Sung Jig; Sohn, Il Suk; Ihm, Chun-Gyoo

    2016-07-01

    The intrarenal renin-angiotensin system (RAS) has an important role in generating and maintaining hypertension in two-kidney, one-clip (2K1C) rats. This study evaluated how various intrarenal RAS components contributed to hypertension not only in the maintenance period (5w; 5 wk after operation) but also earlier (2w; 2 wk after operation). We inserted a 2.5-mm clip into the left renal artery of Sprague-Dawley rats and euthanized them at 2w and 5w following the operation. Systolic blood pressure increased within 1 wk after the operation, and left ventricular hypertrophy occurred in 2K1C rats. At 2w, juxtaglomerular apparatus (JGA) and collecting duct (CD) renin increased in clipped kidney (CK) of 2K1C rats. The tubular angiotensin I-converting enzyme (ACE) was not changed, but peritubular ACE2 decreased in nonclipped kidney (NCK) and CK of 2K1C rats. At 5w, ACE and CD renin were enhanced, and ACE2 was still lessened in both kidneys of 2K1C rats. However, plasma renin activity (PRA) was not different from that in sham rats. In proximal tubules of CK, the ANG II type 1 receptor (AT1R) was not suppressed, but the Mas receptor (MasR) was reduced; thus the AT1R/MasR ratio was elevated. Although hypoxic change in CK could not be excluded, the JGA renin of CK and CD renin in both kidneys was highly expressed independent of time. Peritubular ACE2 changed in the earlier period, and uninhibited AT1R in proximal tubules of CK was presented in the maintenance period. In 2K1C rats, attenuated ACE2 seems to contribute to initiating hypertension while upregulated ACE in combination with unsuppressed AT1R may have a key role in maintaining hypertension.

  13. The compensatory renin-angiotensin system in the central regulation of arterial pressure: new avenues and new challenges.

    PubMed

    Mendoza, Alberto; Lazartigues, Eric

    2015-08-01

    Hypertension is a widespread condition that affects millions of people around the world and has a major impact in public health. The classic renin-angiotensin system is a complex system comprised of multiple peptides and pathways that have been the driver of drug development over the years to control hypertension. However, there are still patients whose hypertension is very difficult to control with current drugs and strategies, thus motivating further research in this field. In the past two decades, important discoveries have expanded our knowledge of this system and new pathways are emerging that are helping us understand the complex interaction taking place not only in the periphery, but also in the central nervous system where the renin-angiotensin system is also very active. A new arm, called the ACE2/Ang-(1-7)/Mas receptor axis, was shown to exert antihypertensive properties and serve as a counterbalance to the classic ACE/angiotensin II/AT1 receptor axis, in this way modulating or even counteracting the negative effects of angiotensin II in blood pressure regulation and water retention. Modulation of this new axis through ACE2 activation, ADAM17 regulation or AT1 receptor internalization are some of the novel avenues and challenges that have the potential to become a target for new drug research and development for the treatment of hypertension.

  14. Characterization of a local renin-angiotensin system in rat gingival tissue

    PubMed Central

    Santos, C.F.; Akashi, A.E.; Dionísio, T.J.; Sipert, C.R.; Didier, D.N.; Greene, A.S.; Oliveira, S.H.P.; Pereira, H.J.; Becari, C.; Oliveira, E.B.; Salgado, M.C.O.

    2009-01-01

    Background Systemic renin-angiotensin system (RAS) promotes plasmatic production of angiotensin (Ang) II, which acts through interaction with specific receptors. There is growing evidence that local systems in various tissues and organs are capable of generating angiotensins independently of circulating RAS. The aims of this work were to: 1) study the expression and localization of RAS components in rat gingival tissue and 2) evaluate the in vitro production of Ang II and other peptides catalyzed by rat gingival tissue homogenates incubated with different Ang II precursors. Methods Reverse transcription-polymerase chain reaction (RT-PCR) assessed mRNA expression. Immunohistochemical (IHC) analysis aimed to detect and localize renin. Standardized fluorimetric method with tripeptide Hippuryl-Histidyl-Leucine (Hip-His-Leu) was used to measure tissue ACE activity, while high performance liquid chromatography (HLPC) showed products formed after incubation of tissue homogenates with Ang I or tetradecapeptide renin substrate (TDP). Results mRNA for renin, angiotensinogen, ACE and Ang II receptors (AT1a, AT1b and AT2) was detected in gingival tissue; cultured gingival fibroblasts expressed renin, angiotensinogen and AT1a receptor. Renin was present in the vascular endothelium and intensely expressed in the epithelial basal layer of periodontally affected gingival tissue. ACE activity was detected (4.95±0.89 nmol His-Leu/g.min). When Ang I was used as substrate, Ang 1-9 (0.576±0.128 nmol/mg.min), Ang II (0.066±0.008 nmol/mg.min) and Ang 1-7 (0.111±0.017 nmol/mg.min) were formed, whereas these same peptides (0.139±0.031; 0.206±0.046 and 0.039±0.007 nmol/mg.min, respectively) and Ang I (0.973±0.139 nmol/mg.min) were formed when TDP was the substrate. Conclusion Results presented here clearly show existence of a local RAS in rat gingival tissue, which is capable of generating Ang II and other vasoactive peptides in vitro. PMID:19228099

  15. The Interplay between the Renin Angiotensin System and Pacing Postconditioning Induced Cardiac Protection

    PubMed Central

    Babiker, Fawzi; Al-Jarallah, Aishah; Joseph, Shaji

    2016-01-01

    Background Accumulating evidence suggests a cardioprotective role of pacing postconditioning (PPC) maneuvers in animal models and more recently in humans. The procedure however remains to be optimized and its interaction with physiological systems remains to be further explored. The renin angiotensin system (RAS) plays a dual role in ischemia/reperfusion (I/R) injury. The interaction between RAS and PPC induced cardiac protection is however not clearly understood. We have recently demonstrated that angiotensin (1–7) via Mas receptor played a significant role in PPC mediated cardiac protection against I/R injury. Objective The objective of this study was to investigate the role of angiotensin converting enzyme (ACE)—chymase—angiotensin II (Ang II)—angiotensin receptor 1 (AT1) axes of RAS in PPC mediated cardiac protection. Methods Isolated rat hearts were subjected to I/R (control) or PPC in the presence or absence of Ang II, chymostatin (inhibitor of locally produced Ang II), ACE blocker (captopril) or AT1 antagonist (irbesartan). Hemodynamics data was computed digitally and infarct size was determined histologically using TTC staining and biochemically by measuring creatine kinase (CK) and lactate dehydrogenase levels. Results Cardiac hemodynamics were significantly (P<0.001) improved and infarct size and cardiac enzymes were significantly (P<0.001) reduced in hearts subjected to PPC relative to hearts subjected to I/R injury. Exogenous administration of Ang II did not affect I/R injury or PPC mediated protection. Nonetheless inhibition of endogenously synthesized Ang II protected against I/R induced cardiac damage yet did not block or augment the protective effects of PPC. The administration of AT1 antagonist did not alleviate I/R induced damage. Interestingly it abrogated PPC induced cardiac protection in isolated rat hearts. Finally, PPC induced protection and blockade of locally produced Ang II involved enhanced activation of ERK1/2 and Akt components

  16. 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.

  17. 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; Zile, M. R.

    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

  18. 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

  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.

  20. Activation of the renin-angiotensin system, specifically in the subfornical organ is sufficient to induce fluid intake.

    PubMed

    Coble, Jeffrey P; Cassell, Martin D; Davis, Deborah R; Grobe, Justin L; Sigmund, Curt D

    2014-08-15

    Increased activity of the renin-angiotensin system within the brain elevates fluid intake, blood pressure, and resting metabolic rate. Renin and angiotensinogen are coexpressed within the same cells of the subfornical organ, and the production and action of ANG II through the ANG II type 1 receptor in the subfornical organ (SFO) are necessary for fluid intake due to increased activity of the brain renin-angiotensin system. We generated an inducible model of ANG II production by breeding transgenic mice expressing human renin in neurons controlled by the synapsin promoter with transgenic mice containing a Cre-recombinase-inducible human angiotensinogen construct. Adenoviral delivery of Cre-recombinase causes SFO-selective induction of human angiotensinogen expression. Selective production of ANG II in the SFO results in increased water intake but did not change blood pressure or resting metabolic rate. The increase in water intake was ANG II type 1 receptor-dependent. When given a choice between water and 0.15 M NaCl, these mice increased total fluid and sodium, but not water, because of an increased preference for NaCl. When provided a choice between water and 0.3 M NaCl, the mice exhibited increased fluid, water, and sodium intake, but no change in preference for NaCl. The increase in fluid intake was blocked by an inhibitor of PKC, but not ERK, and was correlated with increased phosphorylated cyclic AMP response element binding protein in the subfornical organ. Thus, increased production and action of ANG II specifically in the subfornical organ are sufficient on their own to mediate an increase in drinking through PKC.

  1. A systematic review of the role of renin angiotensin aldosterone system genes in diabetes mellitus, diabetic retinopathy and diabetic neuropathy

    PubMed Central

    Rahimi, Zohreh; Moradi, Mahmoudreza; Nasri, Hamid

    2014-01-01

    Background: The renin angiotensin aldosterone system (RAAS) plays a vital role in regulating glucose metabolism and blood pressure, electrolyte and fluid homeostasis. The aim of this systematic review is to assess the association of the RAAS genes with diabetes mellitus (DM) and its complications of retinopathy, neuropathy and cardiovascular disease (CVD). Materials and Methods: The relevant English-language studies were identified using the key words of DM, type 1 diabetes mellitus (T1DM), T2DM, renin angiotensin aldosterone polymorphisms or genotypes and RAAS from the search engines of MEDLINE/PubMed, and Scopus from January 1, 1995 to July 30, 2014. Inclusion criteria for selecting relevant studies were reporting the role of RAAS gene variants in the pathogenesis of T1DM or T2DM, diabetic retinopathy (DR), diabetic neuropathy and cardiovascular complication of DM. Results: The reviewers identified 204 studies of which 73 were eligible for inclusion in the present systematic review. The review indicates the angiotensinogen (AGT) M235T polymorphism might not affect the risk of DM. The role of angiotensin converting enzyme insertion/deletion (ACE I/D) and angiotensin II type 1 receptor gene (AT1R) A1166C polymorphisms in the pathogenesis of DM could not be established. Studies indicate the absence of an association between three polymorphisms of AGT M235T, ACE I/D and AT1R A1166C and DR in DM patients. A protective role for ACE II genotype against diabetic peripheral neuropathy has been suggested. Also, the ACE I/D polymorphism might be associated with the risk of CVD in DM patients. Conclusion: More studies with adequate sample size that investigate the influence of all RAAS gene variants together on the risk of DM and its complications are necessary to provide a more clear picture of the RAAS genes polymorphisms involvement in the pathogenesis of DM and its complications. PMID:25657757

  2. Silver and titanium dioxide nanoparticles alter oxidative/inflammatory response and renin-angiotensin system in brain.

    PubMed

    Krawczyńska, Agata; Dziendzikowska, Katarzyna; Gromadzka-Ostrowska, Joanna; Lankoff, Anna; Herman, Andrzej Przemysław; Oczkowski, Michał; Królikowski, Tomasz; Wilczak, Jacek; Wojewódzka, Maria; Kruszewski, Marcin

    2015-11-01

    The study was designed to examine the effects of silver AgNPs, 20 nm) and titanium dioxide (Aeroxide(®) P25 TiO2NPs, 21 nm) nanoparticles on brain oxidative stress parameters, its antioxidant potential and brain renin-angiotensin system (RAS) in vivo. The analysis was performed 28 days after single dose injection of TiO2NPs and AgNPs (10 or 5 mg/kg body weight, respectively). The AgNPs, but not TiO2NPs, administration resulted in decreased lipid and cholesterol peroxidation. Antioxidant enzymes gene expression and/or activity were changed differently for TiO2NPs and AgNPs group. The TiO2NPs decreased aromatase gene expression, and glutathione peroxidase and reductase activities. In AgNPs group the sodium dismutase 1 and glutathione reductase mRNA levels were decreased as opposed to their activities. Both NPs altered the expression of brain RAS genes (angiotensinogen, renin, angiotensin I converting enzyme 1 and 2), but only TiO2NPs caused similar changes on protein level. The expression of amyloid beta precursor protein gene was not altered by any kind of injected NPs. The TiO2NPs were more potent modulator of gene expression in the brain than AgNPs, despite the two times lower dosage. These results suggest that AgNPs and TiO2NPs exposure may modulate the brain function, but with different strength.

  3. Relationship of venous thromboembolism and myocardial infarction with the renin-angiotensin system in African-Americans.

    PubMed

    Hooper, W Craig; Dowling, Nicole F; Wenger, Nanette K; Dilley, Anne; Ellingsen, Dorothy; Evatt, Bruce L

    2002-05-01

    Genetic polymorphisms/mutations associated with venous thrombosis have largely been confined to the genes that encode for proteins in either the coagulant or the anticoagulant pathway. Although genetic alterations in the renin-angiotensin system have been reported to have a role in myocardial infarction and hypertension, there is recent evidence to suggest that there may also be an association with venous thrombosis. To extend our earlier observation of an association between the ACE DD genotype in African-American males and venous thrombosis, other genes in the renin-angiotensin pathway were investigated for possible disease association and were compared with African-Americans with myocardial infarction. African-American patients with a documented history of venous thrombosis or a history of myocardial infarction were eligible for participation as cases in the study. Control subjects were African-American outpatients attending a clinical laboratory for routine blood tests who had comparable age and gender distributions to the cases. Persons with a history of myocardial infarction, stroke, or thrombosis were excluded. Genes that were analyzed for known polymorphisms included angiotensinogen, angiotensin-converting enzyme (ACE), and the angiotensin II type I receptor. Our results showed that the ACE DD genotype was also associated with MI in African-American males but not in females. Racial/ethnic and sex differences were also found with respect to the genotype distribution of the ACE 4656(CT)(2/3) polymorphism. It was observed that the 2/2 genotype had a protective effective in males for myocardial infarction and venous thrombosis. The data also demonstrated that the allele frequencies of the A1166C variant of the angiotensin II type I receptor were different in African-Americans as compared to Caucasians.

  4. Daily sesame oil supplementation attenuates local renin-angiotensin system via inhibiting MAPK activation and oxidative stress in cardiac hypertrophy.

    PubMed

    Liu, Chuan-Teng; Liu, Ming-Yie

    2017-04-01

    The renin-angiotensin system (RAS) is involved in the development of left ventricular hypertrophy (LVH) by which increases cardiac morbidity and mortality. Activation of mitogen-activated protein kinases (MAPKs) and oxidative stress are important in RAS-mediated cardiac hypertrophy. Sesame oil, a potent antioxidant, attenuates hypertension-dependent LVH. We examined the protective role of sesame oil on RAS-mediated MAPK activation and oxidative stress in rats. We induced LVH using a hypertensive model by subcutaneously injecting deoxycorticosterone acetate (DOCA; 15 mg/ml/kg in mineral oil; twice weekly for 5 weeks) and supplementing with 1% sodium chloride drinking water (DOCA/salt) to uninephrectomized rats. Sesame oil was gavaged (0.5 or 1 ml/kg/day for 7 days) after 4 weeks of DOCA/salt treatment. Cardiac histopathology, RAS parameters, expression of MAPKs, reactive oxygen species and lipid peroxidation were assessed 24 h after the last dose of sesame oil. Sesame oil significantly decreased the size of cardiomyocytes and the levels of cardiac renin, angiotensin-converting enzyme and angiotensin II. In addition, sesame oil down-regulated the expression of angiotensin type 1 receptor, JNK and p38 MAPK and apoptosis signal regulating kinase 1, c-Fos and c-Jun in rats receiving DOCA/salt. Furthermore, the induction of nicotinamide adenine dinucleotide phosphate oxidase, superoxide anion and hydroxyl radical and lipid peroxidation by DOCA/salt were inhibited by sesame oil. Sesame oil modulates cardiac RAS to ameliorate LVH by inhibiting MAPK activation and lowering oxidative stress.

  5. Combination therapy with renin-angiotensin-aldosterone system inhibitor telmisartan and serine protease inhibitor camostat mesilate provides further renoprotection in a rat chronic kidney disease model.

    PubMed

    Narita, Yuki; Ueda, Miki; Uchimura, Kohei; Kakizoe, Yutaka; Miyasato, Yoshikazu; Mizumoto, Teruhiko; Morinaga, Jun; Hayata, Manabu; Nakagawa, Terumasa; Adachi, Masataka; Miyoshi, Taku; Sakai, Yoshiki; Kadowaki, Daisuke; Hirata, Sumio; Mukoyama, Masashi; Kitamura, Kenichiro

    2016-02-01

    We previously reported that camostat mesilate (CM) had renoprotective and antihypertensive effects in rat CKD models. In this study, we examined if CM has a distinct renoprotective effect from telmisartan (TE), a renin-angiotensin-aldosterone system (RAS) inhibitor, on the progression of CKD. We evaluated the effect of CM (400 mg/kg/day) and/or TE (10 mg/kg/day) on renal function, oxidative stress, renal fibrosis, and RAS components in the adenine-induced rat CKD model following 5-weeks treatment period. The combination therapy with CM and TE significantly decreased the adenine-induced increase in serum creatinine levels compared with each monotherapy, although all treatment groups showed similar reduction in blood pressure. Similarly, adenine-induced elevation in oxidative stress markers and renal fibrosis markers were significantly reduced by the combination therapy relative to each monotherapy. Furthermore, the effect of the combination therapy on plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was similar to that of TE monotherapy, and CM had no effect on both PRA and PAC, suggesting that CM has a distinct pharmacological property from RAS inhibition. Our findings indicate that CM could be a candidate drug for an add-on therapy for CKD patients who had been treated with RAS inhibitors.

  6. Renin-angiotensin system gene polymorphisms as potential modifiers of hypertrophic and dilated cardiomyopathy phenotypes.

    PubMed

    Rani, Bindu; Kumar, Amit; Bahl, Ajay; Sharma, Rajni; Prasad, Rishikesh; Khullar, Madhu

    2017-03-01

    The renin-angiotensin (RAS) pathway has an important role in the etiology of heart failure and given the importance of RAS as a therapeutic target in various cardiomyopathies, genetic polymorphisms in the RAS genes may modulate the risk and severity of disease in cardiomyopathy patients. In the present study, we examined the association of RAS pathway gene polymorphisms, angiotensin converting enzyme (ACE), angiotensinogen (AGT), and angiotensin receptor type 1 (AGTR1) with risk and disease severity in Asian Indian idiopathic cardiomyopathy patients. The case-control study was conducted in 400 cardiomyopathy patients diagnosed with HCM, DCM, or restrictive cardiomyopathy (RCM) and 235 healthy controls. Genotyping of patients and controls was done by PCR-RFLP assays. Left ventricular wall thickness and left ventricular ejection fraction were measured by means of M-mode echocardiography. We observed significantly higher prevalence of ACE DD and AGTR1 1166CC genotypes in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) patients. Also, 235TT genotype of AGT (M235T) was significantly associated with enhanced risk of the disease phenotype in HCM, DCM, and RCM.

  7. Clinical trials update from the European Society of Cardiology-Heart Failure meeting 2015: AUGMENT-HF, TITRATION, STOP-HF, HARMONIZE, LION HEART, MOOD-HF, and renin-angiotensin inhibitors in patients with heart and renal failure.

    PubMed

    Pellicori, Pierpaolo; Clark, Andrew L

    2015-09-01

    This article provides an overview on the key trials relevant to the pathophysiology, prevention, and treatment of heart failure (HF) presented at the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) annual meeting held in Seville, Spain in May 2015. Trials reported include AUGMENT-AF (myocardial injections of calcium-alginate hydrogel), a propensity score-matched study of renin-angiotensin system antagonists in patients with HF and severe renal dysfunction, HARMONIZE (sodium zirconium cyclosilicate used to bind potassium), TITRATION, comparing two regimes for introducing LCZ696, STOP-HF, a trial of intramyocardial stromal cell-derived factor-1, MOOD-HF (escitalopram for patients with heart failure and depression), and LION HEART, a trial of intermittent levosimendan therapy. Unpublished reports should be considered as preliminary, since analyses may change in the final publication.

  8. Leptin Mediates High-Fat Diet Sensitization of Angiotensin II-Elicited Hypertension by Upregulating the Brain Renin-Angiotensin System and Inflammation.

    PubMed

    Xue, Baojian; Yu, Yang; Zhang, Zhongming; Guo, Fang; Beltz, Terry G; Thunhorst, Robert L; Felder, Robert B; Johnson, Alan Kim

    2016-05-01

    Obesity is characterized by increased circulating levels of the adipocyte-derived hormone leptin, which can increase sympathetic nerve activity and raise blood pressure. A previous study revealed that rats fed a high-fat diet (HFD) have an enhanced hypertensive response to subsequent angiotensin II administration that is mediated at least, in part, by increased activity of brain renin-angiotensin system and proinflammatory cytokines. This study tested whether leptin mediates this HFD-induced sensitization of angiotensin II-elicited hypertension by interacting with brain renin-angiotensin system and proinflammatory cytokine mechanisms. Rats fed an HFD for 3 weeks had significant increases in white adipose tissue mass, plasma leptin levels, and mRNA expression of leptin and its receptors in the lamina terminalis and hypothalamic paraventricular nucleus. Central infusion of a leptin receptor antagonist during HFD feeding abolished HFD sensitization of angiotensin II-elicited hypertension. Furthermore, central infusion of leptin mimicked the sensitizing action of HFD. Concomitant central infusions of the angiotensin II type 1 receptor antagonist irbesartan, the tumor necrosis factor-α synthesis inhibitor pentoxifylline, or the inhibitor of microglial activation minocycline prevented the sensitization produced by central infusion of leptin. RT-PCR analysis indicated that either HFD or leptin administration upregulated mRNA expression of several components of the renin-angiotensin system and proinflammatory cytokines in the lamina terminalis and paraventricular nucleus. The leptin antagonist and the inhibitors of angiotensin II type 1 receptor, tumor necrosis factor-α synthesis, and microglial activation all reversed the expression of these genes. The results suggest that HFD-induced sensitization of angiotensin II-elicited hypertension is mediated by leptin through upregulation of central renin-angiotensin system and proinflammatory cytokines.

  9. Activation of the Cardiac Renin-Angiotensin System in High Oxygen-Exposed Newborn Rats: Angiotensin Receptor Blockade Prevents the Developmental Programming of Cardiac Dysfunction.

    PubMed

    Bertagnolli, Mariane; Dios, Anne; Béland-Bonenfant, Sarah; Gascon, Gabrielle; Sutherland, Megan; Lukaszewski, Marie-Amélie; Cloutier, Anik; Paradis, Pierre; Schiffrin, Ernesto L; Nuyt, Anne Monique

    2016-04-01

    Newborn rats exposed to high oxygen (O2), mimicking preterm birth-related neonatal stress, develop later in life cardiac hypertrophy, dysfunction, fibrosis, and activation of the renin-angiotensin system. Cardiac renin-angiotensin system activation in O2-exposed adult rats is characterized by an imbalance in angiotensin (Ang) receptors type 1/2 (AT1/2), with prevailing AT1 expression. To study the role of renin-angiotensin system in the developmental programming of cardiac dysfunction, we assessed Ang receptor expression during neonatal high O2 exposure and whether AT1 receptor blockade prevents cardiac alterations in early adulthood. Sprague-Dawley newborn rats were kept with their mother in 80% O2 or room air (control) from days 3 to 10 (P3-P10) of life. Losartan or water was administered by gavage from P8 to P10 (n=9/group). Rats were studied at P3 (before O2 exposure), P5, P10 (end of O2), and P28. Losartan treatment had no impact on growth or kidney development. AT1 and Ang type 2 receptors were upregulated in the left ventricle by high O2 exposure (P5 and P10), which was prevented by Losartan treatment at P10. Losartan prevented the cardiac AT1/2 imbalance at P28. Losartan decreased cardiac hypertrophy and fibrosis and improved left ventricle fraction of shortening in P28 O2-exposed rats, which was associated with decreased oxidation of calcium/calmodulin-dependent protein kinase II, inhibition of the transforming growth factor-β/SMAD3 pathway, and upregulation of cardiac angiotensin-converting enzyme 2. In conclusion, short-term Ang II blockade during neonatal high O2 prevents the development of cardiac alterations later in life in rats. These findings highlight the key role of neonatal renin-angiotensin system activation in the developmental programming of cardiac dysfunction induced by deleterious neonatal conditions.

  10. 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

  11. 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.

  12. Palmitoylethanolamide treatment reduces blood pressure in spontaneously hypertensive rats: involvement of cytochrome p450-derived eicosanoids and renin angiotensin system.

    PubMed

    Mattace Raso, Giuseppina; Pirozzi, Claudio; d'Emmanuele di Villa Bianca, Roberta; Simeoli, Raffaele; Santoro, Anna; Lama, Adriano; Di Guida, Francesca; Russo, Roberto; De Caro, Carmen; Sorrentino, Raffaella; Calignano, Antonio; Meli, Rosaria

    2015-01-01

    Palmitoylethanolamide (PEA), a peroxisome proliferator-activated receptor-α agonist, has been demonstrated to reduce blood pressure and kidney damage secondary to hypertension in spontaneously hypertensive rat (SHR). Currently, no information is available concerning the putative effect of PEA on modulating vascular tone. Here, we investigate the mechanisms underpinning PEA blood pressure lowering effect, exploring the contribution of epoxyeicosatrienoic acids, CYP-dependent arachidonic acid metabolites, as endothelium-derived hyperpolarizing factors (EDHF), and renin angiotensin system (RAS) modulation. To achieve this aim SHR and Wistar-Kyoto rats were treated with PEA (30 mg/kg/day) for five weeks. Functional evaluations on mesenteric bed were performed to analyze EDHF-mediated vasodilation. Moreover, mesenteric bed and carotid were harvested to measure CYP2C23 and CYP2J2, the key isoenzymes in the formation of epoxyeicosatrienoic acids, and the soluble epoxide hydrolase, which is responsible for their degradation in the corresponding diols. Effect of PEA on RAS modulation was investigated by analyzing angiotensin converting enzyme and angiotensin receptor 1 expression. Here, we showed that EDHF-mediated dilation in response to acetylcholine was increased in mesenteric beds of PEA-treated SHR. Western blot analysis revealed that the increase in CYP2C23 and CYP2J2 observed in SHR was significantly attenuated in mesenteric beds of PEA-treated SHR, but unchanged in the carotids. Interestingly, in both vascular tissues, PEA significantly decreased the soluble epoxide hydrolase protein level, accompanied by a reduced serum concentration of its metabolite 14-15 dihydroxyeicosatrienoic acid, implying a reduction in epoxyeicosatrienoic acid hydrolisis. Moreover, PEA treatment down-regulated angiotensin receptor 1 and angiotensin converting enzyme expression, indicating a reduction in angiotensin II-mediated effects. Consistently, a damping of the activation of

  13. Palmitoylethanolamide Treatment Reduces Blood Pressure in Spontaneously Hypertensive Rats: Involvement of Cytochrome P450-Derived Eicosanoids and Renin Angiotensin System

    PubMed Central

    Mattace Raso, Giuseppina; Pirozzi, Claudio; d'Emmanuele di Villa Bianca, Roberta; Simeoli, Raffaele; Santoro, Anna; Lama, Adriano; Di Guida, Francesca; Russo, Roberto; De Caro, Carmen; Sorrentino, Raffaella; Calignano, Antonio; Meli, Rosaria

    2015-01-01

    Palmitoylethanolamide (PEA), a peroxisome proliferator-activated receptor-α agonist, has been demonstrated to reduce blood pressure and kidney damage secondary to hypertension in spontaneously hypertensive rat (SHR). Currently, no information is available concerning the putative effect of PEA on modulating vascular tone. Here, we investigate the mechanisms underpinning PEA blood pressure lowering effect, exploring the contribution of epoxyeicosatrienoic acids, CYP-dependent arachidonic acid metabolites, as endothelium-derived hyperpolarizing factors (EDHF), and renin angiotensin system (RAS) modulation. To achieve this aim SHR and Wistar-Kyoto rats were treated with PEA (30 mg/kg/day) for five weeks. Functional evaluations on mesenteric bed were performed to analyze EDHF-mediated vasodilation. Moreover, mesenteric bed and carotid were harvested to measure CYP2C23 and CYP2J2, the key isoenzymes in the formation of epoxyeicosatrienoic acids, and the soluble epoxide hydrolase, which is responsible for their degradation in the corresponding diols. Effect of PEA on RAS modulation was investigated by analyzing angiotensin converting enzyme and angiotensin receptor 1 expression. Here, we showed that EDHF-mediated dilation in response to acetylcholine was increased in mesenteric beds of PEA-treated SHR. Western blot analysis revealed that the increase in CYP2C23 and CYP2J2 observed in SHR was significantly attenuated in mesenteric beds of PEA-treated SHR, but unchanged in the carotids. Interestingly, in both vascular tissues, PEA significantly decreased the soluble epoxide hydrolase protein level, accompanied by a reduced serum concentration of its metabolite 14-15 dihydroxyeicosatrienoic acid, implying a reduction in epoxyeicosatrienoic acid hydrolisis. Moreover, PEA treatment down-regulated angiotensin receptor 1 and angiotensin converting enzyme expression, indicating a reduction in angiotensin II-mediated effects. Consistently, a damping of the activation of

  14. Combination therapy of renin-angiotensin system inhibitors plus calcium channel blockers versus other two-drug combinations for hypertension: a systematic review and meta-analysis.

    PubMed

    Lu, Z; Chen, Y; Li, L; Wang, G; Xue, H; Tang, W

    2017-01-01

    Many randomized clinical trials (RCTs) have investigated the efficacy and safety of renin-angiotensin system inhibitors (RASIs) plus calcium channel blockers (CCBs), compared with other two-drug combinations, but systematic assessment in this aspect is still lacking. We carried out the present meta-analysis of randomized controlled trials to evaluate the long-term effect and safety of RASIs plus CCBs. Literatures were searched in MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials in September 2014. A fixed-effect model was used to estimate the pooled effect of trials identified. Thirty-four trials with 41 694 patients were included. Compared with RASIs plus diuretics, RASIs plus CCBs decreased total cardiovascular (CV) events (relative risk (RR) 0.82, 95% confidence interval (CI): 0.75, 0.91, adjusted RR (ARR) 1.7%) and withdrawals due to adverse effect (WDAE) (RR 0.87, 95% CI: 0.80, 0.94, ARR 1.3%). Compared with CCBs plus diuretics, RASIs plus CCBs decreased WDAE (RR 0.63, 95% CI: 0.45, 0.90, ARR 1.1%). Our meta-analysis indicates that RASIs plus CCBs provide a superior safety and prevention of CV events to RASIs plus diuretics, whereas this combination is also safer than CCBs plus diuretics. We also raise a new hypothesis. More high-quality RCTs focused on hard end points with CV, cerebrovascular and renal events are needed to confirm the hypothesis we have brought out.

  15. Role of neurons and glia in the CNS actions of the renin-angiotensin system in cardiovascular control.

    PubMed

    de Kloet, Annette D; Liu, Meng; Rodríguez, Vermalí; Krause, Eric G; Sumners, Colin

    2015-09-01

    Despite tremendous research efforts, hypertension remains an epidemic health concern, leading often to the development of cardiovascular disease. It is well established that in many instances, the brain plays an important role in the onset and progression of hypertension via activation of the sympathetic nervous system. Further, the activity of the renin-angiotensin system (RAS) and of glial cell-mediated proinflammatory processes have independently been linked to this neural control and are, as a consequence, both attractive targets for the development of antihypertensive therapeutics. Although it is clear that the predominant effector peptide of the RAS, ANG II, activates its type-1 receptor on neurons to mediate some of its hypertensive actions, additional nuances of this brain RAS control of blood pressure are constantly being uncovered. One of these complexities is that the RAS is now thought to impact cardiovascular control, in part, via facilitating a glial cell-dependent proinflammatory milieu within cardiovascular control centers. Another complexity is that the newly characterized antihypertensive limbs of the RAS are now recognized to, in many cases, antagonize the prohypertensive ANG II type 1 receptor (AT1R)-mediated effects. That being said, the mechanism by which the RAS, glia, and neurons interact to regulate blood pressure is an active area of ongoing research. Here, we review the current understanding of these interactions and present a hypothetical model of how these exchanges may ultimately regulate cardiovascular function.

  16. Regulation of nonclassical renin-angiotensin system receptor gene expression in the adrenal medulla by acute and repeated immobilization stress.

    PubMed

    Nostramo, Regina; Serova, Lidia; Laukova, Marcela; Tillinger, Andrej; Peddu, Chandana; Sabban, Esther L

    2015-03-15

    The involvement of the nonclassical renin-angiotensin system (RAS) in the adrenomedullary response to stress is unclear. Therefore, we examined basal and immobilization stress (IMO)-triggered changes in gene expression of the classical and nonclassical RAS receptors in the rat adrenal medulla, specifically the angiotensin II type 2 (AT2) and type 4 (AT4) receptors, (pro)renin receptor [(P)RR], and Mas receptor (MasR). All RAS receptors were identified, with AT2 receptor mRNA levels being the most abundant, followed by the (P)RR, AT1A receptor, AT4 receptor, and MasR. Following a single IMO, AT2 and AT4 receptor mRNA levels decreased by 90 and 50%, respectively. Their mRNA levels were also transiently decreased by repeated IMO. MasR mRNA levels displayed a 75% transient decrease as well. Conversely, (P)RR mRNA levels were increased by 50% following single or repeated IMO. Because of its abundance, the function of the (P)RR was explored in PC-12 cells. Prorenin activation of the (P)RR increased phosphorylation of extracellular signal-regulated kinase 1/2 and tyrosine hydroxylase at Ser(31), likely increasing its enzymatic activity and catecholamine biosynthesis. Together, the broad and dynamic changes in gene expression of the nonclassical RAS receptors implicate their role in the intricate response of the adrenomedullary catecholaminergic system to stress.

  17. Urinary Sodium Excretion Has Positive Correlation with Activation of Urinary Renin Angiotensin System and Reactive Oxygen Species in Hypertensive Chronic Kidney Disease

    PubMed Central

    Ahn, Shin-Young; Kim, Sejoong; Kim, Dong Ki; Shin, Sung Joon; Lee, Sang Ho; Choi, Bum Soon; Lim, Chun Soo

    2014-01-01

    It is not well described the pathophysiology of renal injuries caused by a high salt intake in humans. The authors analyzed the relationship between the 24-hr urine sodium-to-creatinine ratio (24HUna/cr) and renal injury parameters such as urine angiotensinogen (uAGT/cr), monocyte chemoattractant peptide-1 (uMCP1/cr), and malondialdehyde-to-creatinine ratio (uMDA/cr) by using the data derived from 226 hypertensive chronic kidney disease patients. At baseline, the 24HUna/cr group or levels had a positive correlation with uAGT/cr and uMDA/cr adjusted for related factors (P<0.001 for each analysis). When we estimated uAGT/cr in the 24HUna/cr groups by ANCOVA, the uAGT/cr in patients with ≥200 mEq/g cr was higher than in patients with <100 mEq/g cr (708 [95% CI, 448-967] vs. 334 [95% CI, 184-483] pg/mg cr, P=0.014). Similarly, uMDA/cr was estimated as 0.17 (95% CI, 0.14-0.21) pM/mg cr in patients with <100 mEq/g cr and 0.27 (95% CI, 0.20-0.33) pM/mg cr in patients with ≥200 mEq/g cr (P=0.016). During the 16-week follow-up period, an increase in urinary sodium excretion predicted an increase in urinary angiotensinogen excretion. In conclusion, high salt intake increases renal renin-angiotensin-system (RAS) activation, primarily, and directly or indirectly affects the production of reactive oxygen species through renal RAS activation. PMID:25317016

  18. High pulse pressure is not associated with abnormal activation of the renin-angiotensin-aldosterone system in repaired aortic coarctation.

    PubMed

    Pedersen, T A L; Pedersen, E B; Munk, K; Hjortdal, V E; Emmertsen, K; Andersen, N H

    2015-04-01

    We investigated the relationship between pulse pressure (PP)--a surrogate marker of arterial stiffness-and activity of the renin-angiotensin-aldosterone system (RAAS) in adult patients with repaired coarctation and normal left ventricular (LV) function. A total of 114 patients (44 (26-74) years, 13 (0.1-40) years at repair) and 20 healthy controls were examined with 24-h ambulatory blood pressure monitoring, echocardiography, vasoactive hormone levels and magnetic resonance of the thoracic aorta. Forty-one patients (36%) were taking antihypertensives (28 RAAS inhibitors). Fifty-one had mean 24-h blood pressures >130/80 mm Hg. Hypertension was not associated with age at repair (P=0.257). Patients had higher PP and LV mass compared with controls (52±11 vs. 45±5 mm Hg and 221±71 vs. 154±55 g, respectively; both P<0.05). Differences were more pronounced in the presence of recoarctation, but independently of RAA levels. Even normotensive patients had higher LV mass than controls. LV mass and recoarctation were correlated with PP levels. In conclusion, adult patients with repaired coarctation have increased PP and LV mass compared with controls. PP increased with increasing recoarctation. Hypertension was present also in the absence of recoarctation. These changes could not be explained by abnormal activation of the RAAS.

  19. Evaluation of the contribution of renin angiotensin system polymorphisms to the risk of coronary artery disease among Tunisians.

    PubMed

    Abboud, Nesrine; Ghazouani, Lakhder; Kaabi, Belhassen; Ben-Hadj-Khalifa, Sonia; Addad, Fawzi; Marwen, Mahjoub; Almawi, Wassim Y; Mahjoub, Touhami

    2010-10-01

    Recent studies have identified genetic markers that may directly influence the risk of the coronary artery disease (CAD), in particular the renin angiotensin system genes. Since there are no existing data for the Tunisian population, we investigated the association between these polymorphisms (angiotensin-converting enzyme [ACE] insertion/deletion [Ins/Del]; the angiotensinogen T174M and M235T; and the angiotensin II type 1 receptor A1166C polymorphisms) and CAD in Tunisians. Study subjects comprised 341 cases and 316 age- and sex-matched healthy individuals. Clinical characteristics and other biochemical and environmental risk factors were collected for both. The distribution of the Ins/Del genotypes was significantly different between cases and controls (p = 0.049) with the genotype Ins/Ins identified as a risk, p = 0.02. Similarly, the distributions of the T174M and M235T genotypes were significantly different between cases and controls (p = 0.037 and 0.047, respectively) with 174 M/M and 235 T/T as the risky genotypes (p = 0.001 and 0.026, respectively). However, A1166C genotype frequencies were not significantly different between patients and controls. In conclusion, our results suggest that a significantly higher risk of CAD was associated with the Ins/Del, the M235T, and T174M polymorphisms; other environmental variables such as body mass index; and biochemical variables such as cholesterol.

  20. Renin angiotensin system-regulating aminopeptidase activities in serum of pre- and postmenopausal women with breast cancer.

    PubMed

    Martínez-Martos, José Manuel; del Pilar Carrera-González, María; Dueñas, Basilio; Mayas, María Dolores; García, María Jesús; Ramírez-Expósito, María Jesús

    2011-10-01

    Angiotensin peptides regulate vascular tone and natriohydric balance through the renin angiotensin system (RAS) and are related with the angiogenesis which plays an important role in the metastatic pathway. Estrogen influences the aminopeptidases (APs) involved in the metabolism of bioactive peptides of RAS through several pathways. We analyze RAS-regulating AP activities in serum of pre- and postmenopausal women with breast cancer to evaluate the putative value of these activities as biological markers of the development of breast cancer. We observed an increase in aminopeptidase N (APN) and aminopeptidase B (APB) activities in women with breast cancer; however, a decrease in aspartyl-aminopeptidase (AspAP) activity in premenopausal women. These results suggest a slow metabolism of angiotensin II (Ang II) to angiotensin III (Ang III) in premenopausal women and a rapid metabolism of Ang III to angiotensin IV (Ang IV) in pre- and postmenopausal women with breast cancer. An imbalance in the signals activated by Ang II may produce abnormal vascular growth with different response between pre- and postmenopausal women depending on the hormonal profile and the development of the disease.

  1. Effects of Local Pancreatic Renin-Angiotensin System on the Microcirculation of Rat with Severe Acute Pancreatitis

    PubMed Central

    Feng, Ling; Long, Haocheng; Wang, Hui; Feng, Jiarui; Chen, Feixiang

    2015-01-01

    Severe acute pancreatitis (SAP) is normally related to multiorgan dysfunction and local complications. Studies have found that local pancreatic renin-angiotensin system (RAS) was significantly upregulated in drug-induced SAP. The present study aimed to investigate the effects of angiotensin II receptors inhibitor valsartan on dual role of RAS in SAP in a rat model and to elucidate the underlying mechanisms. 3.8% sodium taurocholate (1 ml/kg) was injected to the pancreatic capsule in order for pancreatitis induction. Rats in the sham group were injected with normal saline in identical locations. We also investigated the regulation of experimentally induced SAP on local RAS expression in the pancreas through determination of the activities of serum amylase, lipase and myeloperoxidase, histological and biochemical analysis, radioimmunoassay, fluorescence quantitative PCR and Western blot analysis. The results indicated that valsartan could effectively suppress the local RAS to protect against experimental acute pancreatitis through inhibition of microcirculation disturbances and inflammation. The results suggest that pancreatic RAS plays a critical role in the regulation of pancreatic functions and demonstrates application potential as AT1 receptor antagonists. Moreover, other RAS inhibitors could be a new therapeutic target in acute pancreatitis. PMID:26170733

  2. Exercise Training Improves the Altered Renin-Angiotensin System in the Rostral Ventrolateral Medulla of Hypertensive Rats

    PubMed Central

    Ren, Chang-zhen; Yang, Ya-Hong; Sun, Jia-cen; Wu, Zhao-Tang; Zhang, Ru-Wen; Shen, Du; Wang, Yang-Kai

    2016-01-01

    The imbalance between angiotensin II (Ang II) and angiotensin 1–7 (Ang 1–7) in the brain has been reported to contribute to cardiovascular dysfunction in hypertension. Exercise training (ExT) is beneficial to hypertension and the mechanism is unclear. This study was aimed to determine if ExT improves hypertension via adjusting renin angiotensin system in cardiovascular centers including the rostral ventrolateral medulla (RVLM). Spontaneously hypertensive rats (SHR, 8 weeks old) were subjected to low-intensity ExT or kept sedentary (Sed) for 12 weeks. Blood pressure elevation coupled with increase in age was significantly decreased in SHR received ExT compared with Sed. The results in vivo showed that ExT significantly reduced or increased the cardiovascular responses to central application of sarthran (antagonist of Ang II) or A779 (antagonist of Ang 1–7), respectively. The protein expression of the Ang II acting receptor AT1R and the Ang 1–7 acting receptor Mas in the RVLM was significantly reduced and elevated in SHR following ExT, respectively. Moreover, production of reactive oxygen species in the RVLM was significantly decreased in SHR following ExT. The current data suggest that ExT improves hypertension via improving the balance of Ang II and Ang 1–7 and antioxidative stress at the level of RVLM. PMID:26881037

  3. Role of the renin-angiotensin system in the nandrolone-decanoate-induced attenuation of the Bezold-Jarisch reflex.

    PubMed

    Andrade, Tadeu Uggere; Uggere de Andrade, Tadeu; Loiola, Leonardo Zanoteli; Alcure, Samira Merces Nascimento; Medeiros, Ana Raquel Santos; Santos, Maria Carmen Lopes Ferreira Silva; Moysés, Margareth Ribeiro; Abreu, Gláucia Rodrigues de; Lenz, Dominik; Bissoli, Nazaré Souza

    2011-12-01

    The androgen nandrolone decanoate (ND) is known to cause cardiovascular abnormalities, such as attenuation of the Bezold-Jarisch Reflex (BJR), cardiac hypertrophy, and elevation of mean arterial pressure (MAP). Futhermore, a relationship between androgens and the renin-angiotensin system (RAS) has been reported. The purpose of this study was to evaluate the influence of RAS on the BJR, cardiac and prostatic hypertrophy, and MAP evoked by ND. For this, male Wistar rats were treated with ND (10 mg·(kg body mass)(-1) for 8 weeks; DECA), or vehicle (control animals; CON), or enalapril (10 mg·(kg body mass)(-1), daily; CONE), or ND and enalapril (10 mg ND + 10 mg enalapril per kilogram of body mass; DECAE). After 8 weeks of treatment, the BJR was evaluated by bradycardia and hypotensive responses that were elicited by serotonin administration (2-32 µg·(kg body mass)(-1)). MAP was assessed; cardiac and prostate hypertrophy were determined by the ratio of the tissue mass:body mass, and by histological analysis of the heart. Animals from the DECA group showed prostatic and cardiac hypertrophy, elevation in mean arterial pressure, and an impairment of BJR. Co-treatment with enalapril inhibited these changes. The data from the present study suggest that RAS has an impact on BJR attenuation, cardiac and prostatic hypertrophy, and the elevation in MAP evoked by ND.

  4. Role of MicroRNAs in Renin-Angiotensin-Aldosterone System-Mediated Cardiovascular Inflammation and Remodeling

    PubMed Central

    Tchounwou, Paul B.

    2015-01-01

    MicroRNAs are endogenous regulators of gene expression either by inhibiting translation or protein degradation. Recent studies indicate that microRNAs play a role in cardiovascular disease and renin-angiotensin-aldosterone system- (RAAS-) mediated cardiovascular inflammation, either as mediators or being targeted by RAAS pharmacological inhibitors. The exact role(s) of microRNAs in RAAS-mediated cardiovascular inflammation and remodeling is/are still in early stage of investigation. However, few microRNAs have been shown to play a role in RAAS signaling, particularly miR-155, miR-146a/b, miR-132/122, and miR-483-3p. Identification of specific microRNAs and their targets and elucidating microRNA-regulated mechanisms associated RAS-mediated cardiovascular inflammation and remodeling might lead to the development of novel pharmacological strategies to target RAAS-mediated vascular pathologies. This paper reviews microRNAs role in inflammatory factors mediating cardiovascular inflammation and RAAS genes and the effect of RAAS pharmacological inhibition on microRNAs and the resolution of RAAS-mediated cardiovascular inflammation and remodeling. Also, this paper discusses the advances on microRNAs-based therapeutic approaches that may be important in targeting RAAS signaling. PMID:26064773

  5. Involvement of Renin-Angiotensin System in Damage of Angiotensin-Converting Enzyme Inhibitor Captopril on Bone of Normal Mice.

    PubMed

    Liu, Jin-Xin; Wang, Liang; Zhang, Yan

    2015-01-01

    This study was performed to investigate the effect of angiotensin-converting enzyme inhibitor, captopril, on bone metabolism and histology, and the action of captopril on the components of the skeletal renin-angiotensin system (RAS) and bradykinin receptor in normal male mice. The mice were orally administered captopril (10 mg/kg) for 4 weeks with vehicle-treated mice as normal control. The histology of trabecular bone at the distal femoral end was determined by hematoxylin & eosin, Safranin O and Masson-Trichrome staining. The captopril-treated mice showed a decreased level of testosterone (p<0.05) and procollagen type I N-terminal propeptide (p<0.05) in serum as compared to those in the control group. Captopril has detrimental effects on trabecular bone as demonstrated by the loss of cancellous bone mass and network connections as well as changes to the chondrocytes zone. The expression of angiotensin-converting enzyme (p<0.05), renin receptor (p<0.01), angiotensin II (p<0.05) and bradykinin receptor 2 (p<0.05) was significantly up-regulated following the captopril treatment. Thus, the potential underlying mechanism of the damage of captopril on bone can be attributed the increased activity of local bone RAS and the activation of bradykinin receptor.

  6. The PGE(2)-EP4 receptor is necessary for stimulation of the renin-angiotensin-aldosterone system in response to low dietary salt intake in vivo.

    PubMed

    Pöschke, Antje; Kern, Niklas; Maruyama, Takayuki; Pavenstädt, Hermann; Narumiya, Shuh; Jensen, Boye L; Nüsing, Rolf M

    2012-11-15

    Increased cyclooxygenase-2 (COX-2) expression and PGE(2) synthesis have been shown to be prerequisites for renal renin release after Na(+) deprivation. To answer the question of whether EP4 receptor type of PGE(2) mediates renin regulation under a low-salt diet, we examined renin regulation in EP4(+/+), EP4(-/-), and in wild-type mice treated with EP4 receptor antagonist. After 2 wk of a low-salt diet (0.02% wt/wt NaCl), EP4(+/+) mice showed diminished Na(+) excretion, unchanged K(+) excretion, and reduced Ca(2+) excretion. Diuresis and plasma electrolytes remained unchanged. EP4(-/-) exhibited a similar attenuation of Na(+) excretion; however, diuresis and K(+) excretion were enhanced, and plasma Na(+) concentration was higher, whereas plasma K(+) concentration was lower compared with control diet. There were no significant differences between EP4(+/+) and EP4(-/-) mice in blood pressure, creatinine clearance, and plasma antidiuretic hormone (ADH) concentration. Following salt restriction, plasma renin and aldosterone concentrations and kidney renin mRNA level rose significantly in EP4(+/+) but not in EP4(-/-) and in wild-type mice treated with EP4 antagonist ONO-AE3-208. In the latter two groups, the low-salt diet caused a significantly greater rise in PGE(2) excretion. Furthermore, mRNA expression for COX-2 and PGE(2) synthetic activity was significantly greater in EP4(-/-) than in EP4(+/+) mice. We conclude that low dietary salt intake induces expression of COX-2 followed by enhanced renal PGE(2) synthesis, which stimulates the renin-angiotensin-aldosterone system by activation of EP4 receptor. Most likely, defects at the step of EP4 receptor block negative feedback mechanisms on the renal COX system, leading to persistently high PGE(2) levels, diuresis, and K(+) loss.

  7. 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

  8. 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.

  9. Estrogen regulation of the brain renin-angiotensin system in protection against angiotensin II-induced sensitization of hypertension.

    PubMed

    Xue, Baojian; Zhang, Zhongming; Beltz, Terry G; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2014-07-15

    This study investigated sex differences in the sensitization of angiotensin (ANG) II-induced hypertension and the role of central estrogen and ANG-(1-7) in this process. Male and female rats were implanted for telemetered blood pressure (BP) recording. A subcutaneous subpressor dose of ANG II was given alone or concurrently with intracerebroventricular estrogen, ANG-(1-7), an ANG-(1-7) receptor antagonist A-779 or vehicle for 1 wk (induction). After a 1-wk rest (delay), a pressor dose of ANG II was given for 2 wk (expression). In males and ovariectomized females, subpressor ANG II had no sustained effect on BP during induction, but produced an enhanced hypertensive response to the subsequent pressor dose of ANG II during expression. Central administration of estrogen or ANG-(1-7) during induction blocked ANG II-induced sensitization. In intact females, subpressor ANG II treatment produced a decrease in BP during induction and delay, and subsequent pressor ANG II treatment given during expression produced only a slight but significant increase in BP. However, central blockade of ANG-(1-7) by intracerebroventricular infusion of A-779 during induction restored the decreased BP observed in females during induction and enhanced the pressor response to the ANG II treatment during expression. RT-PCR analyses indicated that estrogen given during induction upregulated mRNA expression of the renin-angiotensin system (RAS) antihypertensive components, whereas both central estrogen and ANG-(1-7) downregulated mRNA expression of RAS hypertensive components in the lamina terminalis. The results indicate that females are protected from ANG II-induced sensitization through central estrogen and its regulation of brain RAS.

  10. 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.

  11. Characterization of the cardiac renin angiotensin system in oophorectomized and estrogen-replete mRen2.Lewis rats.

    PubMed

    Wang, Hao; Jessup, Jewell A; Zhao, Zhuo; Da Silva, Jaqueline; Lin, Marina; MacNamara, Lindsay M; Ahmad, Sarfaraz; Chappell, Mark C; Ferrario, Carlos M; Groban, Leanne

    2013-01-01

    The cardioprotective effects of estrogen are well recognized, but the mechanisms remain poorly understood. Accumulating evidence suggests that the local cardiac renin-angiotensin system (RAS) is involved in the development and progression of cardiac hypertrophy, remodeling, and heart failure. Estrogen attenuates the effects of an activated circulating RAS; however, its role in regulating the cardiac RAS is unclear. Bilateral oophorectomy (OVX; n = 17) or sham-operation (Sham; n = 13) was performed in 4-week-old, female mRen2.Lewis rats. At 11 weeks of age, the rats were randomized and received either 17 β-estradiol (E2, 36 µg/pellet, 60-day release, n = 8) or vehicle (OVX-V, n = 9) for 4 weeks. The rats were sacrificed, and blood and hearts were used to determine protein and/or gene expression of circulating and tissue RAS components. E2 treatment minimized the rise in circulating angiotensin (Ang) II and aldosterone produced by loss of ovarian estrogens. Chronic E2 also attenuated OVX-associated increases in cardiac Ang II, Ang-(1-7) content, chymase gene expression, and mast cell number. Neither OVX nor OVX+E2 altered cardiac expression or activity of renin, angiotensinogen, angiotensin-converting enzyme (ACE), and Ang II type 1 receptor (AT1R). E2 treatment in OVX rats significantly decreased gene expression of MMP-9, ACE2, and Ang-(1-7) mas receptor, in comparison to sham-operated and OVX littermates. E2 treatment appears to inhibit upsurges in cardiac Ang II expression in the OVX-mRen2 rat, possibly by reducing chymase-dependent Ang II formation. Further studies are warranted to determine whether an E2-mediated reduction in cardiac chymase directly contributes to this response in OVX rats.

  12. 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

    2017-01-26

    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.

  13. Aberrant Activation of the Intrarenal Renin-Angiotensin System in the Developing Kidneys of Type 2 Diabetic Rats

    PubMed Central

    Fan, Y.-Y.; Kobori, H.; Nakano, D.; Hitomi, H.; Mori, H.; Masaki, T.; Sun, Y.-X.; Zhi, N.; Zhang, L.; Huang, W.; Zhu, B.; Li, P.; Nishiyama, A.

    2013-01-01

    We have previously reported that intrarenal angiotensin II (Ang II) levels are increased long before diabetes becomes apparent in obese Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a model of type 2 diabetes. In this study, we examined the changes in intrarenal renin-angiotensin system (RAS) activity in the developing kidneys of OLETF rats. Ang II contents and mRNA levels of RAS components were measured in male OLETF and control Long-Evans Tokushima (LETO) rats at postnatal days (PND) 1, 5, and 15, and at 4–30 weeks of age. In both LETO and OLETF rats, kidney Ang II levels peaked at PND 1, then decreased during the pre- and post-weaning periods. However, Ang II levels and gene expression of RAS components, including angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE), were not significantly different between LETO and OLETF rats. Intrarenal Ang II contents further decreased during puberty (from 7 to 11 weeks of age) in LETO rats, bur not in OLETF rats. At 11 weeks of age, kidney Ang II levels, urinary AGT excretion, and mRNA levels of AGT and renin were higher in OLETF rats than in LETO rats, while blood glucose levels were not significantly different between these groups of rats. These data indicate that continued intrarenal expression of Ang II during pubescence contributes to the increases in intrarenal Ang II levels in prediabetic OLETF rats, and is associated with increased intrarenal AGT and renin expression. Inappropriate activation of the intrarenal RAS in the prediabetic stage may facilitate the onset and development of diabetic nephropathy in later life. PMID:23322513

  14. Central renin-angiotensin system activation and inflammation induced by high fat diet sensitize angiotensin II-elicited hypertension

    PubMed Central

    Xue, Baojian; Thunhorst, Robert L.; Yu, Yang; Guo, Fang; Beltz, Terry G.; Felder, Robert B.; Johnson, Alan Kim

    2016-01-01

    Obesity has been shown to promote renin-angiotensin system (RAS) activity and inflammation in the brain and to be accompanied by increased sympathetic activity and blood pressure (BP). Our previous studies demonstrated that administration of a subpressor dose of angiotensin (Ang) II sensitizes subsequent Ang II-elicited hypertension. The present study tested whether high fat diet (HFD) feeding also sensitizes the Ang II-elicited hypertensive response and whether HFD-induced sensitization is mediated by an increase in RAS activity and inflammatory mechanisms in the brain. HFD did not increase baseline BP, but enhanced the hypertensive response to Ang II compared to a normal fat diet. The sensitization produced by the HFD was abolished by concomitant central infusions of either a tumor necrosis factor α (TNF-α) synthesis inhibitor, pentoxifylline, an Ang II type 1 receptor (AT1-R) blocker, irbesartan or an inhibitor of microglial activation, minocycline. Furthermore, central pretreatment with TNF-α mimicked the sensitizing action of a central subpressor dose of Ang II, whereas central pentoxifylline or minocycline abolished this Ang II-induced sensitization. RT-PCR analysis of lamina terminalis tissue indicated that HFD feeding, central TNF-α or a central subpressor dose of Ang II upregulated mRNA expression of several components of the RAS and proinflammatory cytokines, whereas inhibition of AT1-R and of inflammation reversed these changes. The results suggest that HFD-induced sensitization of Ang II-elicited hypertension is mediated by upregulation of the brain RAS and of central proinflammatory cytokines. PMID:26573717

  15. Estrogen regulation of the brain renin-angiotensin system in protection against angiotensin II-induced sensitization of hypertension

    PubMed Central

    Zhang, Zhongming; Beltz, Terry G.; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2014-01-01

    This study investigated sex differences in the sensitization of angiotensin (ANG) II-induced hypertension and the role of central estrogen and ANG-(1–7) in this process. Male and female rats were implanted for telemetered blood pressure (BP) recording. A subcutaneous subpressor dose of ANG II was given alone or concurrently with intracerebroventricular estrogen, ANG-(1–7), an ANG-(1–7) receptor antagonist A-779 or vehicle for 1 wk (induction). After a 1-wk rest (delay), a pressor dose of ANG II was given for 2 wk (expression). In males and ovariectomized females, subpressor ANG II had no sustained effect on BP during induction, but produced an enhanced hypertensive response to the subsequent pressor dose of ANG II during expression. Central administration of estrogen or ANG-(1–7) during induction blocked ANG II-induced sensitization. In intact females, subpressor ANG II treatment produced a decrease in BP during induction and delay, and subsequent pressor ANG II treatment given during expression produced only a slight but significant increase in BP. However, central blockade of ANG-(1–7) by intracerebroventricular infusion of A-779 during induction restored the decreased BP observed in females during induction and enhanced the pressor response to the ANG II treatment during expression. RT-PCR analyses indicated that estrogen given during induction upregulated mRNA expression of the renin-angiotensin system (RAS) antihypertensive components, whereas both central estrogen and ANG-(1–7) downregulated mRNA expression of RAS hypertensive components in the lamina terminalis. The results indicate that females are protected from ANG II-induced sensitization through central estrogen and its regulation of brain RAS. PMID:24858844

  16. 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

  17. 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

  18. A NOVEL ROLE FOR MIR-133A IN CENTRALLY MEDIATED ACTIVATION OF THE RENIN-ANGIOTENSIN SYSTEM IN CONGESTIVE HEART FAILURE.

    PubMed

    Sharma, Neeru M; Nandi, Shyam Sundar; Zheng, Hong; Mishra, Paras K; Patel, Kaushik P

    2017-03-10

    Activated renin-angiotensin system (RAS) within the central nervous system has been implicated in sympathoexcitation during various disease conditions including congestive heart failure (CHF). In particular, activation of RAS in the paraventricular nucleus (PVN) of the hypothalamus has been recognized to augment sympathoexcitation in CHF. We observed a 2.6-fold increase in angiotensinogen (AGT) in the PVN of CHF. To elucidate the molecular mechanism for increased expression of AGT, we performed in silico analysis of 3'-untranslated region (3'UTR) of AGT and found potential binding site for microRNA-133a(miR-133a). We hypothesized that decreased miR-133a might contribute to increased AGT in the PVN of CHF rats. Overexpression of miR-133a in NG108 cells resulted in 1.4 and 1.5 fold decreases in AGT and Ang II-type1 receptor (AT1) mRNA levels, respectively. Luciferase reporter assay performed on NG108 cells confirmed miR-133a binding to 3'-UTR of AGT. Further, we observed a 1.9-fold decrease in miR-133a expression with a concomitant increase in AGT and AT1R expression within the PVN of CHF rats. Furthermore, restoring the levels of miR-133a within the PVN of CHF rats with viral transduction resulted in significant reduction of AGT(1.4-fold) and AT1R(1.5-fold) levels with a concomitant decrease in basal renal sympathetic nerve activity (RSNA). Restoration of miR-133a also abrogated the enhanced RSNA responses to Ang II microinjections within the PVN of CHF rats. These results reveal a novel and potentially unique role for miR-133a in the regulation of AngII within the PVN of CHF rats, which may potentially contribute to the commonly observed sympathoexcitation in CHF.

  19. Antiproteinuric effect of cilnidipine in hypertensive Japanese treated with renin-angiotensin-system inhibitors - a multicenter, open, randomized trial using 24-hour urine collection.

    PubMed

    Miwa, Yoshikazu; Tsuchihashi, Takuya; Ohta, Yuko; Tominaga, Mitsuhiro; Kawano, Yuhei; Sasaguri, Toshiyuki; Ueno, Michio; Matsuoka, Hiroaki

    2010-01-01

    Sustained proteinuria is an important risk factor for not only renal but also cardiovascular morbidity and mortality. Although inhibitors of the renin-angiotensin system (RAS) have been shown to reduce proteinuria. Monotherapy with those drugs is often insufficient for optimal blood pressure (BP)-lowering and therefore, combined therapy is needed. Recent reports suggested that cilnidipine, a dual L-/N-type calcium channel blocker, has renoprotective effect by dilating both efferent and afferent arterioles. In this study, a multicenter, open, randomized trial was designed to compare the antiproteinuric effect between cilnidipine and amlodipine when coupled with RAS inhibitors in hypertensive patients with significant proteinuria. Proteinuria was evaluated by 24-h home urine collection for all patients. A total of 35 proteinuric (>0.1 g/day) patients with uncontrolled BP (>135/85 mmHg) were randomized to receive either cilnidipine (n = 18) or amlodipine (n = 17) after a 6-month treatment with RAS inhibitors and were followed for 48 weeks. At baseline, the cilnidipine group was older and had lower body mass index (BMI) compared to the amlodipine group. After 32 weeks of treatment, diastolic blood pressure (DBP) was slightly, but significantly reduced, in the cilnidipine group, although systolic blood pressure (SBP) and mean BP did not differ. The urinary protein did not differ at baseline (cilnidipine group 0.48 g/day, amlodipine group 0.52 g/day); however, it significantly decreased in the cilnidipine group (0.22 g/day) compared to the amlodipine group (0.50 g/day) after 48 weeks of treatment. Our findings suggest that cilnidipine is superior to amlodipine in preventing the progression of proteinuria in hypertensive patients even undergoing treatment with RAS inhibitors.

  20. Addition of hydrochlorothiazide to angiotensin receptor blocker therapy can achieve a lower sodium balance with no acceleration of intrarenal renin angiotensin system in patients with chronic kidney disease

    PubMed Central

    Fuwa, Daisuke; Fukuda, Michio; Ogiyama, Yoshiaki; Sato, Ryo; Mizuno, Masashi; Miura, Toshiyuki; Abe-Dohmae, Sumiko; Michikawa, Makoto; Kobori, Hiroyuki; Ohte, Nobuyuki

    2016-01-01

    Objective Angiotensin receptor blockers (ARBs) produce a lower sodium (Na) balance, and the natriuretic effect is enhanced under Na deprivation, despite falls in blood pressure (BP) and glomerular filtration rate (GFR). Methods The effect of additional hydrochlorothiazide (HCTZ; 12.5 mg/day) to ARB treatment (valsartan; 80 mg/day) on glomerulotubular Na balance was evaluated in 23 patients with chronic kidney disease. Results Add-on HCTZ decreased GFR, tubular Na load, and tubular Na reabsorption (tNa), although 24-hour urinary Na excretion (UNaV) remained constant. Daily urinary angiotensinogen excretion (UAGTV, 152±10→82±17 μg/g Cre) reduced (p=0.02). Changes in tubular Na load (r2=0.26) and tNa (r2=0.25) correlated with baseline 24-hour UAGTV. Changes in filtered Na load correlated with changes in nighttime systolic BP (r2=0.17), but not with changes in daytime systolic BP. The change in the tNa to filtered Na load ratio was influenced by the change in daytime UNaV (β=−0.67, F=16.8), rather than the change in nighttime UNaV. Conclusions Lower Na balance was produced by add-on HCTZ to ARB treatment without an increase of intra-renal renin-angiotensin system activity, leading to restoration of nocturnal hypertension. A further study is needed to demonstrate that the reduction of UAGTV by additional diuretics to ARBs prevents the progression of nephropathy or cardiovascular events. PMID:27283968

  1. 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

  2. Role of the renin-angiotensin system in control of sodium excretion and arterial pressure.

    PubMed

    Hall, J E; Guyton, A C; Mizelle, H L

    1990-01-01

    The RAS is part of an extremely powerful feedback system for long-term control of arterial pressure and volume homeostasis as illustrated in Figure 4. Disturbances that tend to lower blood pressure such as heart failure, cirrhosis, and peripheral vasodilation, cause sodium and water retention until blood pressure returns to normal due in large part to the combined actions of ANGII and reduced renal perfusion pressure. In response to disturbances such as high sodium intake, suppression of ANGII greatly amplifies the effectiveness of the basic pressure natriuresis and diuresis mechanism, thereby preventing large increases in body fluid volumes and blood pressure. In circumstances in which the RAS is inappropriately activated, the sodium-water retaining effects of ANGII necessitate increased blood pressure to maintain sodium and water balance via pressure natriuresis. The sodium retaining actions of the RAS are mediated by intrarenal as well as extrarenal mechanisms. The intrarenal actions of ANGII include a direct effect on tubular sodium transport as well as a potent constrictor action on efferent arterioles which increases tubular reabsorption by altering peritubular capillary physical forces. The constrictor action of ANGII on efferent arterioles also plays an important role in stabilizing GFR and therefore in preventing fluctuations in excretion of metabolic waste products that depend upon a high GFR for excretion. ANGII is known to stimulate proximal reabsorption, but the effects on more distal tubular segments have not been completely elucidated. The primary extra-known to stimulate proximal reabsorption, but the effects on more distal tubular segments have not been completely elucidated. The primary extra-renal effect of ANGII which influences sodium excretion is stimulation of aldosterone secretion. Current evidence, however, suggests that the various intrarenal actions of ANGII are quantitatively more important in causing sodium retention than those mediated

  3. The renin-angiotensin system. Normal physiology and changes in older hypertensives.

    PubMed

    Hall, J E; Coleman, T G; Guyton, A C

    1989-08-01

    The long-term effects of angiotensin (ANGII) on arterial pressure regulation appear to be closely linked to volume homeostasis, via the renal-pressure natriuresis mechanism, both in normal humans and in older hypertensives. In response to disturbances such as increased sodium intake, suppression of ANGII and aldosterone formation greatly amplifies the effectiveness of the pressure natriuresis mechanism, thereby preventing large increases in body fluid volumes and minimizing the rise in blood pressure needed to maintain sodium balance. When ANGII levels are inappropriately elevated, the antinatriuretic effects of ANGII cause increased arterial pressure, which then serves to maintain sodium and water balance via the pressure natriuresis mechanism. The primary intrarenal and extrarenal mechanisms by which ANGII controls renal excretion and arterial pressure include: (1) a direct effect of ANGII on tubular sodium transport; (2) a preferential constrictor action of ANGII on efferent arterioles, which increases sodium reabsorption by altering peritubular capillary physical forces (efferent arteriolar constriction also prevents excessive decreases in glomerular filtration rate when renal perfusion is compromised, such as in renal artery stenosis); and (3) extrarenal effects of ANGII, including stimulation of aldosterone secretion. Current evidence suggests that the direct effects of ANGII on the kidney are quantitatively more important than indirect effects mediated by aldosterone. In older hypertensives, plasma renin activity and aldosterone concentration are often suppressed, perhaps due to loss of functional nephrons and increased sodium chloride delivery to the macula densa of the remaining nephrons.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Statins and Renin Angiotensin System Inhibitors Dose-Dependently Protect Hypertensive Patients against Dialysis Risk

    PubMed Central

    Wu, Szu-Yuan

    2016-01-01

    Background Taiwan has the highest renal disease incidence and prevalence in the world. We evaluated the association of statin and renin–angiotensin system inhibitor (RASI) use with dialysis risk in hypertensive patients. Methods Of 248,797 patients who received a hypertension diagnosis in Taiwan during 2001–2012, our cohort contained 110,829 hypertensive patients: 44,764 who used RASIs alone; 7,606 who used statins alone; 27,836 who used both RASIs and statins; and 33,716 who used neither RASIs or statins. We adjusted for the following factors to reduce selection bias by using propensity scores (PSs): age; sex; comorbidities; urbanization level; monthly income; and use of nonstatin lipid-lowering drugs, metformin, aspirin, antihypertensives, diuretics, and beta and calcium channel blockers. The statin and RASI use index dates were considered the hypertension confirmation dates. To examine the dose–response relationship, we categorized only statin or RASI use into four groups in each cohort: <28 (nonusers), 28–90, 91–365, and >365 cumulative defined daily doses (cDDDs). Results In the main model, PS-adjusted hazard ratios (aHRs; 95% confidence intervals [CIs]) for dialysis risk were 0.57 (0.50–0.65), 0.72 (0.53–0.98), and 0.47 (0.41–0.54) in the only RASI, only statin, and RASI + statin users, respectively. RASIs dose-dependently reduced dialysis risk in most subgroups and in the main model. RASI use significantly reduced dialysis risk in most subgroups, regardless of comorbidities or other drug use (P < 0.001). Statins at >365 cDDDs protected hypertensive patients against dialysis risk in the main model (aHR = 0.62, 95% CI: 0.54–0.71), regardless of whether a high cDDD of RASIs, metformin, or aspirin was used. Conclusion Statins and RASIs independently have a significant dose-dependent protective effect against dialysis risk in hypertensive patients. The combination of statins and RASIs can additively protect hypertensive patients against dialysis

  5. Comparison of the Antialbuminuric Effects of Benidipine and Hydrochlorothiazide in Renin-Angiotensin System (RAS) Inhibitor-Treated Hypertensive Patients with Albuminuria: the COSMO-CKD (COmbination Strategy on Renal Function of Benidipine or Diuretics TreatMent with RAS inhibitOrs in a Chronic Kidney Disease Hypertensive Population) Study

    PubMed Central

    Ando, Katsuyuki; Nitta, Kosaku; Rakugi, Hiromi; Nishizawa, Yoshiki; Yokoyama, Hitoshi; Nakanishi, Takeshi; Kashihara, Naoki; Tomita, Kimio; Nangaku, Masaomi; Takahashi, Katsutoshi; Isshiki, Masashi; Shimosawa, Tatsuo; Fujita, Toshiro

    2014-01-01

    Objective: This study evaluated the non-inferiority of renoprotection afforded by benidipine versus hydrochlorothiazide in hypertensive patients with chronic kidney disease (CKD). Methods: In this prospective, multicenter, open-labeled, randomized trial, the antialbuminuric effects of benidipine and hydrochlorothiazide were examined in renin-angiotensin system (RAS) inhibitor-treated patients with blood pressure (BP) readings of ≥ 130/80 mmHg and ≤ 180/110 mmHg, a urinary albumin to creatinine ratio (UACR) of ≥ 300 mg/g, and an estimated glomerular filtration rate (eGFR) of ≥ 30 ml/min/1.73m2. Patients received benidipine (n = 176, final dose: 4.8 mg/day) or hydrochlorothiazide (n = 170, 8.2 mg/day) for 12 months. Results: Benidipine and hydrochlorothiazide exerted similar BP- and eGFR-decreasing actions. The UACR values for benidipine and hydrochlorothiazide were 930.8 (95% confidence interval: 826.1, 1048.7) and 883.1 (781.7, 997.7) mg/g at baseline, respectively. These values were reduced to 790.0 (668.1, 934.2) and 448.5 (372.9, 539.4) mg/g at last observation carried forward (LOCF) visits. The non-inferiority of benidipine versus hydrochlorothiazide was not demonstrated (benidipine/hydrochlorothiazide ratio of LOCF value adjusted for baseline: 1.67 (1.40, 1.99)). Conclusions: The present study failed to demonstrate the non-inferiority of the antialbuminuric effect of benidipine relative to that of hydrochlorothiazide in RAS inhibitor-treated hypertensive patients with macroalbuminuria. PMID:25013370

  6. Angiotensin(1-7) and ACE2, “The Hot Spots” of Renin-Angiotensin System, Detected in the Human Aqueous Humor

    PubMed Central

    Holappa, Mervi; Valjakka, Jarkko; Vaajanen, Anu

    2015-01-01

    Background: The main purpose of the study was to establish whether essential components of the renin-angiotensin system (RAS) exist in the human aqueous humor. Methods: Forty-five patients ≥ 60 (74±7) years of age undergoing cataract surgery at Tampere University Hospital were randomly selected for the prospective study. The exclusion criterion was the use of oral antihypertensive medicine acting via renin-angiotensin system. Aqueous humor samples were taken at the beginning of normal cataract extraction. The samples were frozen and stored at -80 °C. The concentrations of intraocular endogenous RAS components Ang(1-7), ACE2, and ACE1 were measured using ELISA. Results: Concentration medians of Ang(1-7), ACE2, and ACE1 in the aqueous humor were: Ang(1-7) 4.08 ng/ml, ACE2 2.32 ng/ml and ACE1 0.35 ng/ml. The concentrations were significantly higher in glaucomatous than in non-glaucomatous eyes, ACE1 (p=0.014) and Ang(1-7) (p=0.026) vs non-glaucomatous eyes. Conclusions: Ang(1-7), ACE2 and ACE1 are found in the human aqueous humor. The observations are consistent with the conception that local tissue-RAS exists in the human eye and it might have a role in the control of intraocular pressure. PMID:25926900

  7. Medullary Endocannabinoids Contribute to the Differential Resting Baroreflex Sensitivity in Rats with Altered Brain Renin-Angiotensin System Expression

    PubMed Central

    Schaich, Chris L.; Grabenauer, Megan; Thomas, Brian F.; Shaltout, Hossam A.; Gallagher, Patricia E.; Howlett, Allyn C.; Diz, Debra I.

    2016-01-01

    CB1 cannabinoid receptors are expressed on vagal afferent fibers and neurons within the solitary tract nucleus (NTS), providing anatomical evidence for their role in arterial baroreflex modulation. To better understand the relationship between the brain renin-angiotensin system (RAS) and endocannabinoid expression within the NTS, we measured dorsal medullary endocannabinoid tissue content and the effects of CB1 receptor blockade at this brain site on cardiac baroreflex sensitivity (BRS) in ASrAOGEN rats with low glial angiotensinogen, normal Sprague-Dawley rats and (mRen2)27 rats with upregulated brain RAS expression. Mass spectrometry revealed higher levels of the endocannabinoid 2-arachidonoylglycerol in (mRen2)27 compared to ASrAOGEN rats (2.70 ± 0.28 vs. 1.17 ± 0.09 ng/mg tissue; P < 0.01), while Sprague-Dawley rats had intermediate content (1.85 ± 0.27 ng/mg tissue). Microinjection of the CB1receptor antagonist SR141716A (36 pmol) into the NTS did not change cardiac BRS in anesthetized Sprague-Dawley rats (1.04 ± 0.05 ms/mmHg baseline vs. 1.17 ± 0.11 ms/mmHg after 10 min). However, SR141716A in (mRen2)27 rats dose-dependently improved BRS in this strain: 0.36 pmol of SR141716A increased BRS from 0.43 ± 0.03 to 0.71 ± 0.04 ms/mmHg (P < 0.001), and 36 pmol of SR141716A increased BRS from 0.47 ± 0.02 to 0.94 ± 0.10 ms/mmHg (P < 0.01). In contrast, 0.36 pmol (1.50 ± 0.12 vs. 0.86 ± 0.08 ms/mmHg; P < 0.05) and 36 pmol (1.38 ± 0.16 vs. 0.46 ± 0.003 ms/mmHg; P < 0.01) of SR141716A significantly reduced BRS in ASrAOGEN rats. These observations reveal differential dose-related effects of the brain endocannabinoid system that influence cardiovagal BRS in animals with genetic alterations in the brain RAS. PMID:27375489

  8. Early apoptosis in different models of cardiac hypertrophy induced by high renin-angiotensin system activity involves CaMKII

    PubMed Central

    Velez Rueda, J. Omar; Mattiazzi, Alicia

    2012-01-01

    The objective of this study was to establish whether 1) hyperactivity of renin-angiotensin-aldosterone system (RAAS) produces apoptosis in early stages of cardiac disease; and 2) Ca2+-calmodulin-dependent protein kinase II (CaMKII) is involved in these apoptotic events. Two models of hypertrophy were used at an early stage of cardiac disease: spontaneously hypertensive rats (SHR) and isoproterenol-treated rats (Iso-rats). At 4 mo, SHR showed blood pressure, aldosterone serum levels, used as RAAS activity index, and left ventricular mass index, used as hypertrophy index, above control values by 84.2 ± 2.6 mmHg, 211.2 ± 25.8%, and 8.6 ± 1.1 mg/mm, respectively. There was also an increase in apoptotis (Bax-to-Bcl-2 ratio and terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling positive cells) associated with an enhancement of CaMKII activity with respect to age-matched controls (phosphorylated-CaMKII, 98.7 ± 14.1 above control). Similar results were observed in 4-mo-old Iso-rats. Cardiac function studied by echocardiography remained unaltered in all groups. Enalapril treatment significantly prevented hypertrophy, apoptosis, and CaMKII activity. Moreover, intracellular Ca2+ handling in isolated myocytes was similar between SHR, Iso-rats, and their aged-matched controls. However, SHR and Iso-rats showed a significant increase in superoxide anion generation (lucigenin) and lipid peroxidation (thiobarbituric acid reactive substance). In transgenic mice with targeted cardiomyocyte expression of a CaMKII inhibitory peptide (AC3-I) or a scrambled control peptide (AC3-C), Iso treatment increased thiobarbituric acid reactive substance in both strains, whereas it increased CaMKII activity and apoptosis only in AC3-C mice. Endogenous increases in RAAS activity induce ROS and CaMKII-dependent apoptosis in vivo. CaMKII activation could not be associated with intracellular Ca2+ increments and was directly related to the increase in oxidative stress. PMID

  9. 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; Parsons-Wingerter, Patricia; Oudit, Gavin Y.; Grant, Maria B.

    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

  10. Effect of the 5-hydroxytryptamine type 2 receptor antagonist, ketanserin, on blood pressure, the renin-angiotensin system and sympatho-adrenal function in patients with essential hypertension.

    PubMed Central

    Zabludowski, J R; Zoccali, C; Isles, C G; Murray, G D; Robertson, J I; Inglis, G C; Fraser, R; Ball, S G

    1984-01-01

    Ketanserin, a 5-HT type 2 receptor antagonist, was administered intravenously to nine patients with essential hypertension in a double-blind placebo controlled study to investigate the drug's effects on blood pressure, heart rate, the renin-angiotensin system and sympatho-adrenal function. Average blood-pressure for the group prior to injection of the drug was 150 +/- 7/94 +/- 4 (s.e. mean) mm Hg and decreased significantly (P less than 0.01) to 137 +/- 8/88 +/- 5 mm Hg during the 2 h after injection; heart rate increased immediately after injection of ketanserin, reaching a maximum of 81 +/- 4 beats/min. After drug administration systolic and diastolic blood pressure decreased on tilting, but the heart rate response was not different from that with placebo. Ketanserin did not affect the blood pressure response to graded infusion of the alpha 1-adrenoceptor agonist phenylephrine. Plasma active renin, angiotensin II and aldosterone concentrations increased slightly but not significantly after the drug; plasma noradrenaline increased transiently. 5-HT may be important in the maintenance of blood pressure but alternative mechanisms for the action of ketanserin in reducing blood pressure require investigation. PMID:6712863

  11. Acute effect of potassium canrenoate administration on renin-angiotensin, kallikrein-kinin and prostaglandin systems.

    PubMed

    Lahera, V; Cachofeiro, V; Duran, F; Cañizo, F J; Rodriguez, F J; Tresguerres, J A

    1988-01-01

    1. To investigate the possible effects of potassium canrenoate (PC) on plasma renin activity (PRA) and on renal prostaglandins (PGS) and kinins under elevated sodium and/or potassium intakes, a single dose of PC was administered to four groups of Wistar male rats. 2. They were fed a normal diet (C), a diet supplemented with 4% of NaCl, (Na), with 1% of KCl: (K) or both supplements (NaK). 3. PRA and urinary PGS excretion did not show changes after PC administration, but total urinary kinins showed higher values after the treatment in all groups. 4. A diuretic but not natriuretic effect was observed only in C animals. 5. In conclusion, the single dose of PC was able to stimulate urinary kinins and to spare potassium independently of dietary electrolyte supplements that were able to block the diuretic effect of the drug.

  12. Imaging the renin-angiotensin system: an important target of anti-hypertensive therapy.

    PubMed

    Kang, Jung Julie; Toma, Ildikó; Sipos, Arnold; McCulloch, Fiona; Peti-Peterdi, János

    2006-09-15

    Multiphoton fluorescence microscopy allows visualization, manipulation, and quantification of the structure-function relationships between pharmacological interventions and their physiological effects. The application of these methods to live animals permits direct observation of acute physical responses that lack chemically detectable signals in the blood or urine and would otherwise remain unknown. With the use of special fluorescent dyes, chemical/hormonal responses may also be detected. The delivery and site-specific effects of drugs can be monitored in real-time. The capacity to simultaneously visualize both proximal and distal segments of the nephron permits observation of the dynamic processes within the living kidney and a quantitative assessment of the various operations. Consequently, a clinically valuable and pending application for multi-photon microscopy will be to provide real-time, quantitative imaging of basic organ functions and their responses to therapeutic intervention. Imaging of the intra-renal renin content and enzymatic activity of renin in situ and in real-time is a new, more informative measure of RAS activity. Direct visualization of the molecular and cellular components of renin release signals and the interactions between the vascular endothelium, tubular epithelium, local mediators, and the renin producing cells provides great insight for drug development. Examples of how the effects of various RAS inhibitors can be visualized in the intact kidney are provided: including angiotensin converting enzyme inhibition (captopril), angiotensin II type 1 receptor blockade (olmesartan), and renin inhibition (aliskiren). The site-specific actions of diuretics, like furosemide, have also been visualized. Quantitative imaging of basic renal functions in health and disease can provide key information to assess the delivery and effects of pharmaceutical interventions.

  13. The Renin-Angiotensin-Aldosterone System in Vascular Inflammation and Remodeling

    PubMed Central

    Pacurari, Maricica; Kafoury, Ramzi; Tchounwou, Paul B.; Ndebele, Kenneth

    2014-01-01

    The RAAS through its physiological effectors plays a key role in promoting and maintaining inflammation. Inflammation is an important mechanism in the development and progression of CVD such as hypertension and atherosclerosis. In addition to its main role in regulating blood pressure and its role in hypertension, RAAS has proinflammatory and profibrotic effects at cellular and molecular levels. Blocking RAAS provides beneficial effects for the treatment of cardiovascular and renal diseases. Evidence shows that inhibition of RAAS positively influences vascular remodeling thus improving CVD outcomes. The beneficial vascular effects of RAAS inhibition are likely due to decreasing vascular inflammation, oxidative stress, endothelial dysfunction, and positive effects on regeneration of endothelial progenitor cells. Inflammatory factors such as ICAM-1, VCAM-1, TNFα, IL-6, and CRP have key roles in mediating vascular inflammation and blocking RAAS negatively modulates the levels of these inflammatory molecules. Some of these inflammatory markers are clinically associated with CVD events. More studies are required to establish long-term effects of RAAS inhibition on vascular inflammation, vascular cells regeneration, and CVD clinical outcomes. This review presents important information on RAAS's role on vascular inflammation, vascular cells responses to RAAS, and inhibition of RAAS signaling in the context of vascular inflammation, vascular remodeling, and vascular inflammation-associated CVD. Nevertheless, the review also equates the need to rethink and rediscover new RAAS inhibitors. PMID:24804145

  14. Uptitration of renin-angiotensin system blocker and beta-blocker therapy in patients hospitalized for heart failure with reduced versus preserved left ventricular ejection fractions.

    PubMed

    Verbrugge, Frederik H; Duchenne, Jürgen; Bertrand, Philippe B; Dupont, Matthias; Tang, W H Wilson; Mullens, Wilfried

    2013-12-15

    In ambulatory patients with heart failure (HF) and reduced ejection fraction (rEF), renin-angiotensin system (RAS) and β-blockers at guideline-recommended target dose reduce all-cause mortality and readmissions. Benefits in HF with preserved ejection fraction (pEF), as well as uptitration after a hospitalization, remain uncertain. This study assesses the impact of RAS- and β-blocker uptitrations in patients with HFrEF versus HFpEF during and immediately after a hospital admission. In consecutive patients (209 HFrEF with left ventricular ejection fraction <40% and 108 HFpEF with left ventricular ejection fraction ≥40%), RAS- and β-blocker dose changes were followed during 6 months after an index HF hospitalization. Patients with a RAS- and β-blocker dose increase of ≥10% of the recommended target dose were compared with patients without uptitration. Patients who received uptitration were significantly younger, with a higher heart rate and better renal function, and received spironolactone more often. Both RAS- and β-blocker uptitrations were associated with significant reductions in the composite end-point of all-cause mortality or HF readmissions in HFrEF (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.22 to 0.60 and HR 0.51, 95% CI 0.32 to 0.81, respectively). After correction for age, heart rate, blood pressure, renal function, and spironolactone use, this association remained significant for RAS blockers (HR 0.54, 95% CI 0.31 to 0.93, p = 0.027) but not for β-blockers (HR 0.65, 95% CI 0.39 to 1.09, p = 0.101). No benefit of RAS- or β-blocker uptitration was observed in HFpEF. In conclusion, uptitration of neurohumoral blockers after an HF hospitalization is more frequently performed in younger patients with low co-morbidity burden. RAS-blocker uptitration independently predicts clinical outcome in patients with HFrEF but not in those with HFpEF.

  15. Meta-analysis of effects of obstructive sleep apnea on the renin-angiotensin-aldosterone system

    PubMed Central

    Jin, Ze-Ning; Wei, Yong-Xiang

    2016-01-01

    Background Obstructive sleep apnea (OSA) is the most common cause of resistant hypertension, which has been proposed to result from activation of the renin–angiotensin–aldosterone system (RAAS). We meta-analyzed the effects of OSA on plasma levels of RAAS components. Methods Full-text studies published on MEDLINE and EMBASE analyzing fasting plasma levels of at least one RAAS component in adults with OSA with or without hypertension. OSA was diagnosed as an apnea-hypopnea index or respiratory disturbance index ≥ 5. Study quality was evaluated using the Newcastle-Ottawa Scale, and heterogeneity was assessed using the I2 statistic. Results from individual studies were synthesized using inverse variance and pooled using a random-effects model. Subgroup analysis, sensitivity analysis, and meta-regression were performed, and risk of publication bias was assessed. Results The meta-analysis included 13 studies, of which 10 reported results on renin (n = 470 cases and controls), 7 on angiotensin II (AngII, n = 384), and 9 on aldosterone (n = 439). AngII levels were significantly higher in OSA than in controls [mean differences = 3.39 ng/L, 95% CI: 2.00–4.79, P < 0.00001], while aldosterone levels were significantly higher in OSA with hypertension than OSA but not with hypertension (mean differences = 1.32 ng/dL, 95% CI: 0.58–2.07, P = 0.0005). Meta-analysis of all studies suggested no significant differences in aldosterone between OSA and controls, but a significant pooled mean difference of 1.35 ng/mL (95% CI: 0.88–1.82, P < 0.00001) emerged after excluding one small-sample study. No significant risk of publication bias was detected among all included studies. Conclusions OSA is associated with higher AngII and aldosterone levels, especially in hypertensive patients. OSA may cause hypertension, at least in part, by stimulating RAAS activity. PMID:27403143

  16. Hormonal status modifies renin-angiotensin system-regulating aminopeptidases and vasopressin-degrading activity in the hypothalamus-pituitary-adrenal axis of male mice.

    PubMed

    García, María Jesús; Martínez-Martos, José Manuel; Mayas, María Dolores; Carrera, María Pilar; Ramírez-Expósito, María Jesús

    2003-06-20

    Local renin-angiotensin systems (RAS) have been postulated in brain, pituitary and adrenal glands. These local RAS have been implicated, respectively, in the central regulation of the cardiovascular system and body water balance, the secretion of pituitary hormones and the secretion of aldosterone by adrenal glands. By other hand, it is known that the hypothalamus-pituitary-adrenal (HPA) axis is involved in blood pressure regulation, and is affected by sex hormones. The aim of the present work is to analyze the influence of testosterone on RAS-regulating aminopeptidase A, B and M activities and vasopressin-degrading activity in the HPA axis, measuring these activities in their soluble and membrane-bound forms in the hypothalamus, pituitary and adrenal glands of orchidectomized males and orchidectomized males treated subcutaneously with several doses of testosterone. The present data suggest that in male mice, testosterone influences the RAS- and vasopressin-degrading activities at all levels of the HPA axis.

  17. Hormonal status modifies renin-angiotensin system-regulating aminopeptidases and vasopressin-degrading activity in the hypothalamus-pituitary-adrenal axis of female mice.

    PubMed

    García, María Jesús; Martínez-Martos, José Manuel; Mayas, María Dolores; Carrera, María Pilar; De la Chica, Susana; Cortés, Pedro; Ramírez-Expósito, María Jesús

    2008-07-01

    The hypothalamus-pituitary-adrenal axis (HPA) participates in the maintenance of cardiovascular functions and in the control of blood pressure. By other hand, it is known that blood pressure regulation and HPA activity are affected by sex hormones. The aim of the present work is to analyze the influence of estradiol and progesterone on renin-angiotensin system (RAS)-regulating aminopeptidase A, aminopeptidase B and aminopeptidase N activities and vasopressin-degrading activity in the HPA axis of ovariectomized mice and ovariectomized mice treated subscutaneously with different doses of estradiol and progesterone. Our data suggest that in female mice, estradiol and progesterone influence RAS-regulating and vasopressin-degrading activities at different levels of the HPA axis.

  18. 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

  19. 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

  20. 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.

  1. 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.

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

    PubMed

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

    2015-11-12

    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. Sildenafil further 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.

  3. 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

  4. Plasma renin-angiotensin system-regulating aminopeptidase activities are modified in early stage Alzheimer's disease and show gender differences but are not related to apolipoprotein E genotype.

    PubMed

    Puertas, María Del Carmen; Martínez-Martos, José Manuel; Cobo, Manuela; Lorite, Pedro; Sandalio, Rosa María; Palomeque, Teresa; Torres, María Isabel; Carrera-González, María Pilar; Mayas, María Dolores; Ramírez-Expósito, María Jesús

    2013-06-01

    Alterations in blood pressure and components of the renin-angiotensin system (RAS) contribute to the development and progression of Alzheimer's disease (AD), resulting in changes that can lead or contribute to cognitive decline. Aspartyl aminopeptidase (ASAP), aminopeptidase A (APA), aminopeptidase N (APN) and aminopeptidase B (APB) catabolise circulating angiotensins, whereas insulin-regulated aminopeptidase (IRAP) has been described as the AT4 receptor. We have found in AD patients a significant decrease of APA activity in men but not in women, and of APN, APB and IRAP in both genders, when compared with control subjects. No changes were found in ASAP activity. Also, APN, APB and IRAP but not APA correlated with the Mini-Mental test, but no relationship with APOE genotype was found. We conclude that several components of the RAS are modified in AD patients, with gender differences. Furthermore, ROC analysis indicates that APN, APB and IRAP activities could be useful non-invasive biomarkers of AD from the earliest stages.

  5. 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.

  6. Prenatal inflammation-induced NF-κB dyshomeostasis contributes to renin-angiotensin system over-activity resulting in prenatally programmed hypertension in offspring

    PubMed Central

    Deng, Youcai; Deng, Yafei; He, Xiaoyan; Chu, Jianhong; Zhou, Jianzhi; Zhang, Qi; Guo, Wei; Huang, Pei; Guan, Xiao; Tang, Yuan; Wei, Yanling; Zhao, Shanyu; Zhang, Xingxing; Wei, Chiming; Namaka, Michael; Yi, Ping; Yu, Jianhua; Li, Xiaohui

    2016-01-01

    Studies involving the use of prenatally programmed hypertension have been shown to potentially contribute to prevention of essential hypertension (EH). Our previous research has demonstrated that prenatal inflammatory stimulation leads to offspring’s aortic dysfunction and hypertension in pregnant Sprague-Dawley rats challenged with lipopolysaccharide (LPS). The present study found that prenatal LPS exposure led to NF-κB dyshomeostasis from fetus to adult, which was characterized by PI3K-Akt activation mediated degradation of IκBα protein and impaired NF-κB self-negative feedback loop mediated less newly synthesis of IκBα mRNA in thoracic aortas (gestational day 20, postnatal week 7 and 16). Prenatal or postnatal exposure of the IκBα degradation inhibitor, pyrollidine dithiocarbamate, effectively blocked NF-κB activation, endothelium dysfunction, and renin-angiotensin system (RAS) over-activity in thoracic aortas, resulting in reduced blood pressure in offspring that received prenatal exposure to LPS. Surprisingly, NF-κB dyshomeostasis and RAS over-activity were only found in thoracic aortas but not in superior mesenteric arteries. Collectively, our data demonstrate that the early life NF-κB dyshomeostasis induced by prenatal inflammatory exposure plays an essential role in the development of EH through triggering RAS over-activity. We conclude that early life NF-κB dyshomeostasis is a key predictor of EH, and thus, NF-κB inhibition represents an effective interventional strategy for EH prevention. PMID:26877256

  7. Plasma and tissue levels of proangiotensin-12 and components of the renin-angiotensin system (RAS) following low- or high-salt feeding in rats.

    PubMed

    Nagata, Sayaka; Kato, Johji; Kuwasako, Kenji; Kitamura, Kazuo

    2010-05-01

    The renin-angiotensin system (RAS) is an essential regulator of the blood pressure and body fluid balance, but the processing cascade or role of the tissue RAS remains obscure. Proangiotensin-12 (proang-12), a novel angiotensin peptide recently discovered in rat tissues, is assumed to function as a factor of the tissue RAS. To investigate the tissue production of proang-12, we measured the circulating and tissue components of the RAS including proang-12 following low-, normal-, or high-salt feeding in rats. Twelve-week-old male Wistar rats were fed a low-salt 0.3% NaCl or high-salt 8% NaCl diet for 7 days and compared with those fed a normal-salt diet of 0.7% NaCl. Low-salt feeding elevated the plasma renin activity and aldosterone concentration, resulting in significant increases in Ang I and Ang II levels in the plasma or kidney tissue, as compared with the normal- or high-salt group. Despite the increases in plasma renin activity, Ang I, and Ang II, the proang-12 levels in plasma and various tissues including the kidneys, small intestine, cardiac ventricles, and brain remained unchanged following low-salt feeding. These results suggest that peptide levels of proang-12 in rat plasma and tissues are regulated in a manner independent of the circulating RAS.

  8. Expression of components of the renin-angiotensin system in proliferating infantile haemangioma may account for the propranolol-induced accelerated involution.

    PubMed

    Itinteang, Tinte; Brasch, Helen D; Tan, Swee T; Day, Darren J

    2011-06-01

    Infantile haemangioma is a benign tumour of the microvasculature characterised by excessive proliferation of immature endothelial cells. It typically undergoes rapid proliferation during infancy followed by spontaneous slow involution during childhood often leaving a fibro-fatty residuum. In 2008, propranolol, a non-selective β-blocker, was serendipitously discovered to induce accelerated involution of a proliferating infantile haemangioma. However, the mechanism by which propranolol causes this dramatic effect is unclear. Using immunohistochemical staining, we show that the CD34+ endothelial progenitor cells of the microvessels in proliferating infantile haemangioma express angiotensin-converting enzyme and angiotensin II receptor-2, but not angiotensin II receptor-1. We have also shown using our in vitro explant model that the cells emanating from proliferating haemangioma biopsies form blast-like structures that proliferate in the presence of angiotensin II. We present here a plausible model involving the renin-angiotensin system that may account for the propranolol-induced accelerated involution of proliferating infantile haemangioma.

  9. Activation of systemic, but not local, renin-angiotensin system is associated with upregulation of TNF-α during prolonged fasting in northern elephant seal pups.

    PubMed

    Suzuki, Miwa; Vázquez-Medina, José Pablo; Viscarra, Jose A; Soñanez-Organis, José G; Crocker, Daniel E; Ortiz, Rudy M

    2013-09-01

    Northern elephant seal pups naturally endure a 2-3 month post-weaning fast that is associated with activation of systemic renin-angiotensin system (RAS), a decrease in plasma adiponectin (Acrp30), and insulin resistance (IR)-like conditions. Angiotensin II (Ang II) and tumor necrosis factor-alpha (TNF-α) are potential causal factors of IR, while Acrp30 may improve insulin signaling. However, the effects of fasting-induced activation of RAS on IR-like conditions in seals are not well described. To assess the effects of prolonged food deprivation on systemic and local RAS, and their potential contribution to TNF-α as they relate to an IR condition, the mRNA expressions of adipose and muscle RAS components and immuno-relevant molecules were measured along with plasma RAS components. Mean plasma renin activity and Ang II concentrations increased by 89 and 1658%, respectively, while plasma angiotensinogen (AGT) decreased by 49% over the fast, indicative of systemic RAS activation. Prolonged fasting was associated with decreases in adipose and muscle AGT mRNA expressions of 69 and 68%, respectively, corresponding with decreases in tissue protein content, suggesting suppression of local AGT production. Muscle TNF-α mRNA and protein increased by 239 and 314%, whereas those of adipose Acrp30 decreased by 32 and 98%, respectively. Collectively, this study suggests that prolonged fasting activates a systemic RAS, which contributes to an increase in muscle TNF-α and suppression of adipose Acrp30. This targeted and tissue-specific regulation of TNF-α and Acrp30 is likely coordinated to synergistically contribute to the development of an IR-like condition, independent of local RAS activity. These data enhance our understanding of the adaptive mechanisms evolved by elephant seals to tolerate potentially detrimental conditions.

  10. 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.

  11. The enigma of continual plasma volume expansion in pregnancy: critical role of the renin-angiotensin-aldosterone system.

    PubMed

    West, Crystal A; Sasser, Jennifer M; Baylis, Chris

    2016-12-01

    Pregnancy is characterized by avid renal sodium retention and plasma volume expansion in the presence of decreased blood pressure. Decreased maternal blood pressure is a consequence of reduced systemic vascular tone, which results from an increased production of vasodilators [nitric oxide (NO), prostaglandins, and relaxin] and decreased vascular responsiveness to the potent vasoconstrictor (angiotensin II). The kidneys participate in this vasodilatory response, resulting in marked increases in renal plasma flow and glomerular filtration rate (GFR) during pregnancy. In women, sodium retention drives plasma volume expansion (∼40%) and is necessary for perfusion of the growing uterus and fetus. For there to be avid sodium retention in the presence of the potent natriuretic influences of increased NO and elevated GFR, there must be modifications of the tubules to prevent salt wasting. The purpose of this review is to summarize these adaptations.

  12. Antiproliferative effects of palladium(II) complexes of 5-nitrosopyrimidines and interactions with the proteolytic regulatory enzymes of the renin-angiotensin system in tumoral brain cells.

    PubMed

    Illán-Cabeza, Nuria A; García-García, Antonio R; Martínez-Martos, José M; Ramírez-Expósito, María J; Moreno-Carretero, Miguel N

    2013-09-01

    Seventeen new palladium(II) complexes of general formulaes PdCl2L, PdCl(LH-1)(solvent) and PdCl2(PPh3)2L containing pyrimidine ligands derived from 6-amino-5-nitrosouracil and violuric acid have been prepared and characterized by elemental analysis, IR and NMR ((1)H and (13)C) methods and, two of them, PdCl(DANUH-1)(CH3CN)]·½H2O and [PdCl(2MeOANUH-1)(CH3CN)] by X-ray single-crystal diffraction (DANU: 6-amino-1,3-dimethyl-5-nitrosouracil; 2MeOANU: 6-amino-2-methoxy-5-nitroso-3H-pyrimidin-4-one). The coordination environment around palladium is nearly square planar in the two compounds with different supramolecular arrangements. Crystallographic and spectral data are consistent with a bidentate coordination mode through N5 and O4 atoms when the ligands act in neutral form and N5 and N6 atoms in the monodeprotonated ones. The cytotoxicity of the complexes against human neuroblastoma (NB69) and human glioma (U373-MG) cell lines has been tested showing a considerable antiproliferative activity. Also, the study of the effects of palladium(II) complexes on the renin-angiotensin system (RAS) regulating proteolytic regulatory enzymes aminopeptidase A (APA), aminopeptidase N (APN) and insulin-regulated aminopeptidase (IRAP) shows a strong dependence on the compound tested and the tumoral cell type, also affecting different catalytic routes; the compounds affect in a different way the activities of enzymes of the RAS system, changing their functional roles as initiators of cell proliferation in tumors as autocrine/paracrine mediators.

  13. Role of the renin angiotensin system on bone marrow-derived stem cell function and its impact on skeletal muscle angiogenesis.

    PubMed

    de Resende, Micheline M; Stodola, Timothy J; Greene, Andrew S

    2010-08-01

    Autologous bone marrow cell (BMC) transplantation has been shown as a potential approach to treat various ischemic diseases. However, under many conditions BMC dysfunction has been reported, leading to poor cell engraftment and a failure of tissue revascularization. We have previously shown that skeletal muscle angiogenesis induced by electrical stimulation (ES) is impaired in the SS/Mcwi rats and that this effect is related to a dysregulation of the renin angiotensin system (RAS) that is normalized by the replacement of chromosome 13 derived from the Brown Norway rat (SS-13(BN)/Mcwi consomic rats). The present study explored bone marrow-derived endothelial cell (BM-EC) function in the SS/Mcwi rat and its impact on skeletal muscle angiogenesis induced by ES. SS/Mcwi rats were randomized to receive BMC from: SS/Mcwi; SS-13(BN)/Mcwi; SS/Mcwi rats infused with saline or ANG II (3 ng kg(-1) min(-1)). BMC were injected in the stimulated tibialis anterior muscle of SS/Mcwi rats. Vessel density was evaluated in unstimulated and stimulated muscles after 7 days of ES. BMC isolated from SS/Mcwi or SS/Mcwi rats infused with saline failed to restore angiogenesis induced by ES. However, BMC isolated from SS-13(BN)/Mcwi and SS/Mcwi rats infused with ANG II effectively restored the angiogenesis response in the SS/Mcwi recipient. Furthermore, ANG II infusion increased the capacity of BM-EC to induce endothelial cell tube formation in vitro and slightly increased VEGF protein expression. This study suggests that dysregulation of the RAS in the SS/Mcwi rat contributes to impaired BM-EC function and could impact the angiogenic therapeutic potential of BMC.

  14. Similarities and differences of X and Y chromosome homologous genes, SRY and SOX3, in regulating the renin-angiotensin system promoters.

    PubMed

    Araujo, Fabiano C; Milsted, Amy; Watanabe, Ingrid K M; Del Puerto, Helen L; Santos, Robson A S; Lazar, Jozef; Reis, Fernando M; Prokop, Jeremy W

    2015-05-01

    The renin-angiotensin system (RAS) is subject to sex-specific modulation by hormones and gene products. However, sex differences in the balance between the vasoconstrictor/proliferative ACE/ANG II/AT1 axis, and the vasodilator/antiproliferative ACE2/ANG-(1-7)/MAS axis are poorly known. Data in the rat have suggested the male-specific Y-chromosome gene Sry to contribute to balance between these two axes, but why the testis-determining gene has these functions remains unknown. A combination of in silico genetic/protein comparisons, functional luciferase assays for promoters of the human RAS, and RNA-Seq profiling in rat were used to address if regulation of Sry on the RAS is conserved in the homologous X-chromosome gene, Sox3. Both SRY and SOX3 upregulated the promoter of Angiotensinogen (AGT) and downregulated the promoters of ACE2, AT2, and MAS, likely through overlapping mechanisms. The regulation by both SRY and SOX3 on the MAS promoter indicates a cis regulation through multiple SOX binding sites. The Renin (REN) promoter is upregulated by SRY and downregulated by SOX3, likely through trans and cis mechanisms, respectively. Sry transcripts are found in all analyzed male rat tissues including the kidney, while Sox3 transcripts are found only in the brain and testis, suggesting that the primary tissue for renin production (kidney) can only be regulated by SRY and not SOX3. These results suggest that SRY regulation of the RAS is partially shared with its X-chromosome homolog SOX3, but SRY gained a sex-specific control in the kidney for the rate-limiting step of the RAS, potentially resulting in male-specific blood pressure regulation.

  15. Endoplasmic reticulum stress increases brain MAPK signaling, inflammation and renin-angiotensin system activity and sympathetic nerve activity in heart failure.

    PubMed

    Wei, Shun-Guang; Yu, Yang; Weiss, Robert M; Felder, Robert B

    2016-10-01

    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.

  16. The association of renin-angiotensin system blockade use with the risks of cognitive impairment of aging and Alzheimer's disease: A meta-analysis.

    PubMed

    Zhuang, Shan; Wang, Hai-Feng; Wang, Xin; Li, Jun; Xing, Cheng-Ming

    2016-11-01

    A quantitative meta-analysis was performed to evaluate the association of renin-angiotensin system blockade (RASB) use with the incidence of cognitive impairment of aging and Alzheimer's disease (AD). Pubmed, Embase, and Cochrane Library databases were searched up to October 2015. Ten studies that assessed the relationship between RASB use and the incidence of cognitive impairment of aging or AD were included. When randomized trials and observational studies were combined, the use of RASB was significantly associated with a reduced risk of AD (risk ratio [RR], 0.80; 95% confidence interval [CI] 0.68-0.92) and cognitive impairment of aging (RR, 0.65; 95% CI 0.35-0.94) compared no use of RASB. Meanwhile, in an analysis of subgroups, both subjects with angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) use were lower incidence of AD (RR, 0.87; 95% CI 0.74-1.00; RR, 0.69; 95% CI 0.44-0.93, respectively) than those without, whereas, indirect comparison between ACEI and ARB revealed no significance in the risk of AD (RR, 1.27, 95% CI 0.85-1.89, p=0.245). In an analysis of cognitive impairment of aging, ARB use (RR, 0.40; 95% CI 0.02-0.78), rather than ACEI use (RR, 0.72; 95% CI 0.36-1.09), was shown to decrease the risk of cognitive impairment of aging. In conclusion, RASB treatments, regardless of the drug class, have benefits on prevention of AD, and the effects of ACEI may analogous to ARB. However, the benefit differs according to drug classes for cognitive impairment of aging, with ARB use, rather than ACEI use, being a potential treatment for reducing the incidence of cognitive impairment of aging.

  17. 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.

  18. The renin-angiotensin system mediates epidermal growth factor receptor-vitamin D receptor cross-talk in colitis-associated colon cancer

    PubMed Central

    Sadiq, Farhana; Almoghrabi, Anas; Mustafi, Devkumar; Kreisheh, Maggi; Sundaramurthy, Sumana; Liu, Weicheng; Konda, Vani J.; Pekow, Joel; Khare, Sharad; Hart, John; Joseph, Loren; Wyrwicz, Alice; Karczmar, Gregory S.; Li, Yan Chun; Bissonnette, Marc

    2014-01-01

    Purpose We previously showed that epidermal growth factor receptor (EGFR) promotes tumorigenesis in the azoxymethane/dextran sulfate sodium (AOM/DSS) model, whereas vitamin D (VD) suppresses tumorigenesis. EGFR-vitamin D receptor (VDR) interactions, however, are incompletely understood. VD inhibits the renin-angiotensin system (RAS), whereas RAS can activate EGFR. We aimed to elucidate EGFR-VDR cross-talk in colorectal carcinogenesis. Experimental Design To examine VDR-RAS interactions, we treated Vdr+/+ and Vdr/− mice with AOM/DSS. Effects of VDR on RAS and EGFR were examined by Westerns, immunostaining and real time PCR. We also examined the effect of vitamin D3 on colonic RAS in Vdr+/+ mice. EGFR regulation of VDR was examined in hypomorphic EgfrWaved2 (Wa2) and Egfrwildtype mice. Ang II-induced EGFR activation was studied in cell culture. Results Vdr deletion significantly increased tumorigenesis, activated EGFR and βcatenin signaling and increased colonic RAS components: including renin and angiotensin II. Dietary VD3 supplementation suppressed colonic renin. Renin was increased in human colon cancers. In studies in vitro, Ang II activated EGFR and stimulated colon cancer cell proliferation by an EGFR-mediated mechanism. Ang II also activated macrophages and colonic fibroblasts. Compared to tumors from EgfrWaved2 mice, tumors from Egfrwildtype mice showed up-regulated Snail1, a suppressor of VDR, and down-regulated VDR. Conclusions VDR suppresses the colonic RAS cascade, limits EGFR signals and inhibits colitis-associated tumorigenesis, whereas EGFR increases Snail1 and down-regulates VDR in colonic tumors. Taken together, these results uncover a RAS-dependent mechanism mediating EGFR and VDR cross-talk in colon cancer. PMID:25212605

  19. [Lifestyle-related diseases and anti-aging ophthalmology: suppression of retinal and choroidal pathologies by inhibiting renin-angiotensin system and inflammation].

    PubMed

    Ishida, Susumu

    2009-03-01

    Lifestyle-related diseases cause macro-and microangiopathies in the major organs including the brain, heart, kidney, and eye, and as a result, shorten the lifespan. The renin-angiotensin system (RAS) has recently been shown to contribute to the processes of accelerated aging caused by lifestyle-related diseases from visceral obesity in the early stage to late-onset organ damage. Vision-threatening diabetic retinopathy and age-related macular degeneration (AMD), associated with lifestyle-related diseases as risk factors for progression, develop retinal and choroidal neovascularization (CNV), respectively, in their advanced stages. We have found that tissue RAS is activated in the pathogenesis of diabetic retinopathy and CNV, leading to angiotensin type 1 receptor(AT1-R)-mediated expression of inflammation-related molecules including vascular endothelial growth factor (VEGF), intercellular adhesion molecule (ICAM)-1, and monocyte chemotactic protein(MCP)-1. Neuronal dysfunction in diabetic retinopathy is also shown to result from AT1-R-mediated degradation of synaptic proteins. Moreover, we revealed for the first time that the receptor for prorenin [(pro) renin receptor] is expressed in the eye, although prorenin was until recently believed to be just an inactive precursor of renin. Prorenin binds to the receptor that causes dual activation of its intracellular signaling and tissue RAS, and this pathogenic mechanism is termed receptor-associated prorenin system (RAPS)'. We have demonstrated the contribution of RAPS to the pathogenesis of CNV and dual regulation of VEGF and MCP-1 by signal transduction via (pro) renin receptor and AT1-R. Next, we report the potential validity of food factor supplements as a therapeutic strategy for preventing the retinal and choroidal pathologies driven by RAS-induced inflammatory and angiogenic molecules. Functional food factors examined include lutein in yellow-green vegetables, the omega-3 polyunsaturated fatty acid

  20. Angiotensin II-regulated microRNA 483-3p directly targets multiple components of the Renin-Angiotensin System

    PubMed Central

    Kemp, Jacqueline R.; Unal, Hamiyet; Desnoyer, Russell; Yue, Hong; Bhatnagar, Anushree; Karnik, Sadashiva S.

    2014-01-01

    Improper regulation of signaling in vascular smooth muscle cells (VSMCs) by angiotensin II (AngII) can lead to hypertension, vascular hypertrophy and atherosclerosis. The extent to which the homeostatic levels of the components of signaling networks are regulated through microRNAs (miRNA) modulated by AngII type 1 receptor (AT1R) in VSMCs is not fully understood. Whether AT1R blockers used to treat vascular disorders modulate expression of miRNAs is also not known. To report differential miRNA expression following AT1R activation by AngII, we performed microarray analysis in 23 biological and technical replicates derived from humans, rats and mice. Profiling data revealed a robust regulation of miRNA expression by AngII through AT1R, but not the AngII type 2 receptor (AT2R). The AT1R-specific blockers, losartan and candesartan antagonized >90% of AT1R-regulated miRNAs and AngII-activated AT2R did not modulate their expression. We discovered VSMC-specific modulation of 22 miRNAs by AngII, and validated AT1R-mediated regulation of 17 of those miRNAs by real-time polymerase chain reaction analysis. We selected miR-483-3p as a novel representative candidate for further study because mRNAs of multiple components of the renin angiotensin system (RAS) were predicted to contain the target sequence for this miRNA. MiR-483-3p inhibited the expression of luciferase reporters bearing 3′-UTRs of four different RAS genes and the inhibition was reversed by antagomir-483-3p. The AT1R-regulated expression levels of angiotensinogen and Angiotensin Converting Enzyme 1 (ACE-1) proteins in VSMCs are modulated specifically by miR-483-3p. Our study demonstrates that the AT1R-regulated miRNA expression fingerprint is conserved in VSMCs of humans and rodents. Furthermore, we identify the AT1R-regulated miR-483-3p as a potential negative regulator of steady-state levels of RAS components in VSMCs. Thus, miRNA-regulation by AngII to affect cellular signaling is a novel aspect of RAS

  1. Antiproteinuric effect of add-on paricalcitol in CKD patients under maximal tolerated inhibition of renin-angiotensin system: a prospective observational study

    PubMed Central

    2012-01-01

    Background Whether paricalcitol (PCT) reduces proteinuria in the presence of intensified inhibition of Renin-Angiotensin-System (RAS) is poorly studied. We evaluated the antiproteinuric effect of PCT in non-dialysis chronic kidney disease (CKD) patients with proteinuria greater than 0.5 g/24 h persisting despite anti-RAS therapy titrated to minimize proteinuria in the absence of adverse effects. Methods Forty-eight CKD patients were studied in the first six months of add-on oral PCT (1 mcg/day) and three months after drug withdrawal. Results Males were 87.5%, age 63 ± 14 yrs, systolic/diastolic blood pressure (BP) 143 ± 22/78 ± 11 mmHg, eGFR 29.7 ± 14.5 mL/min/1.73 m2, diabetes 40%, and cardiovascular disease 38%. At referral in the center (28 months prior to study baseline), proteinuria was 2.44 (95% CI 1.80-3.04) g/24 h with 6 patients not receiving any anti-RAS and 42 treated with a single agent, at low dosage in most cases. At study baseline, twenty patients were under 2–3 anti-RAS drugs while twenty-eight received 1 agent at full dose and proteinuria resulted to be reduced versus referral to 1.23 g/24 h (95%CI 1.00-1.51). Six months of add-on PCT significantly decreased proteinuria to 0.61 g/24 h (95%CI 0.40-0.93), with levels less than 0.5 g/24 h achieved in 37.5% patients, in the absence of changes of BP and GFR. Proteinuria recovered to basal value after drug withdrawal. The extent of antiproteinuric response to PCT was positively associated with diabetes, eGFR and daily Na excretion (R2 = 0.459, P < 0.0001). PTH decreased from 201 (IQR 92–273) to 83 (IQR 50–189) pg/mL. Conclusions In CKD patients, add-on PCT induces a significant reduction of proteinuria that is evident despite intensified anti-RAS therapy and larger in the presence of diabetes, higher GFR and unrestricted salt intake. PMID:23167771

  2. Renin angiotensin system inhibitors for patients with stable coronary artery disease without heart failure: systematic review and meta-analysis of randomized trials

    PubMed Central

    Fakheri, Robert; Wandel, Simon; Toklu, Bora; Wandel, Jasmin; Messerli, Franz H

    2017-01-01

    Objective To critically evaluate the efficacy of renin angiotensin system inhibitors (RASi) in patients with coronary artery disease without heart failure, compared with active controls or placebo. Design Meta-analysis of randomized trials. Data sources PubMed, EMBASE, and CENTRAL databases until 1 May 2016. Eligibility criteria for selecting studies Randomized trials of RASi versus placebo or active controls in patients with stable coronary artery disease without heart failure (defined as left ventricular ejection fraction ≥40% or without clinical heart failure). Each trial had to enroll at least 100 patients with coronary artery disease without heart failure, with at least one year’s follow-up. Studies were excluded if they were redacted or compared use of angiotensin converting enzyme inhibitors with angiotensin receptor blockers. Outcomes were death, cardiovascular death, myocardial infarction, angina, stroke, heart failure, revascularization, incident diabetes, and drug withdrawal due to adverse effects. Results 24 trials with 198 275 patient years of follow-up were included. RASi reduced the risk of all cause mortality (rate ratio 0.84, 95% confidence interval 0.72 to 0.98), cardiovascular mortality (0.74, 0.59 to 0.94), myocardial infarction (0.82, 0.76 to 0.88), stroke (0.79, 0.70 to 0.89), angina, heart failure, and revascularization when compared with placebo but not when compared with active controls (all cause mortality, 1.05, 0.94 to 1.17; Pinteraction=0.006; cardiovascular mortality, 1.08, 0.93 to 1.25, Pinteraction<0.001; myocardial infarction, 0.99, 0.87 to 1.12, Pinteraction=0.01; stroke, 1.10, 0.93 to 1.31; Pinteraction=0.002). Bayesian meta-regression analysis showed that the effect of RASi when compared with placebo on all cause mortality and cardiovascular mortality was dependent on the control event rate, such that RASi was only beneficial in trials with high control event rates (>14.10 deaths and >7.65 cardiovascular deaths per

  3. Dietary t10,c12-CLA but not c9,t11 CLA reduces adipocyte size in the absence of changes in the adipose renin-angiotensin system in fa/fa Zucker rats.

    PubMed

    DeClercq, Vanessa; Zahradka, Peter; Taylor, Carla G

    2010-11-01

    In obesity, increased activity of the local renin-angiotensin system (RAS) and enlarged adipocytes with altered adipokine production are linked to the development of obesity-related health problems and cardiovascular disease. Mixtures of conjugated linoleic acid (CLA) isomers have been shown to reduce adipocyte size and alter the production of adipokines. The objective of this study was to investigate the effects of feeding individual CLA isomers on adipocyte size and adipokines associated with the local adipose RAS. Male fa/fa Zucker rats received either (a) control, (b) cis(c)9,trans(t)11-CLA, or (c) t10,c12-CLA diet for 8 weeks. The t10,c12-CLA isomer reduced adipocyte size and increased cell number in epididymal adipose tissue. RT-PCR and Western blot analysis revealed that neither CLA isomer altered mRNA or protein levels of angiotensinogen or AngII receptors in adipose tissue. Likewise, levels of the pro-inflammatory cytokines TNF-α and IL-6 or the anti-inflammatory cytokine IL-10 were unchanged in adipose tissue. Similarly, neither CLA isomer had any effect on phosphorylation nor DNA binding of NF-κB. Our results suggest that although the t10,c12-CLA isomer had beneficial effects on reducing adipocyte size in obese rats, this did not translate into changes in the local adipose RAS or associated adipokines.

  4. Renin-angiotensin system acting on reactive oxygen species in paraventricular nucleus induces sympathetic activation via AT1R/PKCγ/Rac1 pathway in salt-induced hypertension

    PubMed Central

    Su, Qing; Huo, Chan-Juan; Li, Hong-Bao; Liu, Kai-Li; Li, Xiang; Yang, Qing; Song, Xin-Ai; Chen, Wen-Sheng; Cui, Wei; Zhu, Guo-Qing; Shi, Xiao-Lian; Liu, Jin-Jun; Kang, Yu-Ming

    2017-01-01

    Brain renin-angiotensin system (RAS) could regulate oxidative stress in the paraventricular nucleus (PVN) in the development of hypertension. This study was designed to explore the precise mechanisms of RAS acting on reactive oxygen species (ROS) in salt-induced hypertension. Male Wistar rats were administered with a high-salt diet (HS, 8.0% NaCl) for 8 weeks to induced hypertension. Those rats were received PVN infusion of AT1R antagonist losartan (LOS, 10 μg/h) or microinjection of small interfering RNAs for protein kinase C γ (PKCγ siRNA) once a day for 2 weeks. High salt intake resulted in higher levels of AT1R, PKCγ, Rac1 activity, superoxide and malondialdehyde (MDA) activity, but lower levels of copper/zinc superoxide dismutase (Cu/Zn-SOD), superoxide dismutase (SOD) and glutathione (GSH) in PVN than control animals. PVN infusion of LOS not only attenuated the PVN levels of AT1R, PKCγ, Rac1 activity, superoxide and decreased the arterial pressure, but also increased the PVN antioxidant capacity in hypertension. PVN microinjection of PKCγ siRNA had the same effect on LOS above responses to hypertension but no effect on PVN level of AT1R. These results, for the first time, identified that the precise signaling pathway of RAS regulating ROS in PVN is via AT1R/PKCγ/Rac1 in salt-induced hypertension. PMID:28338001

  5. 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.

  6. The central mechanism underlying hypertension: a review of the roles of sodium ions, epithelial sodium channels, the renin-angiotensin-aldosterone system, oxidative stress and endogenous digitalis in the brain.

    PubMed

    Takahashi, Hakuo; Yoshika, Masamichi; Komiyama, Yutaka; Nishimura, Masato

    2011-11-01

    The central nervous system has a key role in regulating the circulatory system by modulating the sympathetic and parasympathetic nervous systems, pituitary hormone release, and the baroreceptor reflex. Digoxin- and ouabain-like immunoreactive materials were found >20 years ago in the hypothalamic nuclei. These factors appeared to localize to the paraventricular and supraoptic nuclei and the nerve fibers at the circumventricular organs and supposed to affect electrolyte balance and blood pressure. The turnover rate of these materials increases with increasing sodium intake. As intracerebroventricular injection of ouabain increases blood pressure via sympathetic activation, an endogenous digitalis-like factor (EDLF) was thought to regulate cardiovascular system-related functions in the brain, particularly after sodium loading. Experiments conducted mainly in rats revealed that the mechanism of action of ouabain in the brain involves sodium ions, epithelial sodium channels (ENaCs) and the renin-angiotensin-aldosterone system (RAAS), all of which are affected by sodium loading. Rats fed a high-sodium diet develop elevated sodium levels in their cerebrospinal fluid, which activates ENaCs. Activated ENaCs and/or increased intracellular sodium in neurons activate the RAAS; this releases EDLF in the brain, activating the sympathetic nervous system. The RAAS promotes oxidative stress in the brain, further activating the RAAS and augmenting sympathetic outflow. Angiotensin II and aldosterone of peripheral origin act in the brain to activate this cascade, increasing sympathetic outflow and leading to hypertension. Thus, the brain Na(+)-ENaC-RAAS-EDLF axis activates sympathetic outflow and has a crucial role in essential and secondary hypertension. This report provides an overview of the central mechanism underlying hypertension and discusses the use of antihypertensive agents.

  7. Pirfenidone controls the feedback loop of the AT1R/p38 MAPK/renin-angiotensin system axis by regulating liver X receptor-α in myocardial infarction-induced cardiac fibrosis

    PubMed Central

    Li, Chunmei; Han, Rui; Kang, Le; Wang, Jianping; Gao, Yonglin; Li, Yanshen; He, Jie; Tian, Jingwei

    2017-01-01

    Pirfenidone (PFD), an anti-fibrotic small molecule drug, is used to treat fibrotic diseases, but its effects on myocardial infarction (MI)-induced cardiac fibrosis are unknown. The aim of this study was to determine the effects of PFD on MI-induced cardiac fibrosis and the possible underlying mechanisms in rats. After establishment of the model, animals were administered PFD by gavage for 4 weeks. During the development of MI-induced cardiac fibrosis, we found activation of a positive feedback loop between the angiotensin II type 1 receptor (AT1R)/phospho-p38 mitogen-activated protein kinase (p38 MAPK) pathway and renin-angiotensin system (RAS), which was accompanied by down-regulation of liver X receptor-α (LXR-α) expression. PFD attenuated body weight, heart weight, left ventricular weight, left ventricular systolic pressure, and ±dp/dtmax changes induced by MI, which were associated with a reduction in cardiac fibrosis, infarct size, and hydroxyproline concentration. Moreover, PFD inhibited the AT1R/p38 MAPK pathway, corrected the RAS imbalance [decreased angiotensin-converting enzyme (ACE), angiotensin II, and angiotensin II type 1 receptor expression, but increased ACE2 and angiotensin (1-7) activity and Mas expression] and strongly enhanced heart LXR-α expression. These results indicate that the cardioprotective effects of PFD may be due, in large part, to controlling the feedback loop of the AT1R/p38 MAPK/RAS axis by activation of LXR-α. PMID:28091615

  8. Structural and theoretical studies on rhodium and iridium complexes with 5-nitrosopyrimidines. Effects on the proteolytic regulatory enzymes of the renin-angiotensin system in human tumoral brain cells.

    PubMed

    Illán-Cabeza, Nuria A; Jiménez-Pulido, Sonia B; Ramírez-Expósito, María J; García-García, Antonio R; Peña-Ruiz, Tomás; Martínez-Martos, José M; Moreno-Carretero, Miguel N

    2015-02-01

    The reactions of [RhCl(CO)(PPh3)2], [RhCl(CO)2]2 and [IrCl(CO)(PPh3)2] with different 5-nitrosopyrimidines afforded sixteen complexes which have been structurally characterized by elemental analysis, IR and NMR ((1)H and (13)C) spectral methods and luminescence spectroscopy. The crystal and molecular structures of [Rh(III)Cl(VIOH-1)2(PPh3)], [Rh(III)Cl(DVIOH-1)2(PPh3)] and [Rh(II)(DVIOH-1)2(PPh3)2] have been established from single crystal x-ray structure analyses. The three complexes are six-coordinated with both violurato ligands into an equatorial N5,O4-bidentate fashion, but with different mutually arrangements. Theoretical studies were driven on the molecular structure of [Rh(III)Cl(VIOH-1)2(PPh3)] to assess the nature of the metal-ligand interaction as well as the foundations of the cis-trans (3L-2L) isomerism. An assortment of density functional (SOGGA11-X, B1LYP, B3LYP, B3LYP-D3 and wB97XD) has been used, all of them leading to a similar description of the target system. Thus, a topological analysis of the electronic density within AIM scheme and the study of the Mulliken charges yield a metal-ligand link of ionic character. Likewise, it has been proved that the cis-trans isomerism is mainly founded on that metal-ligand interaction with the relativistic effects playing a significant role. Although most of the compounds showed low direct toxicity against the human cell lines NB69 (neuroblastoma) and U373-MG (astroglioma), they differently modify in several ways the renin-angiotensin system (RAS)-regulating proteolytic regulatory enzymes aminopeptidase A (APA), aminopeptidase N (APN) and insulin-regulated aminopeptidase (IRAP). Therefore, these complexes could exert antitumor activity against both brain tumor types, acting through the paracrine regulating system mediated by tissue RAS rather than exerting a direct cytotoxic effect on tumor cells.

  9. Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy in TYpe 2 diabetic patients with normoalbuminuria (PRIORITY): essential study design and rationale of a randomised clinical multicentre trial

    PubMed Central

    Lindhardt, Morten; Currie, Gemma; Pontillo, Claudia; Beige, Joachim; Delles, Christian; von der Leyen, Heiko; Mischak, Harald; Navis, Gerjan; Noutsou, Marina; Ortiz, Alberto; Ruggenenti, Piero Luigi; Rychlik, Ivan; Spasovski, Goce; Rossing, Peter

    2016-01-01

    Introduction Diabetes mellitus affects 9% of the European population and accounts for 15% of healthcare expenditure, in particular, due to excess costs related to complications. Clinical trials aiming for earlier prevention of diabetic nephropathy by renin angiotensin system blocking treatment in normoalbumuric patients have given mixed results. This might reflect that the large fraction of normoalbuminuric patients are not at risk of progression, thereby reducing power in previous studies. A specific risk classifier based on urinary proteomics (chronic kidney disease (CKD)273) has been shown to identify normoalbuminuric diabetic patients who later progressed to overt kidney disease, and may hold the potential for selection of high-risk patients for early intervention. Combining the ability of CKD273 to identify patients at highest risk of progression with prescription of preventive aldosterone blockade only to this high-risk population will increase power. We aim to confirm performance of CKD273 in a prospective multicentre clinical trial and test the ability of spironolactone to delay progression of early diabetic nephropathy. Methods and analysis Investigator-initiated, prospective multicentre clinical trial, with randomised double-masked placebo-controlled intervention and a prospective observational study. We aim to include 3280 type 2 diabetic participants with normoalbuminuria. The CKD273 classifier will be assessed in all participants. Participants with high-risk pattern are randomised to treatment with spironolactone 25 mg once daily, or placebo, whereas, those with low-risk pattern will be observed without intervention other than standard of care. Treatment or observational period is 3 years. The primary endpoint is development of confirmed microalbuminuria in 2 of 3 first morning voids urine samples. Ethics and dissemination The study will be conducted under International Conference on Harmonisation – Good clinical practice (ICH-GCP) requirements

  10. Eplerenone inhibits the intracrine and extracellular actions of angiotensin II on the inward calcium current in the failing heart. On the presence of an intracrine renin angiotensin aldosterone system

    PubMed Central

    De Mello, Walmor C.; Gerena, Yamil

    2009-01-01

    angiotensin aldosterone system. PMID:18585409

  11. Venous responses during exercise in rainbow trout, Oncorhynchus mykiss: alpha-adrenergic control and the antihypotensive function of the renin-angiotensin system.

    PubMed

    Sandblom, Erik; Axelsson, Michael; McKenzie, David J

    2006-08-01

    The role of the alpha-adrenergic system in the control of cardiac preload (central venous blood pressure; P(ven)) and venous capacitance during exercise was investigated in rainbow trout (Oncorhynchus mykiss). In addition, the antihypotensive effect of the renin-angiotesin system (RAS) was investigated during exercise after alpha-adrenoceptor blockade. Fish were subjected to a 20-min exercise challenge at 0.66 body lengths s(-1) (BL s(-1)) while P(ven), dorsal aortic blood pressure (P(da)) and relative cardiac output (Q) was recorded continuously. Heart rate (f(H)), cardiac stroke volume (SV) and total systemic resistance (R(sys)) were derived from these variables. The mean circulatory filling pressure (MCFP) was measured at rest and at the end of the exercise challenge, to investigate potential exercise-mediated changes in venous capacitance. The protocol was repeated after alpha-adrenoceptor blockade with prazosin (1 mg kg(-1)M(b)) and again after additional blockade of angiotensin converting enzyme (ACE) with enalapril (1 mg kg(-1)M(b)). In untreated fish, exercise was associated with a rapid (within approx. 1-2 min) and sustained increase in Q and P(ven) associated with a significant increase in MCFP (0.17+/-0.02 kPa at rest to 0.27+/-0.02 kPa at the end of exercise). Prazosin treatment did not block the exercise-mediated increase in MCFP (0.25+/-0.04 kPa to 0.33+/-0.04 kPa at the end of exercise), but delayed the other cardiovascular responses to swimming such that Q and P(ven) did not increase significantly until around 10-13 min of exercise, suggesting that an endogenous humoral control mechanism had been activated. Subsequent enalapril treatment revealed that these delayed responses were in fact due to activation of the RAS, because resting P(da) and R(sys) were decreased further and essentially all cardiovascular changes during exercise were abolished. This study shows that the alpha-adrenergic system normally plays an important role in the control of

  12. QGQS Granule in SHR Serum Metabonomics Study Based on Tools of UPLC-Q-TOF and Renin-Angiotensin-Aldosterone System Form Protein Profilin-1

    PubMed Central

    2017-01-01

    QGQS granule is effective for the therapeutic of hypertension in clinic. The aim of this research is to observe the antihypertension effect of QGQS granule on SHR and explain the mechanism of its lowering blood pressure. 30 SHR were selected as model group, captopril group, and QGQS group, 10 WKYr were used as control group, and RBP were measured on tail artery consciously. And all the serum sample analysis was carried out on UPLC-TOF-MS system to determine endogenous metabolites and to find the metabonomics pathways. Meanwhile, ELISA kits for the determination pharmacological indexes of PRA, AngI, AngII, and ALD were used for pathway confirmatory; WB for determination of profilin-1 protein expression was conducted for Ang II pathway analysis as well. It is demonstrated that QGQS granule has an excellent therapeutic effect on antihypertension, which exerts effect mainly on metabonomics pathway by regulating glycerophospholipid, sphingolipid, and arachidonic acid metabolism, and it could inhibit the overexpression of the profilin-1 protein. We can come to a conclusion that RAAS should be responsible mainly for the metabonomics pathway of QGQS granule on antihypertension, and it plays a very important role in protein of profilin-1 inhibition. PMID:28367224

  13. [Effect of 5-month guanfacine treatment on the renin-angiotensin-aldosterone system and some metabolic factors in patients with diabetes mellitus type II and hypertension].

    PubMed

    Jaromczyk-Slisz, J; Kubasik, A; Jasiel-Wojculewicz, H; Badzio, T; Krupa-Wojciechowska, B

    The group of the investigated included 25 individuals (11 F, 14 M), aged 55 +/- 1.5 years, with diabetes type II and hypertension. Known diabetes duration was 4.9 +/- 0.8 years and known hypertension duration--7.4 +/- 1.4 years. Two weeks after administering placebo in place of hypertension drugs applied so far, guanfacine was included as the only hypertensive drug. The dosage was increased from 0.5 mg up to 3 mg daily until a good control of blood pressure was achieved. The diabetic treatment, diet and the smoking habit were unchanged. The resting activity of the renin-angiotension-aldosterone system (RAA), cholesterol, triglycerides, HDL and LDL, serum glucose levels and HbA1c were assayed after a 5-month guanfacine period. After treatment a significant decrease in blood pressure both systolic and diastolic (p < 0.001), heart rate (p < 0.005) and plasma renin activity (p < 0.02) were observed. Preliminary measurements of RAA activity and its changes during treatment were not helpful in predicting guanfacine hypotensive effect. The level of lipids, lipoproteins, atherogenic factors, glucose and HbA1c did not change significantly during the study.

  14. [A 100-year perspective on renal function and hypertension. Anti-renin therapy has made hypertensive renal failure a rarity].

    PubMed

    Bergström, G; Herlitz, H; Himmelmann, A; Ljungman, S; Aurell, M

    1999-11-24

    One hundred years ago, in 1898, Professor Robert Tigerstedt, Karolinska institutet, Sweden, discovered renin. The subsequent elaboration in 1960 of the renin-angiotensin-aldosterone system signalled the start of modern hypertension research. The kidney takes part in blood pressure regulation in a number of ways. Indications are that increased renovascular resistance due to increased renin-angiotensin activity is of importance for the barostatic function of the kidneys and for the pathogenesis of human hypertension. Several commonly used, efficacious and well tolerated antihypertensive agents act by blocking the renin-angiotensin system, thus normalising kidney function. A number of current large-scale trials--utilising ACE inhibitors and angiotensin receptor antagonists--will, it is hoped, elucidate the proper role of 'anti-renin therapy' in the treatment of hypertension. Thanks to effective modern management of hypertension, renal failure due to hypertensive kidney disease is rare in Sweden today.

  15. Recurrence of Acute Page Kidney in a Renal Transplant Allograft

    PubMed Central

    Zayas, Carlos; Mulloy, Laura; Jagadeesan, Muralidharan

    2016-01-01

    Acute Page Kidney (APK) phenomenon is a rare cause of secondary hypertension, mediated by activation of renin-angiotensin-aldosterone system (RAAS). Timely intervention is of great importance to prevent any end organ damage from hypertension. We present a unique case of three episodes of APK in the same renal transplant allograft. PMID:27725836

  16. Recurrence of Acute Page Kidney in a Renal Transplant Allograft.

    PubMed

    Kapoor, Rajan; Zayas, Carlos; Mulloy, Laura; Jagadeesan, Muralidharan

    2016-01-01

    Acute Page Kidney (APK) phenomenon is a rare cause of secondary hypertension, mediated by activation of renin-angiotensin-aldosterone system (RAAS). Timely intervention is of great importance to prevent any end organ damage from hypertension. We present a unique case of three episodes of APK in the same renal transplant allograft.

  17. Signaling Pathways Involved in Renal Oxidative Injury: Role of the Vasoactive Peptides and the Renal Dopaminergic System

    PubMed Central

    Rukavina Mikusic, N. L.; Kravetz, M. C.; Kouyoumdzian, N. M.; Della Penna, S. L.; Rosón, M. I.; Fernández, B. E.; Choi, M. R.

    2014-01-01

    The physiological hydroelectrolytic balance and the redox steady state in the kidney are accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Angiotensin II, atrial natriuretic peptide and intrarenal dopamine play a pivotal role in this interactive network. The balance between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide, by one side, and the prooxidant effect of the renin angiotensin system, by the other side, contributes to ensuring the normal function of the kidney. Different pathological scenarios, as nephrotic syndrome and hypertension, where renal sodium excretion is altered, are associated with an impaired interaction between two natriuretic systems as the renal dopaminergic system and atrial natriuretic peptide that may be involved in the pathogenesis of renal diseases. The aim of this review is to update and comment the most recent evidences about the intracellular pathways involved in the relationship between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide and the prooxidant effect of the renin angiotensin system in the pathogenesis of renal inflammation. PMID:25436148

  18. MicroRNA in diabetic nephropathy: renin angiotensin, aGE/RAGE, and oxidative stress pathway.

    PubMed

    Hagiwara, Shinji; McClelland, Aaron; Kantharidis, Phillip

    2013-01-01

    MicroRNAs (miRNA) are a novel class of small, noncoding RNA molecules that have gained the attention of many researchers in recent years due to their ability to posttranscriptionally regulate the expression of families of genes simultaneously. Their role in normal physiology and pathobiology is intriguing and their regulation in normal and disease states is fascinating. That the cells can return to a state of homeostasis when these small molecules are perturbed is truly remarkable given the multiple cellular targets of each miRNA and that many mRNAs are targeted by multiple miRNAs. Several reviews have covered aspects of miRNA function in biology and disease. Here, we review the role of miRNA in regulating the renin-angiotensin system, AGE/RAGE signalling, and under conditions of oxidative stress in the context of diabetic nephropathy.

  19. [Sympathetic nerve activity in chronic renal failure - what are the therapeutic options?].

    PubMed

    Hausberg, M; Tokmak, F

    2013-11-01

    Patients with chronic renal failure are characterized by a tonic elevation of sympathetic tone. This factor largely contributes to their increased cardiovascular risk. The increased sympathetic drive is caused by activiation of renal afferent fibers in the diseased kidneys. Therapeutic options for hypertensive patients with chronic renal failure with respect to their sympathetic overactivity are inhibitors of the renin-angiotensin-system and central sympatholytic drugs. The role of catheter-based renal denervation in these patients is currently under investigation.

  20. Renal adaptation during hibernation.

    PubMed

    Jani, Alkesh; Martin, Sandra L; Jain, Swati; Keys, Daniel; Edelstein, Charles L

    2013-12-01

    Hibernators periodically undergo profound physiological changes including dramatic reductions in metabolic, heart, and respiratory rates and core body temperature. This review discusses the effect of hypoperfusion and hypothermia observed during hibernation on glomerular filtration and renal plasma flow, as well as specific adaptations in renal architecture, vasculature, the renin-angiotensin system, and upregulation of possible protective mechanisms during the extreme conditions endured by hibernating mammals. Understanding the mechanisms of protection against organ injury during hibernation may provide insights into potential therapies for organ injury during cold storage and reimplantation during transplantation.

  1. Renal adaptation during hibernation

    PubMed Central

    Martin, Sandra L.; Jain, Swati; Keys, Daniel; Edelstein, Charles L.

    2013-01-01

    Hibernators periodically undergo profound physiological changes including dramatic reductions in metabolic, heart, and respiratory rates and core body temperature. This review discusses the effect of hypoperfusion and hypothermia observed during hibernation on glomerular filtration and renal plasma flow, as well as specific adaptations in renal architecture, vasculature, the renin-angiotensin system, and upregulation of possible protective mechanisms during the extreme conditions endured by hibernating mammals. Understanding the mechanisms of protection against organ injury during hibernation may provide insights into potential therapies for organ injury during cold storage and reimplantation during transplantation. PMID:24049148

  2. Renin-Angiotensin Activation and Oxidative Stress in Early Heart Failure with Preserved Ejection Fraction

    PubMed Central

    Negi, Smita I.; Jeong, Euy-Myoung; Shukrullah, Irfan; Veleder, Emir; Jones, Dean P.; Fan, Tai-Hwang M.; Varadarajan, Sudhahar; Danilov, Sergei M.; Fukai, Tohru; Dudley, Samuel C.

    2015-01-01

    Animal models have suggested a role of renin-angiotensin system (RAS) activation and subsequent cardiac oxidation in heart failure with preserved ejection fraction (HFpEF). Nevertheless, RAS blockade has failed to show efficacy in treatment of HFpEF. We evaluated the role of RAS activation and subsequent systemic oxidation in HFpEF. Oxidative stress markers were compared in 50 subjects with and without early HFpEF. Derivatives of reactive oxidative metabolites (DROMs), F2-isoprostanes (IsoPs), and ratios of oxidized to reduced glutathione (Eh GSH) and cysteine (Eh CyS) were measured. Angiotensin converting enzyme (ACE) levels and activity were measured. On univariate analysis, HFpEF was associated with male sex (p = 0.04), higher body mass index (BMI) (p = 0.003), less oxidized Eh CyS (p = 0.001), lower DROMs (p = 0.02), and lower IsoP (p = 0.03). Higher BMI (OR: 1.3; 95% CI: 1.1–1.6) and less oxidized Eh CyS (OR: 1.2; 95% CI: 1.1–1.4) maintained associations with HFpEF on multivariate analysis. Though ACE levels were higher in early HFpEF (OR: 1.09; 95% CI: 1.01–1.05), ACE activity was similar to that in controls. HFpEF is not associated with significant systemic RAS activation or oxidative stress. This may explain the failure of RAS inhibitors to alter outcomes in HFpEF. PMID:26504834

  3. Local renin angiotensin expression regulates human mesenchymal stem cell differentiation to adipocytes.

    PubMed

    Matsushita, Kenichi; Wu, Yaojiong; Okamoto, Yoshihisa; Pratt, Richard E; Dzau, Victor J

    2006-12-01

    Clinical and experimental evidence suggest that the renin-angiotensin system (RAS) plays a role in metabolic syndrome. Adipogenesis is suggested to modulate obesity and obesity-related consequences, such as metabolic syndrome. Although mesenchymal stem cells (MSCs) are a major source of adipocyte generation, the influence of RAS on MSC differentiation to adipocyte is unknown. We evaluated the expression of endogenous RAS in human MSCs during its differentiation to adipocytes and studied the effects of angiotensin II (Ang II), Ang II type 1 receptor blocker Valsartan, and type 2 (AT(2)) receptor blocker PD123319. Our data showed that differentiation was associated with an increase in cellular renin and AT(2) receptor expression and a concomitant decrease in angiotensinogen and angiotensin-converting enzyme expression. The net effect is an increase in endogenous cellular angiotensin II production. Incubation with Ang II (exogenous) inhibited adipogenesis. Combined treatment of exogenous Ang II and Valsartan further inhibited adipogenesis, whereas combined treatment of Ang II and PD123319 completely abolished the inhibition of adipogenesis, suggesting an important role for the AT(2) receptor. Blockade of endogenous angiotensin II effect by incubation with Valsartan alone inhibited adipogenesis, whereas PD123319 alone promoted adipogenesis, confirming the data using exogenous Ang II. The combination of Valsartan and PD123319 had no net effect. Our data demonstrate an important role of the expression of the local RAS in the regulation of human MSC differentiation to adipocytes. Elucidation of the molecular mechanism should provide important insight into the pathophysiology of the metabolic syndrome and the development of future therapeutics.

  4. A possible mechanism for the progression of chronic renal disease and congestive heart failure.

    PubMed

    Re, Richard N

    2015-01-01

    Chronic neurologic diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as various forms of chronic renal disease and systolic congestive heart failure, are among the most common progressive degenerative disorders encountered in medicine. Each disease follows a nearly relentless course, albeit at varying rates, driven by progressive cell dysfunction and drop-out. The neurologic diseases are characterized by the progressive spread of disease-causing proteins (prion-like proteins) from cell to cell. Recent evidence indicates that cell autonomous renin angiotensin systems operate in heart and kidney, and it is known that functional intracrine proteins can also spread between cells. This then suggests that certain progressive degenerative cardiovascular disorders such as forms of chronic renal insufficiency and systolic congestive heart failure result from dysfunctional renin angiotensin system intracrine action spreading in kidney or myocardium.

  5. 25 (OH) Vitamin D Levels and Renal Disease Progression in Patients with Type 2 Diabetic Nephropathy and Blockade of the Renin-Angiotensin System

    PubMed Central

    Luño, José; Barrio, Vicente; de Vinuesa, Soledad García; Praga, Manuel; Goicoechea, Marian; Lahera, Vicente; Casas, Luisa; Oliva, Jesús

    2013-01-01

    Summary Background and objectives Experimental studies show that 25 (OH) vitamin D is a suppressor of renin biosynthesis and that vitamin D deficiency has been associated with CKD progression. Patients with type II diabetes and CKD have an exceptionally high rate of severe 25 (OH) vitamin D deficiency; however, it is not known whether this deficiency is a risk factor for progression of diabetic nephropathy. This study aimed to investigate whether there is an association of 25 (OH) vitamin D deficiency with disease progression in type II diabetic nephropathy. Design, setting, participants, & measurements 25 (OH) vitamin D levels were measured at baseline and 4 and 12 months in 103 patients included in a multicenter randomized controlled trial to compare the efficacy of combining an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker with the efficacy of each drug in monotherapy to slow progression of established diabetic nephropathy during 2006–2011. The primary composite endpoint was a >50% increase in baseline serum creatinine, ESRD, or death. All study participants were included in the analysis. Results Fifty-three patients (51.5%) had 25 (OH) vitamin D deficiency (<15 ng/ml). After a median follow-up of 32 months, the endpoint was reached by 23 patients with deficiency (43.4%) and 8 patients without (16%). Multivariate Cox regression analysis adjusted for urinary protein/creatinine ratio, estimated GFR, and baseline aldosterone showed that 25 (OH) vitamin D deficiency was associated with the primary endpoint (hazard ratio, 2.88; 95% confidence interval, 1.84 to 7.67; P=0.04). Conclusions These results show that 25 (OH) vitamin D deficiency is independently associated with a higher risk of the composite outcome in patients with type II diabetic nephropathy. PMID:24135218

  6. Renin-Angiotensin System Suppression Mitigates Experimental Radiation Pneumonitis

    SciTech Connect

    Ghosh, Swarajit N.; Zhang Rong; Fish, Brian L.; Semenenko, Vladimir A.; Li, X. Allen; Moulder, John E.; Jacobs, Elizabeth R.; Medhora, Meetha

    2009-12-01

    Purpose: To find the mitigators of pneumonitis induced by moderate doses of thoracic radiation (10-15 Gy). Methods and Materials: Unanesthetized WAG/RijCmcr female rats received a single dose of X-irradiation (10, 12, or 15 Gy at 1.615 Gy/min) to the thorax. Captopril (an angiotensin-converting enzyme inhibitor) or losartan (an angiotensin receptor blocker) was administered in the drinking water after irradiation. Pulmonary structure and function were assessed after 8 weeks in randomly selected rats by evaluating the breathing rate, ex vivo vascular reactivity, and histopathologic findings. Survival analysis was undertaken on all animals, except those scheduled for death. Results: Survival after a dose of 10 Gy to the thorax was not different from that of unirradiated rats for <=1 year. Survival decreased to <50% by 45 weeks after 12 Gy and by 8-9 weeks after 15 Gy. Captopril (17-56mg/kg/d) improved survival and reduced radiation-induced increases in breathing rate, changes in vascular reactivity, and histopathologic evidence of injury. Radiation-induced increases in the breathing rate were prevented even if captopril was started 1 week after irradiation or if it was discontinued after 5 weeks. Losartan, although effective in reducing mortality, was not as efficacious as captopril in mitigating radiation-induced increases in the breathing rate or altered vasoreactivity. Conclusion: In rats, a moderate thoracic radiation dose induced pneumonitis and morbidity. These injuries were mitigated by captopril even when it was begun 1 week after radiation or if discontinued 5 weeks after exposure. Losartan was less effective in protecting against radiation-induced changes in vascular reactivity or tachypnea.

  7. Systemic arterial and venous determinants of renal hemodynamics in congestive heart failure.

    PubMed

    Braam, Branko; Cupples, William A; Joles, Jaap A; Gaillard, Carlo

    2012-03-01

    Heart and kidney interactions are fascinating, in the sense that failure of the one organ strongly affects the function of the other. In this review paper, we analyze how principal driving forces for glomerular filtration and renal blood flow are changed in heart failure. Moreover, renal autoregulation and modulation of neurohumoral factors, which can both have repercussions on renal function, are analyzed. Two paradigms seem to apply. One is that the renin-angiotensin system (RAS), the sympathetic nervous system (SNS), and extracellular volume control are the three main determinants of renal function in heart failure. The other is that the classical paradigm to analyze renal dysfunction that is widely applied in nephrology also applies to the pathophysiology of heart failure: pre-renal, intra-renal, and post-renal alterations together determine glomerular filtration. At variance with the classical paradigm is that the most important post-renal factor in heart failure seems renal venous hypertension that, by increasing renal tubular pressure, decreases GFR. When different pharmacological strategies to inhibit the RAS and SNS and to assist renal volume control are considered, there is a painful lack in knowledge about how widely applied drugs affect primary driving forces for ultrafiltration, renal autoregulation, and neurohumoral control. We call for more clinical physiological studies.

  8. Hypertension and Angiotensin System Inhibitors in Patients with Metastatic Renal Cell Carcinoma

    PubMed Central

    Derosa, Lisa; Izzedine, Hassane; Albiges, Laurence; Escudier, Bernard

    2016-01-01

    Arterial hypertension (HTN) is a class effect of anti-vascular endothelial growth factor (VEGF) therapies, including the monoclonal antibody bevacizumab. Data are conflicting regarding the role of the renin-angiotensin system on angiogenesis and recent data suggest that the use of angiotensin system inhibitors (ASIs; angiotensin receptor blockers or angiotensin-converting enzyme inhibitors) is associated with improved survival in metastatic renal cell carcinoma (mRCC), particularly when used with VEGF targeted therapies. The aim of this review is to discuss the available treatment options for mRCC and associated incidence of hypertension as well as summarize the known data about ASIs use and mRCC. Additionally, given that the optimal management of HTN remains unclear, we will focus on prevention strategies and propose potential therapeutic approaches. PMID:27994768

  9. Genetics Home Reference: renal tubular dysgenesis

    MedlinePlus

    ... E, Roume J, Joubert M, Antignac C, Gubler MC. Mutations in genes in the renin-angiotensin system ... C, Viot G, Tantau J, Blesson S, Cloarec S, Machet MC, Chitayat D, Thauvin C, Laurent N, Sampson JR, ...

  10. Renal hemodynamic and neurohumoral responses to urapidil in hypertensive man

    SciTech Connect

    de Leeuw, P.W.; van Es, P.N.; de Bruyn, H.A.; Birkenhaeger, W.H.D.

    1988-01-01

    In order to evaluate the acute effects of urapidil on renal vascular tone and on pressor systems we performed a randomized placebo-controlled crossover study in 8 patients with uncomplicated essential hypertension. Each subject received, on two separate days one week apart, an intravenous injection of either placebo or urapidil (25 mg, to be increased to 50 mg if blood pressure did not fall within 5 minutes). Before and following this injection we measured blood pressure and heart rate (Dinamap), renal plasma flow (/sup 125/I-hippuran), renin, angiotensin II, aldosterone, and catecholamines. The results show that urapidil, when compared to placebo, significantly reduced blood pressure, while increasing heart rate, renal blood flow, noradrenaline and adrenaline. Dopamine levels, on the other hand, were suppressed. While renin and angiotensin II were only mildly stimulated, aldosterone levels increased markedly. It is concluded that urapidil, given intravenously, has an immediate blood pressure lowering effect associated with a fall in renal vascular tone and an increase in renal perfusion. As a consequence both the sympathetic system and the renin-angiotensin system are stimulated, although the latter only to a mild degree. The rise in aldosterone may be related to withdrawal of dopaminergic tone.

  11. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms.

    PubMed

    Hall, John E; do Carmo, Jussara M; da Silva, Alexandre A; Wang, Zhen; Hall, Michael E

    2015-03-13

    Excess weight gain, especially when associated with increased visceral adiposity, is a major cause of hypertension, accounting for 65% to 75% of the risk for human primary (essential) hypertension. Increased renal tubular sodium reabsorption impairs pressure natriuresis and plays an important role in initiating obesity hypertension. The mediators of abnormal kidney function and increased blood pressure during development of obesity hypertension include (1) physical compression of the kidneys by fat in and around the kidneys, (2) activation of the renin-angiotensin-aldosterone system, and (3) increased sympathetic nervous system activity. Activation of the renin-angiotensin-aldosterone system is likely due, in part, to renal compression, as well as sympathetic nervous system activation. However, obesity also causes mineralocorticoid receptor activation independent of aldosterone or angiotensin II. The mechanisms for sympathetic nervous system activation in obesity have not been fully elucidated but may require leptin and activation of the brain melanocortin system. With prolonged obesity and development of target organ injury, especially renal injury, obesity-associated hypertension becomes more difficult to control, often requiring multiple antihypertensive drugs and treatment of other risk factors, including dyslipidemia, insulin resistance and diabetes mellitus, and inflammation. Unless effective antiobesity drugs are developed, the effect of obesity on hypertension and related cardiovascular, renal and metabolic disorders is likely to become even more important in the future as the prevalence of obesity continues to increase.

  12. The role of the renal effects of angiotensin II in hypertension.

    PubMed

    Young, D B; Lohmeier, T E; Hall, J E; Declue, J E; Bengis, R G; Coleman, T G; Guyton, A C

    1980-01-01

    The renin-angiotensin system is involved in many forms of clinical and experimental hypertension. Although angiotensin II has powerful vasoconstrictor properties, it is doubtful that any substance can produce sustained hypertension solely by increasing total peripheral resistance. Since the authors have demonstrated previously that alterations in the kidney's ability to excrete sodium can affect long-term arterial blood pressure regulation, they investigated angiotensin's effect on renal function in several experimental models. The results of these studies clearly demonstrate that angiotensin has a powerful direct antinatriuretic effect, the magnitude of which is sufficient to cause marked hypertension at angiotensin concentrations well within the pathophysiological range.

  13. Serum levels of renin, angiotensin-converting enzyme and angiotensin II in patients treated by surgical excision, propranolol and captopril for problematic proliferating infantile haemangioma.

    PubMed

    Sulzberger, L; Baillie, R; Itinteang, T; de Jong, S; Marsh, R; Leadbitter, P; Tan, S T

    2016-03-01

    The role of the renin-angiotensin system (RAS) in the biology of infantile haemangioma (IH) and its accelerated involution induced by β-blockers was first proposed in 2010. This led to the first clinical trial in 2012 using low-dose captopril, an angiotensin-converting enzyme (ACE) inhibitor, demonstrating a similar response in these tumours. This study aimed to compare serial serum levels of the components of the RAS in patients before and after surgical excision, propranolol or captopril treatment for problematic proliferating IH. Patients with problematic proliferating IH underwent measurements of serum levels of plasma renin activity (PRA), ACE and angiotensin II (ATII) before, and 1-2 and 6 months following surgical excision, propranolol or captopril treatment. This study included 27 patients undergoing surgical excision (n = 8), propranolol (n = 11) and captopril (n = 8) treatment. Treatment with either surgical excision or propranolol resulted in significant decrease in the mean levels of PRA. Surgical excision or captopril treatment led to significant decline in the mean levels of ATII. All three treatment modalities had no significant effect on the mean levels of ACE. This study demonstrates the effect of surgical excision, propranolol and captopril treatment in lowering the levels of PRA and ATII, but not ACE, supporting a mechanistic role for the RAS in the biology of IH.

  14. Renal tubular acidosis type IV as a complication of lupus nephritis.

    PubMed

    Sánchez-Marcos, C; Hoffman, V; Prieto-González, S; Hernández-Rodríguez, J; Espinosa, G

    2016-03-01

    Renal tubular acidosis (RTA) is a rare complication of renal involvement of systemic lupus erythematosus (SLE). We describe a 24-year-old male with type IV lupus nephropathy as a presenting manifestation of SLE. He presented with improvement of renal function following induction therapy with three pulses of methylprednisolone and 500 mg biweekly pulses of cyclophosphamide. However, a week after the first pulse of cyclophosphamide, the patient presented with a significant increase in legs edema and severe hyperkalemia. Type IV RTA associated with hyporeninemic hypoaldosteronism was suspected in the presence of metabolic acidosis with a normal anion gap, severe hyperkalemia without worsening renal function, and urinary pH of 5. RTA was confirmed with a transtubular potassium concentration gradient of 2 and low levels of plasma aldosterone, renin, angiotensin II, and cortisol. Intravenous bicarbonate, high-dose furosemide, and fludrocortisone were administered with normalization of potassium levels and renal function.

  15. The Effects of Heart Failure on Renal Function

    PubMed Central

    Udani, Suneel M; Koyner, Jay L

    2010-01-01

    Summary Heart-kidney interactions have been increasingly recognized by clinicians and researchers involved in the study and treatment of heart failure and kidney disease. A classification system has been developed to categorize the different manifestations of cardiac and renal dysfunction. Recent work has highlighted the significant negative prognostic effect of worsening renal function on outcomes for individuals with heart failure. The etiology of the concomitant cardiac and renal dysfunction remains unclear; however, increasing evidence supports alternatives to the established theory of underfilling, including effects of venous congestion and changes in intra-abdominal pressure. Conventional therapy focuses on blockade of the renin-angiotensin-aldosterone system with expanding use of direct renin and aldosterone antagonists. Novel therapeutic interventions using extracorporeal therapy and antagonists of the adenosine pathway show promise and require further investigation. PMID:20621250

  16. Long-term renin-angiotensin blocking therapy in hypertensive patients with normal aorta may attenuate the formation of abdominal aortic aneurysms.

    PubMed

    Silverberg, Daniel; Younis, Anan; Savion, Naphtali; Harari, Gil; Yakubovitch, Dmitry; Sheick Yousif, Basheer; Halak, Moshe; Grossman, Ehud; Schneiderman, Jacob

    2014-08-01

    Renin-angiotensin system (RAS) has been implicated in the pathogenesis of abdominal aortic aneurysm (AAA). Angiotensin II type 1 receptor blocker (ARB), when given with angiotensin II prevents AAA formation in mice, but found ineffective in attenuating the progression of preexisting AAA. This study was designed to evaluate the effect of chronic RAS blockers on abdominal aortic diameter in hypertensive patients without known aortic aneurysm. Consecutive hypertensive outpatients (n = 122) were stratified according to antihypertensive therapy they received for 12 months or more, consisting of ARB (n = 45), angiotensin converting enzyme inhibitor (ACE-I; n = 45), or nonARB/nonACE-I (control therapy; n = 32). Abdominal ultrasonography was performed to measure maximal subrenal aortic diameter. Eighty-four patients were reexamined by ultrasonography 8 months later. The correlation between the different antihypertensive therapies and aortic diameter was examined. Aortic diameters were significantly smaller in ARB than in control patients in the baseline and follow-up measurements (P = .004; P = .0004, respectively). Risk factor adjusted covariance analysis showed significant differences between ARB or ACE-I treated groups and controls (P = .006 or P = .046, respectively). Ultrasound that was performed 8 months later showed smaller increases in mean aortic diameters of the ARB and ACE-I groups than in controls. Both ARB and ACE-I therapy attenuated expansion of nonaneurysmal abdominal aorta in humans. These results indicate that RAS blockade given before advancement of aortic medial remodeling may slow down the development of AAA.

  17. [Effects of vitamin D on the cardiovascular system].

    PubMed

    Shoji, Tetsuo; Nishizawa, Yoshiki

    2006-07-01

    Active vitamin D plays important roles not only in bone and mineral metabolism but also in the cardiovascular system. Cohort studies in hemodialysis patients demonstrated that use of active vitamin D analogs was associated with reduced risk of death, particularly death from cardiovascular disease. Treatment with vitamin D had beneficial effects on cardiac and immune functions in dialysis patients, and inflammatory markers in non-renal subjects. Also, anti-proteinuric effect was recently shown in chronic kidney disease. Experimentally, active vitamin D inhibits atherogenic cellular behaviors and activation of the renin-angiotensin system. Thus, active vitamin D is a regulator of cardiovascular and kidney functions.

  18. Chronic AT2 receptor activation attenuates renal AT1 receptor function and blood pressure in obese Zucker rats

    PubMed Central

    Ali, Quaisar; Wu, Yonnie; Hussain, Tahir

    2013-01-01

    Abnormal regulation of the renin angiotensin system such as enhanced renal AT1R function and reduced ACE2 activity contributes to obesity-related hypertension. Here we tested whether long-term AT2R activation affects renal function in obesity using lean and obese Zucker rats treated with the AT2R agonist CGP42112A for 2-weeks. This caused blood pressure to decrease by 13 mmHg which was associated with increased urinary sodium excretion in the obese rats. Cortical ACE2 expression and activity, the Mas receptor (MasR), and its ligand angiotensin-(1-7) were all increased in CGP-treated obese compared with control rats. Candesartan-induced natriuresis, a measure of AT1R function, was reduced but cortical AT1R expression and angiotensin II levels were similar in CGP-treated obese compared to control rats. Renin and AT2R expression in obese rats was not affected by CGP-treatment. In HK-2 cells in-vitro, CGP-treatment caused increased ACE2 activity and MasR levels but decreased AT1R levels and renin activity. Thus, long-term AT2R activation shifts the opposing arms of renin angiotensin system and contributes to natriuresis and blood pressure reduction in obese animals. Our study highlights the importance of AT2R as a target for treating obesity related hypertension. PMID:23823602

  19. Chronic AT2 receptor activation increases renal ACE2 activity, attenuates AT1 receptor function and blood pressure in obese Zucker rats.

    PubMed

    Ali, Quaisar; Wu, Yonnie; Hussain, Tahir

    2013-11-01

    Abnormal regulation of the renin angiotensin system such as enhanced renal AT1R function and reduced ACE2 activity contributes to obesity-related hypertension. Here, we tested whether long-term AT2R activation affects renal function in obesity using lean and obese Zucker rats treated with the AT2R agonist CGP42112A for 2 weeks. This caused blood pressure to decrease by 13 mm Hg, which was associated with increased urinary sodium excretion in the obese rats. Cortical ACE2 expression and activity, the Mas receptor (MasR), and its ligand angiotensin-(1-7) were all increased in CGP-treated obese compared with control rats. Candesartan-induced natriuresis, a measure of AT₁R function, was reduced but cortical AT₁R expression and angiotensin II levels were similar in CGP-treated obese compared with control rats. Renin and AT2R expression in obese rats was not affected by CGP treatment. In HK-2 cells in vitro, CGP treatment caused increased ACE2 activity and MasR levels but decreased AT₁R levels and renin activity. Thus, long-term AT2R activation shifts the opposing arms of renin angiotensin system and contributes to natriuresis and blood pressure reduction in obese animals. Our study highlights the importance of AT2R as a target for treating obesity-related hypertension.

  20. Role of renal sympathetic nerve activity in prenatal programming of hypertension.

    PubMed

    Baum, Michel

    2016-03-21

    Prenatal insults, such as maternal dietary protein deprivation and uteroplacental insufficiency, lead to small for gestational age (SGA) neonates. Epidemiological studies from many different parts of the world have shown that SGA neonates are at increased risk for hypertension and early death from cardiovascular disease as adults. Animal models, including prenatal administration of dexamethasone, uterine artery ligation and maternal dietary protein restriction, result in SGA neonates with fewer nephrons than controls. These models are discussed in this educational review, which provides evidence that prenatal insults lead to altered sodium transport in multiple nephron segments. The factors that could result in increased sodium transport are discussed, focusing on new information that there is increased renal sympathetic nerve activity that may be responsible for augmented renal tubular sodium transport. Renal denervation abrogates the hypertension in programmed rats but has no effect on control rats. Other potential factors that could cause hypertension in programmed rats, such as the renin-angiotensin system, are also discussed.

  1. Current concepts and perspectives of renal volume regulation in relationship to hypertension.

    PubMed

    Guyton, A C; Manning, R D; Norman, R A; Montani, J P; Lohmeier, T E; Hall, J E

    1986-10-01

    The renal-body fluid mechanism for arterial pressure control is almost certainly the most primitive of all the pressure-regulating mechanisms in animals. Through the stages of evolution, the system has been greatly improved. Nervous controls provide rapid pressure-control mechanisms that function almost instantaneously, many hours or days before the renal-body fluid mechanism can act fully. The renin-angiotensin-aldosterone system plays another important role: this system ensures that very large changes in salt intake, from as little as one-tenth normal up to as high as 10 times normal, have very little effect on the regulated level of the arterial pressure. Finally, the long-term autoregulatory mechanism helps to dissociate the long-term control of cardiac output from long-term control of arterial pressure; it also makes it possible for extremely slight increases in body fluid volume to cause chronic volume-loading hypertension.

  2. Opiorphin increases blood pressure of conscious rats through renin-angiotensin system (RAS).

    PubMed

    Fang, Yuan; Li, Shuo; Zhou, Huabin; Tian, Xiaozhu; Lv, Shuangyu; Chen, Qiang

    2014-05-01

    Human opiorphin is a recently identified endogenous pentapeptide, encoded by ProL1 multigenes family that contributes to cardiovascular modulation. The aim of this study was to evaluate the effect of opiorphin through intravenous injection (i.v.) on mean arterial pressure (MAP) regulation. To investigate the bioactivity of opiorphin, a rat cannulation model was developed for MAP measurement and blood sampling. In our present study, opiorphin (200-700 nmol/kg) increased MAP in dose-related and time-dependent manner in conscious rats, which associated highly with the elevation of angiotensin II (AngII) levels in serum. Furthermore, the MAP elevation induced by opiorphin was completely blocked by AngII receptor antagonist valsartan and partially attenuated by angiotensin-converting enzyme inhibitor captopril. Finally, we tested the effect of opiorphin in hypoxia condition, which exhibited that opiorphin reversed hypoxia induced hypotension in conscious rats. Taken together, these results indicated that opiorphin may play an important role in the modulation of blood pressure through AngII dependent pathway, which may help future development of potent clinical therapeutics for emergency treatment.

  3. 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.

  4. Activation of Renal (Pro)Renin Receptor Contributes to High Fructose-Induced Salt Sensitivity.

    PubMed

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

    2017-02-01

    A high-fructose diet is shown to induce salt-sensitive hypertension, but the underlying mechanism largely remains unknown. The major goal of the present study was to test the role of renal (pro)renin receptor (PRR) in this model. In Sprague-Dawley rats, high-fructose intake increased renal expression of full-length PRR, which were attenuated by allopurinol. High-fructose intake also upregulated renal mRNA and protein expression of sodium/hydrogen exchanger 3 and Na/K/2Cl cotransporter, as well as in vivo Na/K/2Cl cotransporter activity, all of which were nearly completely blocked by a PRR decoy inhibitor PRO20 or allopurinol treatment. Parallel changes were observed for indices of intrarenal renin-angiotensin-system including renal and urinary renin and angiotensin II levels. Radiotelemetry demonstrated that high-fructose or a high-salt diet alone did not affect mean arterial pressure, but the combination of the 2 maneuvers induced a ≈10-mm Hg increase of mean arterial pressure, which was blunted by PRO20 or allopurinol treatment. In cultured human kidney 2 cells, both fructose and uric acid increased protein expression of soluble PRR in a time- and dose-dependent manner; fructose-induced PRR upregulation was inhibited by allopurinol. Taken together, our data suggest that fructose via uric acid stimulates renal expression of PRR/soluble PRR that stimulate sodium/hydrogen exchanger 3 and Na/K/2Cl cotransporter expression and intrarenal renin-angiotensin system to induce salt-sensitive hypertension.

  5. Obstructive renal injury: from fluid mechanics to molecular cell biology.

    PubMed

    Ucero, Alvaro C; Gonçalves, Sara; Benito-Martin, Alberto; Santamaría, Beatriz; Ramos, Adrian M; Berzal, Sergio; Ruiz-Ortega, Marta; Egido, Jesus; Ortiz, Alberto

    2010-04-22

    Urinary tract obstruction is a frequent cause of renal impairment. The physiopathology of obstructive nephropathy has long been viewed as a mere mechanical problem. However, recent advances in cell and systems biology have disclosed a complex physiopathology involving a high number of molecular mediators of injury that lead to cellular processes of apoptotic cell death, cell injury leading to inflammation and resultant fibrosis. Functional studies in animal models of ureteral obstruction using a variety of techniques that include genetically modified animals have disclosed an important role for the renin-angiotensin system, transforming growth factor-β1 (TGF-β1) and other mediators of inflammation in this process. In addition, high throughput techniques such as proteomics and transcriptomics have identified potential biomarkers that may guide clinical decision-making.

  6. Obstructive renal injury: from fluid mechanics to molecular cell biology

    PubMed Central

    Ucero, Alvaro C; Gonçalves, Sara; Benito-Martin, Alberto; Santamaría, Beatriz; Ramos, Adrian M; Berzal, Sergio; Ruiz-Ortega, Marta; Egido, Jesus; Ortiz, Alberto

    2010-01-01

    Urinary tract obstruction is a frequent cause of renal impairment. The physiopathology of obstructive nephropathy has long been viewed as a mere mechanical problem. However, recent advances in cell and systems biology have disclosed a complex physiopathology involving a high number of molecular mediators of injury that lead to cellular processes of apoptotic cell death, cell injury leading to inflammation and resultant fibrosis. Functional studies in animal models of ureteral obstruction using a variety of techniques that include genetically modified animals have disclosed an important role for the renin-angiotensin system, transforming growth factor-β1 (TGF-β1) and other mediators of inflammation in this process. In addition, high throughput techniques such as proteomics and transcriptomics have identified potential biomarkers that may guide clinical decision-making. PMID:24198613

  7. Renal neurohormonal regulation in heart failure decompensation.

    PubMed

    Jönsson, Sofia; Agic, Mediha Becirovic; Narfström, Fredrik; Melville, Jacqueline M; Hultström, Michael

    2014-09-01

    Decompensation in heart failure occurs when the heart fails to balance venous return with cardiac output, leading to fluid congestion and contributing to mortality. Decompensated heart failure can cause acute kidney injury (AKI), which further increases mortality. Heart failure activates signaling systems that are deleterious to kidneys such as renal sympathetic nerve activity (RSNA), renin-angiotensin-aldosterone system, and vasopressin secretion. All three reduce renal blood flow (RBF) and increase tubular sodium reabsorption, which may increase renal oxygen consumption causing AKI through renal tissue hypoxia. Vasopressin contributes to venous congestion through aquaporin-mediated water retention. Additional water retention may be mediated through vasopressin-induced medullary urea transport and hyaluronan but needs further study. In addition, there are several systems that could protect the kidneys and reduce fluid retention such as natriuretic peptides, prostaglandins, and nitric oxide. However, the effect of natriuretic peptides and nitric oxide are blunted in decompensation, partly due to oxidative stress. This review considers how neurohormonal signaling in heart failure drives fluid retention by the kidneys and thus exacerbates decompensation. It further identifies areas where there is limited data, such as signaling systems 20-HETE, purines, endothelin, the role of renal water retention mechanisms for congestion, and renal hypoxia in AKI during heart failure.

  8. Angiotensin-(1-7)-induced renal vasodilation in hypertensive humans is attenuated by low sodium intake and angiotensin II co-infusion.

    PubMed

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

    2013-10-01

    Current evidence suggests that angiotensin-(1-7) plays an important role in the regulation of tissue blood flow. This evidence, however, is restricted to studies in animals and human forearm. Therefore, we studied the effects of intrarenal angiotensin-(1-7) infusion on renal blood flow in hypertensive humans. To assess the influence of renin-angiotensin system activity, sodium intake was varied and co-infusion with angiotensin II was performed in a subgroup. In 57 hypertensive patients who were scheduled for renal angiography, renal blood flow was measured ((133)Xenon washout method) before and during intrarenal infusion of angiotensin-(1-7) (3 incremental doses: 0.27, 0.9, and 2.7 ng/kg per minute). Patients were randomized into low or high sodium intake. These 2 groups of patients received angiotensin-(1-7), with or without intrarenal co-infusion of angiotensin II (0.3 ng/kg per minute). Angiotensin-(1-7) infusion resulted in intrarenal vasodilation in patients adhering to a sodium-rich diet. This vasodilatory effect of angiotensin-(1-7) was clearly attenuated by low sodium intake, angiotensin II co-infusion, or both. Regression analyses showed that the prevailing renin concentration was the only independent predictor of angiotensin-(1-7)-induced renal vasodilation. In conclusion, angiotensin-(1-7) induces renal vasodilation in hypertensive humans, but the effect of angiotensin-(1-7) is clearly attenuated by low sodium intake and co-infusion of angiotensin II. This supports the hypothesis that angiotensin-(1-7) induced renal vasodilation depends on the degree of renin-angiotensin-system activation.

  9. Effect of topical propranolol gel on plasma renin, angiotensin II and vascular endothelial growth factor in superficial infantile hemangiomas.

    PubMed

    Tang, Yu-juan; Zhang, Zai-zhong; Chen, Shao-quan; Chen, Shu-ming; Li, Cheng-jin; Chen, Jian-wei; Yuan, Bo; Xia, Yin; Wang, Lie

    2015-10-01

    The effect of topical propranolol gel on the levels of plasma renin, angiotensin II (ATII) and vascular endothelial growth factor (VEGF) in superficial infantile hemangiomas (IHs) was investigated. Thirty-three consecutive children with superficial IHs were observed pre-treatment, 1 and 3 months after application of topical propranolol gel for the levels of plasma renin, ATII and VEGF in Department of General Surgery of Dongfang Hospital from February 2013 to February 2014. The plasma results of IHs were compared with those of 30 healthy infants of the same age from out-patient department. The clinical efficiency of topical propranolol gel at 1st, and 3rd month after application was 45%, and 82% respectively. The levels of plasma renin, ATII and VEGF in patients pre-treatment were higher than those in healthy infants (565.86 ± 49.66 vs. 18.19 ± 3.56, 3.20 ± 0.39 vs 0.30 ± 0.03, and 362.16 ± 27.29 vs. 85.63 ± 8.14, P < 0.05). The concentrations of VEGF and renin at 1st and 3rd month after treatment were decreased obviously as compared with those pre-treatment (271.51 ± 18.59 vs. 362.16 ± 27.29, and 405.18 ± 42.52 vs. 565.86 ± 49.66 P < 0.05; 240.80 ± 19.89 vs. 362.16 ± 27.29, and 325.90 ± 35.78 vs. 565.86 ± 49.66, P < 0.05, respectively), but the levels of plasma ATII declined slightly (2.96 ± 0.37 vs. 3.20 ± 0.39, and 2.47 ± 0.27 vs. 3.20 ± 0.39, P > 0.05). It was indicated that the increased renin, ATII and VEGF might play a role in the onset or development of IHs. Propranolol gel may suppress the proliferation of IHs by reducing VEGF.

  10. Dissecting the genetic architecture of the cardiovascular and renal stress response.

    PubMed

    Snieder, Harold; Harshfield, Gregory A; Barbeau, Paule; Pollock, David M; Pollock, Jennifer S; Treiber, Frank A

    2002-10-01

    We review the evidence for a genetic basis of the cardiovascular and renal stress response. A bio-behavioral model of stress-induced hypertension is presented that explains how repeated exposure to stress in combination with genetic susceptibility might lead to the development of hypertension. In this model, we focus on three underlying physiological systems that mediate the stress response of the heart, vasculature and kidney: the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS) and the endothelial system (ES). We then review the evidence for a genetic influence on cardiovascular reactivity to psychological stress and stress-induced sodium retention using data from twin and family studies and a limited number of candidate gene studies. Finally, by describing the underlying physiological systems of our model and their genetic underpinning we emphasize the importance of inclusion of genetic measurements in any future studies testing the reactivity hypothesis.

  11. Common drugs for stabilization of renal function in the progression of diabetic nephropathy and their relations with hypertension therapy.

    PubMed

    Wang, Yuxuan; Wang, Chengcheng; Zhang, Xiuli; Gu, Harvest F; Wu, Liang

    2017-02-14

    Diabetic nephropathy is characterized by hypertension, progressive albuminuria, glomerulosclerosis and declines in glomerular filtration rate leading to end stage renal disease. Although the pathogenesis of diabetic nephropathy is not fully understood, current treatment of the patients with diabetic nephropathy is mainly based upon the control of hyperglycaemia and management of blood pressures. Several drugs, which are originally developed for hypertension therapy, have been adopted for stabilization of renal function in diabetic nephropathy. In this review, we first discuss the relationships between diabetic nephropathy and hypertension particularly in the renin-angiotensin-aldosterone system. We then summarize chemical structures, pharmacological characteristics and clinical studies of the common drugs used for treatment of diabetic nephropathy, while these drugs have effects against hypertension. This review may provide the constructive information for further drug development in diabetic nephropathy.

  12. [Management of patients with end-stage renal disease prior to initiation of renal replacement therapy in 2013 in France].

    PubMed

    Tuppin, Philippe; Cuerq, Anne; Torre, Sylvie; Couchoud, Cécile; Fagot-Campagna, Anne

    2017-04-01

    This study evaluated the management of patients with end-stage renal disease prior to initiation of renal replacement therapy. Among the 51 million national health insurance general scheme beneficiaries (77% of the population), persons 18 years and older, starting dialysis or undergoing preemptive renal transplantation in 2013, were included in this study. Data were derived from the French national health insurance system (SNIIRAM). In this population of 6674 patients (median age: 68 years), 88% initiated renal replacement therapy by haemodialysis, 8% by peritoneal dialysis, and 4% by renal transplantation. During the year preceding initiation of dialysis, 76% of patients had been hospitalised with at least one diagnostic code for renal disease in 83% of cases, 16% had not received any reimbursements for serum creatinine assay and 32% had not seen a nephrologist; 87% were taking at least one antihypertensive drug (60% were taking at least a renin-angiotensin system inhibitor) and 30% were taking a combination of 4 or more classes of antihypertensive drugs. For patients initiating haemodialysis in a haemodialysis centre, 39% had undergone a procedure related to arteriovenous fistula and 10% had been admitted to an intensive care unit. This study, based on the available reimbursement data, shows that, despite frequent use of the health care system by this population, there is still room for improvement of screening and management of patients with end-stage renal disease and preparation for renal replacement therapy.

  13. Children's toxicology from bench to bed--Drug-induced renal injury (1): The toxic effects of ARB/ACEI on fetal kidney development.

    PubMed

    Sekine, Takashi; Miura, Ken-ichiro; Takahashi, Kazuhiro; Igarashi, Takashi

    2009-01-01

    Development of fetal kidney is a finely programmed sequence, and is regulated by many important molecules. The perturbation of normal kidney development leads to congenital anomalies of kidney and urinary tract (CAKUT). CAKUT includes hypoplastic/dysplastic kidney, obstructive nephropathy and several other anomalies. CAKUT is of clinically importance, since it could lead to end stage renal failure when its anomaly grade is severe. So far, several causative genes responsible for development of CAKUT have been identified, including genes encoding molecules related to the renin-angiotensin-aldosterone system, RAS system. In humans, maternal administration of agents with inhibitory effects on the RAS system, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin type 1 receptor blockers (ARBs), have been reported to cause severe renal malformation, designated as ACEI/ARB fetopathy. In this paper, we overview the development of fetal kidney and address the effects of ACEIs/ARBs on fetal kidney.

  14. Sex hormones in the cardiovascular system.

    PubMed

    dos Santos, Roger Lyrio; da Silva, Fabrício Bragança; Ribeiro, Rogério Faustino; Stefanon, Ivanita

    2014-05-01

    Gender-associated differences in the development of cardiovascular diseases have been described in humans and animals. These differences could explain the low incidence of cardiovascular disease in women in the reproductive period, such as stroke, hypertension, and atherosclerosis. The cardiovascular protection observed in females has been attributed to the beneficial effects of estrogen on endothelial function. Besides estrogen, sex hormones are able to modulate blood pressure by acting on important systems as cardiovascular, renal, and neural. They can have complementary or antagonistic actions. For example, testosterone can raise blood pressure by stimulating the renin-angiotensin-aldosterone system, whereas estrogen alone or combined with progesterone has been associated with decreased blood pressure. The effects of testosterone in the development of cardiovascular disease are contradictory. Although some researchers suggest a positive effect, others indicate negative actions of testosterone. Estrogens physiologically stimulate the release of endothelium-derived vasodilator factors and inhibit the renin-angiotensin system. Although the cardioprotective effects of estrogen are widely appreciated, little is known about the effects of progesterone, which is commonly used in hormone replacement therapy. Progesterone has both vasodilatory and vasoconstrictive effects in the vasculature, depending on the location of the vessel and the level of exposure. Nevertheless, the mechanisms through which sex hormones modulate blood pressure have not been fully elucidated. Therefore, the characterization of those could lead to a better understanding of hypertension in women and men and perhaps to improved forms of therapy.

  15. Estimation of pressure gradients at renal artery stenoses

    NASA Astrophysics Data System (ADS)

    Yim, Peter J.; Cebral, Juan R.; Weaver, Ashley; Lutz, Robert J.; Vasbinder, G. Boudewijn C.

    2003-05-01

    Atherosclerotic disease of the renal artery can reduce the blood flow leading to renovascular hypertension and ischemic nephopathy. The kidney responds to a decrease in blood flow by activation of the renin-angiotensin system that increases blood pressure and can result in severe hypertension. Percutaneous translumenal angioplasty (PTA) may be indicated for treatment of renovascular hypertension (RVH). However, direct measurement of renal artery caliber and degree of stenosis has only moderate specificity for detection of RVH. A confounding factor in assessment of the proximal renal artery is that diffuse atherosclerotic disease of the distal branches of the renal artery can produce the same effect on blood-flow as atherosclerotic disease of the proximal renal artery. A methodology is proposed for estimation of pressure gradients at renal artery stenoses from magnetic resonance imaging that could improve the evaluation of renal artery disease. In the proposed methodology, pressure gradients are estimated using computational fluid dynamics (CFD) modeling. Realistic CFD models are constructed from images of vessel shape and measurements of blood-flow rates which are available from magnetic resonance angiography (MRA) and phase-contrast magnetic resonance (MR) imaging respectively. CFD measurement of renal artery pressure gradients has been validated in a physical flow-through model.

  16. Renal dysfunction and coronary disease: a high-risk combination.

    PubMed

    Schiele, Francois

    2009-01-01

    Chronic kidney dysfunction is recognized as a risk factor for atherosclerosis and complicates strategies and treatment. Therefore, it is important for cardiologists not only to detect and measure potential kidney dysfunction, but also to know the mechanisms by which the heart and kidney interact, and recognize that in cases of acute coronary syndrome, the presence of renal dysfunction increases the risk of death. The detection and classification of kidney dysfunction into 5 stages is based on the estimated glomerular filtration rate (GFR). The presence of hypertension, endothelial dysfunction, dyslipidemia, inflammation, activation of the renin-angiotensin system and specific calcifications are the main mechanisms by which renal dysfunction can induce or compound cardiovascular disease. The magnitude of renal dysfunction is related to the cardiovascular risk; a linear relation links the extent of GFR decrease and the risk of cardiovascular events. Renal dysfunction and acute coronary syndromes are a dangerous combination: more common comorbidities, more frequent contraindications for effective drugs and higher numbers of drug-related adverse events such as bleeding partially explain the higher mortality in patients with renal dysfunction. In addition, despite higher risk, patients with renal dysfunction often receive fewer guideline-recommended treatments even in the absence of contraindications. Renal dysfunction induces and promotes atherosclerosis by various pathophysiologic pathways and is associated with other cardiovascular risk factors and underuse of appropriate therapy. Therefore, the assessment of renal function is an important step in the risk evaluation of patients with coronary artery disease.

  17. Renal impairment and worsening of renal function in acute heart failure: can new therapies help? The potential role of serelaxin.

    PubMed

    Schmieder, Roland E; Mitrovic, Veselin; Hengstenberg, Christian

    2015-08-01

    Renal dysfunction is a frequent finding in patients with acute heart failure (AHF) and an important prognostic factor for adverse outcomes. Worsening of renal function occurs in 30-50% of patients hospitalised for AHF, and is associated with increased mortality, prolonged hospital stay and increased risk of readmission. Likely mechanisms involved in the decrease in renal function include impaired haemodynamics and activation of neurohormonal factors, such as the renin-angiotensin-aldosterone system, the sympathetic nervous system and the arginine-vasopressin system. Additionally, many drugs currently used to treat AHF have a detrimental effect on renal function. Therefore, pharmacotherapy for AHF should carefully take into account any potential complications related to renal function. Serelaxin, currently in clinical development for the treatment of AHF is a recombinant form of human relaxin-2, identical in structure to the naturally occurring human relaxin-2 peptide hormone that mediates cardiac and renal adaptations during pregnancy. Data from both pre-clinical and clinical studies indicate a potentially beneficial effect of serelaxin on kidney function. In this review, we discuss the mechanisms and impact of impairment of renal function in AHF, and the potential benefits of new therapies, such as serelaxin, in this context.

  18. A re-appraisal of volume status and renal function impairment in chronic heart failure: combined effects of pre-renal failure and venous congestion on renal function.

    PubMed

    Sinkeler, Steef J; Damman, Kevin; van Veldhuisen, Dirk J; Hillege, Hans; Navis, Gerjan

    2012-03-01

    in the context of current treatment where possible reflex neurohumoral activation is ameliorated by the background treatment by blockers of the renin-angiotensin-aldosterone system.

  19. We Avoid RAAS Inhibitors in PD Patients with Residual Renal Function.

    PubMed

    Turner, Jeffrey M

    2016-07-01

    Preserving residual renal function in patients on peritoneal dialysis (PD) positively impacts mortality. While it is important to avoid nephrotoxic agents in this setting, clinicians should appreciate that inhibitors of the renin-angiotensin-aldosterone system (RAAS), including angiotensin converting enzyme inhibitors, and angiotensin receptor blockers are likely to preserve glomerular filtration rate and prolong the time until patients on PD reach anuria, and this may improve mortality in these patients. In addition, RAAS blockade favorably affects the peritoneal membrane by reducing morphologic changes that can lead to ultrafiltration failure. This in turn may delay or prevent modality failure in patients on PD. Thus, clinicians should avoid the impulse to stop RAAS inhibitors in the PD population.

  20. Meta-Analysis of the Effect of Dietary Sodium Restriction with or without Concomitant Renin-Angiotensin-Aldosterone System–Inhibiting Treatment on Albuminuria

    PubMed Central

    D’Elia, Lanfranco; Rossi, Giovanni; Schiano di Cola, Michele; Savino, Ivana; Galletti, Ferruccio

    2015-01-01

    Background and objectives Urinary albumin excretion and/or albumin to creatinine ratio are associated with CKD and higher risk of cardiovascular events. Several studies investigated the effect of reduced dietary sodium intake on urinary albumin excretion and/or albumin to creatinine ratio in adult patient populations, but the majority was inconclusive because of insufficient statistical power. A meta-analysis of the randomized, controlled trials available could overcome this problem and lead to more definitive conclusions. Design, setting, participants, & measurements A systematic search of the online databases available (from 1996 to October of 2014) was conducted of randomized, controlled trials that expressed urinary albumin excretion or albumin to creatinine ratio as the difference between the effects of two different sodium intake regimens. For each study, the mean difference and 95% confidence intervals were pooled using a random effect model. Heterogeneity, publication bias, subgroup, and meta-regression analyses were performed. Results Eleven studies met the predefined inclusion criteria and provided 23 cohorts with 516 participants and 1–6 weeks of follow-up time. In the pooled analysis, an average reduction in sodium intake of 92 mmol/d was associated with a 32.1% (95% confidence interval, −44.3 to −18.8) reduction in urinary albumin excretion. The effect of sodium restriction was higher in the cohorts including patients on concomitant renin-angiotensin-aldosterone system–blocking therapy, in the studies with intervention lasting at least 2 weeks, and among participants with evidence of kidney damage. A greater reduction of urinary albumin excretion was associated with a higher decrease in BP during the intervention. The analysis of changes in albumin to creatinine ratio provided similar results. Conclusions This meta-analysis indicates that sodium intake reduction markedly reduces albumin excretion, more so during concomitant renin-angiotensin

  1. Effect of inhibition of converting enzyme on renal hemodynamics and sodium management in polycystic kidney disease.

    PubMed

    Torres, V E; Wilson, D M; Burnett, J C; Johnson, C M; Offord, K P

    1991-10-01

    We compared the tubular transport of sodium and the erythrocyte sodium-lithium countertransport activity in hypertensive patients with autosomal dominant polycystic kidney disease (ADPKD) and in normotensive control subjects. In addition, we assessed the effects of inhibition of converting enzyme on renal hemodynamics and sodium excretion in hypertensive patients with ADPKD to provide information on mechanisms responsible for the increased renal vascular resistance and filtration fraction and the adjustment of the pressure-natriuresis relationship during saline expansion, observed in patients with ADPKD, hypertension, and preserved renal function. In comparison with normotensive control subjects, the hypertensive patients with ADPKD had lower renal plasma flows, higher renal vascular resistances and filtration fractions, and similar proximal and distal fractional reabsorptions of sodium. The administration of enalapril resulted in significant increases in the renal plasma flow and significant reductions in mean arterial pressure, renal vascular resistance, and filtration fraction, but the glomerular filtration rate remained unchanged. Despite the significant reduction in mean arterial pressure during inhibition of converting enzyme, the distal fractional reabsorption of sodium decreased while the total fractional excretion of sodium remained unchanged or increased slightly. No significant differences were detected between the normotensive control subjects and the hypertensive patients with ADPKD in erythrocyte sodium-lithium countertransport activity, plasma renin activity, plasma aldosterone concentration, or atrial natriuretic factor. These results suggest that the renal renin-angiotensin system plays a central role in the alterations in renal hemodynamics and sodium management associated with the development of hypertension in ADPKD.

  2. Angiotensin II Blockade and Renal Protection

    PubMed Central

    Kobori, Hiroyuki; Mori, Hirohito; Masaki, Tsutomu; Nishiyama, Akira

    2013-01-01

    Current national guidelines have recommended the use of renin-angiotensin system inhibitors, including angiotensin II type 1 receptor blockers (ARBs), in preference to other antihypertensive agents for treating hypertensive patients with chronic kidney disease. However, the mechanisms underlying the renoprotective effects of ARBs are multiple and complex. Blood pressure reduction by systemic vasodilation with an ARB contributes to its beneficial effects in treating kidney disease. Furthermore, ARB-induced renal vasodilation results in an increase in renal blood flow, leading to improvement of renal ischemia and hypoxia. ARBs are also effective in reducing urinary albumin excretion through a reduction in intraglomerular pressure and the protection of glomerular endothelium and/or podocyte injuries. In addition to blocking angiotensin II-induced renal cell and tissue injuries, ARBs can decrease intrarenal angiotensin II levels by reducing proximal tubular angiotensinogen and production of collecting duct renin, as well as angiotensin II accumulation in the kidney. In this review, we will briefly summarize our current understanding of the pharmacological effects of an ARB in the kidney. We will also discuss the possible mechanisms responsible for the renoprotective effects of ARBs on type 2 diabetic nephropathy. PMID:23176216

  3. Renal development: a complex process dependent on inductive interaction.

    PubMed

    Upadhyay, Kiran K; Silverstein, Douglas M

    2014-01-01

    Renal development begins in-utero and continues throughout childhood. Almost one-third of all developmental anomalies include structural or functional abnormalities of the urinary tract. There are three main phases of in-utero renal development: Pronephros, Mesonephros and Metanephros. Within three weeks of gestation, paired pronephri appear. A series of tubules called nephrotomes fuse with the pronephric duct. The pronephros elongates and induces the nearby mesoderm, forming the mesonephric (Woffian) duct. The metanephros is the precursor of the mature kidney that originates from the ureteric bud and the metanephric mesoderm (blastema) by 5 weeks of gestation. The interaction between these two components is a reciprocal process, resulting in the formation of a mature kidney. The ureteric bud forms the major and minor calyces, and the collecting tubules while the metanephrogenic blastema develops into the renal tubules and glomeruli. In humans, all of the nephrons are formed by 32 to 36 weeks of gestation. Simultaneously, the lower urinary tract develops from the vesico urethral canal, ureteric bud and mesonephric duct. In utero, ureters deliver urine from the kidney to the bladder, thereby creating amniotic fluid. Transcription factors, extracellular matrix glycoproteins, signaling molecules and receptors are the key players in normal renal development. Many medications (e.g., aminoglycosides, cyclooxygenase inhibitors, substances that affect the renin-angiotensin aldosterone system) also impact renal development by altering the expression of growth factors, matrix regulators or receptors. Thus, tight regulation and coordinated processes are crucial for normal renal development.

  4. The role of the sympathetic nervous system in obesity-related hypertension.

    PubMed

    da Silva, Alexandre A; do Carmo, Jussara; Dubinion, John; Hall, John E

    2009-06-01

    Obesity is recognized as a major health problem throughout the world. Excess weight is a major cause of increased blood pressure in most patients with essential hypertension and greatly increases the risk for diabetes, cardiovascular diseases, and end-stage renal disease. Although the mechanisms by which obesity raises blood pressure are not completely understood, increased renal sodium reabsorption, impaired pressure natriuresis, and volume expansion appear to play important roles. Several potential mechanisms have been suggested to contribute to altered kidney function and hypertension in obesity, including activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system, as well as physical compression of the kidneys, especially when visceral obesity is present. Activation of the sympathetic nervous system in obesity may be due, in part, to hyperleptinemia and other factors secreted by adipocytes and the gastrointestinal tract, activation of the central nervous system melanocortin pathway, and baroreceptor dysfunction.

  5. Calcium channel blockade in combination with angiotensin-converting enzyme inhibition or angiotensin II (AT(1)-receptor) antagonism in hypertensive diabetics and patients with renal disease and hypertension.

    PubMed

    Swales, Philip; Williams, Bryan

    2002-06-01

    Effective reduction in blood pressure (BP) improves survival and morbidity in hypertensive patients. Combination therapy with multiple antihypertensive agents is frequently required in clinical practice and therapeutic trials to achieve target BP. Patients at elevated cardiovascular risk achieve the greatest benefit from equivalent reduction in BP and also require more stringent BP control. In patients with hypertension and diabetes mellitus or renal disease, BP control is of primary importance and blockade of the renin-angiotensin system (RAS) should be the initial therapeutic intervention. Choice of combination therapy has been insufficiently studied in major clinical cardiovascular endpoint trials. Diuretic therapy remains the logical addition to RAS blockade. Despite previous debate, the available evidence suggests long-acting calcium-channel blockers are also a safe and very effective addition to improve BP control further. The choice of antihypertensive combination therapy should not override the fundamental necessity of lowering BP to target levels.

  6. Renal ischaemia, transient glomerular leak and acute renal tubular damage in patients envenomed by Russell's vipers (Daboia russelii siamensis) in Myanmar.

    PubMed

    Tin-Nu-Swe; Tin-Tun; Myint-Lwin; Thein-Than; Tun-Pe; Robertson, J I; Leckie, B J; Phillips, R E; Warrell, D A

    1993-01-01

    Fifty-two patients who had been bitten by Russell's vipers in Myanmar developed acute renal failure (serum creatinine exceeding 1.3 mg/dL). Thirty-four of them (65%) became oliguric, but the other 18 (35%) maintained a urine output of more than 400 mL/24 h. In oliguric patients, gastrointestinal haemorrhages, renal angle tenderness and conjunctival oedema occurred more commonly, and peak serum creatinine, blood urea nitrogen and the fractional excretion of sodium were significantly higher (P < 0.01) than in non-oliguric patients, indicating a greater degree of renal damage. Urinary concentrations of beta 2 microglobulin and retinol binding protein were raised in most of the patients indicating failure of proximal tubular reabsorption of these proteins, while high urinary N-acetyl glucosaminidase concentrations were consistent with renal tubular damage. Plasma concentrations of active renin were very high, suggesting that renal ischaemia, associated with activation of the renin-angiotensin system, was involved in the development of renal dysfunction.

  7. Hypertension in children with end-stage renal disease.

    PubMed

    Roszkowska-Blaim, Maria; Skrzypczyk, Piotr

    2015-09-01

    This review summarizes current data on the epidemiology, pathophysiology, and treatment of hypertension (HTN) in children with end-stage renal disease (ESRD). Worldwide prevalence of ESRD ranges from 5.0 to 84.4 per million age-related population. HTN is present in 27-79% of children with ESRD, depending on the modality of renal replacement therapy and the exact definition of hypertension. Ambulatory BP monitoring has been recommended for the detection of HTN and evaluation of treatment effectiveness. HTN in dialyzed patients is mostly related to hypervolemia, sodium overload, activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, impaired nitric oxide synthesis, reduced vitamin D levels, and effects of microRNA. In children undergoing chronic dialysis therapy, important factors include optimization of renal replacement therapy and preservation of residual renal function, allowing reduction of volume- and sodium-overload, along with appropriate drug treatment, particularly with calcium channel blockers, RAAS inhibitors, and loop diuretics.

  8. Transplant renal artery stenosis: clinical manifestations, diagnosis and therapy.

    PubMed

    Chen, Wei; Kayler, Liise K; Zand, Martin S; Muttana, Renu; Chernyak, Victoria; DeBoccardo, Graciela O

    2015-02-01

    Transplant renal artery stenosis (TRAS) is a well-recognized vascular complication after kidney transplant. It occurs most frequently in the first 6 months after kidney transplant, and is one of the major causes of graft loss and premature death in transplant recipients. Renal hypoperfusion occurring in TRAS results in activation of the renin-angiotensin-aldosterone system; patients usually present with worsening or refractory hypertension, fluid retention and often allograft dysfunction. Flash pulmonary edema can develop in patients with critical bilateral renal artery stenosis or renal artery stenosis in a solitary kidney, and this unique clinical entity has been named Pickering Syndrome. Prompt diagnosis and treatment of TRAS can prevent allograft damage and systemic sequelae. Duplex sonography is the most commonly used screening tool, whereas angiography provides the definitive diagnosis. Percutaneous transluminal angioplasty with stent placement can be performed during angiography if a lesion is identified, and it is generally the first-line therapy for TRAS. However, there is no randomized controlled trial examining the efficacy and safety of percutaneous transluminal angioplasty compared with medical therapy alone or surgical intervention.

  9. Development of hypertension and effects of benazepril hydrochloride in a canine remnant kidney model of chronic renal failure.

    PubMed

    Mishina, Mika; Watanabe, Toshifumi

    2008-05-01

    In order to determine whether hypertension would develop in dogs with chronic renal failure, we performed 7/8 renal ablation in 6 healthy dogs and compared pre- and post-ablation blood pressures determined by telemetry. One month after the renal ablation, blood urea nitrogen and creatinine were significantly increased (p<0.05), creatinine clearance was decreased (p<0.05), and blood pressure was increased significantly (p<0.05). Simultaneously, plasma renin activity, angiotensin I and II, and aldosterone were elevated significantly (p<0.05) compared with the values obtained from 11 healthy dogs with intact renal function. The dogs with induced renal failure and hypertension were administered an angiotensin-converting enzyme inhibitor, benazepril hydrochloride, once daily for 2 weeks at 2 mg/kg body weight, and changes in blood pressure and the renin-angiotensin-aldosterone (RAA) system were determined. During the administration of benazepril hydrochloride, blood pressure, angiotensin II and aldosterone decreased significantly (p<0.05) and, upon discontinuation of administration, increased to the pre-administration levels (p<0.05). Plasma renin activity and angiotensin I showed no significant changes throughout the administration study. These results provide experimental evidence that hypertension develops in dogs with chronic renal failure through mechanisms involving the RAA system and demonstrate that benazepril hydrochloride improves renal hypertension in dogs.

  10. [Ibopamine--acute hemodynamic, renal and neurohumoral effects].

    PubMed

    Wehling, M; Theisen, K

    1991-01-01

    Ibopamine (IP) is a novel dopamine analogue for which beneficial effects have been shown in chronic heart failure. Hemodynamic effects of the substance include an increase in cardiac output and a decrease in the peripheral resistance. Aside from these hemodynamic effects, changes in renal (increased diuresis) and neurohumoral parameters (decreased plasma renin activity, aldosterone, norepinephrine, increased ANF and cGMP) have been found. The renal effects may originate from three independent mechanisms: 1) direct impact of improved hemodynamic parameters on the renal perfusion; 2) the improved cardiac performance results in a reduction of compensatory hormonal adaptations, such as the activation of the renin-angiotensin-aldosterone-axis or the sympathetic system; 3) direct effects on the intrarenal hemodynamic and glomerular/tubular functions induced by stimulation of renal dopaminergic receptors. The continued decrease of the plasma renin activity by 35% results in a reduction of the plasma levels of angiotensin II and aldosterone. Additionally, an increase in plasma atrial natriuretic factor (ANF) and its second messenger cyclic guanosine monophosphate (cGMP) was observed after ibopamine, which could contribute to the diuretic action of the drug. These findings underline the importance of extrarenal effects of a drug in the treatment of heart failure, this may essentially contribute to the improvement of cardiac performance, independent of positive inotropy.

  11. Renal hypertension and cardiovascular disorder in children with chronic kidney disease.

    PubMed

    Peco-Antić, Amira; Paripović, Dusan

    2014-01-01

    Renal hypertension is one of the earliest and the most prevalent complications of pediatric chronic kidney disease (CKD). Among renal patients, hypertension is frequently underdiagnosed and undertreated. For casual blood pressure measurement, the best method is auscultatory, while for ambulatory blood pressure measurement, oscillometric method is the most commonly used. Both casual and ambulatory blood pressure measurement provide more powerful means of diagnosing hypertension. Masked hypertension is a condition in which casual blood pressure is normal but ambulatory blood pressure is elevated. The risk of cardiovascular morbidity and mortality is higher with masked hypertension as compared to the controls. Children and adolescents with CKD are at high risk of cardiovascular disease that has been established as the leading cause of death in patients with end stage renal disease. Left ventricular hypertrophy remains the most thoroughly documented form of end-organ damage caused by hypertension in children and adolescents with CKD. Based on clear evidence on the correlation between blood pressure and cardiovascular morbidity, mortality, and renal function, renal hypertension must be aggressively treated. Target blood pressure for patients with renal hypertension should be at low normal values: < 75 percentile for patients without proteinuria and <50 percentile for patients with proteinuria. Renin-angiotensin system antagonists are considered the first choice pharmacological option in hypertensive CKD 2-4 patients while the management of volume overload is the most important in dialysis patients. Successful transplantation can eliminate or significantly improve uremia-related cardiovascular risk factors and increase predicted life expectancy.

  12. Sodium sensitive hypertension: renal and adrenal non-modulation in its pathogenesis

    NASA Technical Reports Server (NTRS)

    Hollenberg, N. K.; Williams, G. H.

    1988-01-01

    The thrust of this essay will be to organize a growing body of evidence which indicates that an abnormality of the kidney, and the adrenal, involving disordered regulation through the renin-angiotensin system, is responsible for the pathogenesis in about 45% of patients--a discrete subgroup that may be most common cause of hypertension. That fundamental abnormality leads to disordered renal sodium handling and sodium-sensitive hypertension, abnormalities in the renal vascular response to changes in sodium intake and to angiotensin II, blunted decrements of renin release in response to saline or angiotensin II, and an accentuated renal vasodilator response to angiotensin converting enzyme (ACE) inhibition. ACE inhibition not only increases renal blood flow substantially more in these patients than it does in normal subjects, ACE inhibition also restores to normal the renal vascular and adrenal response to angiotensin II, renin release in response to angiotensin II, renal sodium handling--and ultimately blood pressure. Finally, and perhaps most intriguing, similar abnormalities have been found in 50% of the normotensive offspring of patients with essential hypertension and evidence is accruing to indicate that the abnormality is inherited as a Mendelian dominant.

  13. Protection against age-dependent renal injury in the F344xBrown Norway male rat is associated with maintained nitric oxide synthase.

    PubMed

    Moningka, Natasha C; Sasser, Jennifer M; Croker, Byron; Carter, Christy; Baylis, Chris

    2011-01-01

    Age-dependent renal damage is influenced by genetic background and the Fisher344xBrown Norway (F344xBN) rat is resistant to glomerular injury. In vulnerable strains, a fall in renal nitric oxide synthase (NOS) contributes to age-dependent renal damage. Here, we investigated renal NOS in young (3 months) and old (30 months) male F344xBN to test the hypothesis that renal NOS is maintained in "protected" strains. We also examined if 6 months of renin-angiotensin system (RAS) blockade using angiotensin converting enzyme inhibition (ACEI) and angiotensin receptor blockade (ARB) provides further benefit in these "protected" old rats. Aging increased tubulointerstitial injury but glomerular sclerosis was minimal and NOS and superoxide dismutase abundance increased. There was no change in the NOS inhibitor, ADMA (asymmetric dimethylarginine) or its regulatory enzymes. RAS blockade with ARB protected against tubulointerstitial injury and increased nNOSα, but ACEI, which also increased nNOSα, had no protective effect on the tubulointerstitium. We conclude that the glomerular sclerosis-resistant aged male F344xBN rat maintains renal NOS, thus reinforcing our hypothesis that progressive glomerular injury is related to renal NOS deficiency. The tubulointerstitial injury seen with aging is reversed with 6 months of ARB but not ACEI and is not associated with renal NOS.

  14. The effect of aliskiren on the renal dysfunction following unilateral ureteral obstruction in the rat

    PubMed Central

    Hammad, Fayez T; Lubbad, Loay

    2016-01-01

    Purpose: To investigate the effect of blocking renin-angiotensin system by direct renin inhibition using aliskiren on the renal dysfunction following reversible unilateral ureteral obstruction (UO). Methods: Wistar rats underwent reversible left UO for 72 hours. Group-Alsk (n=12) received aliskiren (30 mg/kg/day) dissolved in water starting one day before creating UO and continued until the terminal experiment five days post reversal when renal functions were measured using clearance techniques. Group-Vx (n=12) underwent similar protocol but had water only. Gene expression analysis of some markers of kidney injury was measured using PCR technique. Results: In Group-Vx, renal blood flow (RBF) and glomerular filtration rate (GFR) in the left kidney were significantly lower than the right kidney (1.82±0.12 vs. 3.19±0.40, P=0.001 and 0.81±0.08 vs. 1.44±0.09, P=0.004, respectively). However, left fractional excretion of sodium (FENa) was higher than the right FENa (0.80±0.15 vs. 0.55±0.04, P=0.05). Comparing the left obstructed kidney in Group-Alsk vs. Group-Vx, RBF and GFR were higher in Group-Alsk (2.44±0.30 vs. 1.82±0.12, P=0.049 and 1.02±0.11 vs. 0.81±0.08, P=0.07, respectively). The left renal FENa was lower in Group-Alsk but did not reach statistical significance (0.54±0.07 vs. 0.80±0.15, P=0.07). Aliskiren also decreased the gene expressions of NGAL, KIM-1 and p53. Conclusion: Direct renin inhibition by aliskiren appears to have protective effect on the renal dysfunction and on the markers of renal injury following UO indicating a potential clinical benefit of this agent. Further, this data and the previous studies indicate that blocking renin-angiotensin system at any level has a protective effect in obstructive nephropathy. PMID:27570581

  15. Structural renal changes in obesity and diabetes.

    PubMed

    Amann, Kerstin; Benz, Kerstin

    2013-01-01

    Overweight, obesity, and associated diseases represent an emerging problem, not only in Western countries but also in the developing world. They are now characterized as epidemic diseases. Obesity is particularly serious because its incidence in children and adolescents increased dramatically: it is estimated that in the United States every eighth adolescent suffers from obesity, which in the long run may reduce life expectancy in the population. Apart from cardiovascular disease (ie, blood pressure, stroke, and coronary heart disease), kidney diseases also have been shown to be associated with obesity. Epidemiologic studies have indicated that obesity can be a risk factor of chronic kidney disease irrespective of the presence or absence of diabetes, arterial hypertension, and other comorbidities. More evidence is accumulated on the link between chronic kidney disease in obesity and abnormalities in adipokine secretion (hyperleptinemia, lack of adiponectin), activation of the renin-angiotensin system, chronic inflammation, endothelial dysfunction, lipid accumulation, impaired renal hemodynamics, and diminished nephron number related to body mass. In general, obesity is known to aggravate the course of many primary renal diseases such as glomerulonephritides, but also impairs renal function after kidney transplantation. Microalbuminuria, proteinuria, hyperfiltration, and impaired renal function are associated with obesity. Histologically, secondary focal segmental sclerosis has been shown to be caused particularly by obesity. Of practical purpose for clinical nephrology, loss of body weight either by lifestyle modification or bariatric surgery improves albuminuria and hyperfiltration in obese patients, making renal disease in obesity accessible for prevention programs. This review specifically addresses the pathogenesis and morphology of renal functional and particularly structural changes in obesity and associated renal disease such as diabetic nephropathy.

  16. Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers.

    PubMed

    Lambers Heerspink, Hiddo J; Holtkamp, Frank A; Parving, Hans-Henrik; Navis, Gerjan J; Lewis, Julia B; Ritz, Eberhard; de Graeff, Pieter A; de Zeeuw, Dick

    2012-08-01

    Dietary sodium restriction has been shown to enhance the short-term response of blood pressure and albuminuria to angiotensin receptor blockers (ARBs). Whether this also enhances the long-term renal and cardiovascular protective effects of ARBs is unknown. Here we conducted a post-hoc analysis of the RENAAL and IDNT trials to test this in patients with type 2 diabetic nephropathy randomized to ARB or non-renin-angiotensin-aldosterone system (non-RAASi)-based antihypertensive therapy. Treatment effects on renal and cardiovascular outcomes were compared in subgroups based on dietary sodium intake during treatment, measured as the 24-h urinary sodium/creatinine ratio of 1177 patients with available 24-h urinary sodium measurements. ARB compared to non-RAASi-based therapy produced the greatest long-term effects on renal and cardiovascular events in the lowest tertile of sodium intake. Compared to non-RAASi, the trend in risk for renal events was significantly reduced by 43%, not changed, or increased by 37% for each tertile of increased sodium intake, respectively. The trend for cardiovascular events was significantly reduced by 37%, increased by 2% and 25%, respectively. Thus, treatment effects of ARB compared with non-RAASi-based therapy on renal and cardiovascular outcomes were greater in patients with type 2 diabetic nephropathy with lower than higher dietary sodium intake. This underscores the avoidance of excessive sodium intake, particularly in type 2 diabetic patients receiving ARB therapy.

  17. Role of the renin-angiotensin system in the regulation of intestinal blood flow and sympathetic neurotransmission

    SciTech Connect

    Suvannapura, A.

    1988-01-01

    The aims of the present studies were (1) to determine if endogenous angiotensin II (Ang II) plays a role in the local control of mesenteric blood flow (MBF) following volume depletion in anesthetized dogs, and (2) to investigate the mechanism(s) of actions of Ang II on the facilitation of sympathetic neurotransmission in the rate jejunum. To investigate the role of endogenous Ang II in the control of MBF, a dose of an antagonist of Ang II, saralasin, that has effects mainly localized to the mesenteric circulation was determined. The data demonstrated that blockage of actions of Ang II in the mesenteric circulation resulted in a decrease in intestinal vasoconstriction which occurred following acute hypotensive hemorrhage. The effect of Ang II on the uptake and release of norepinephrine from sympathetic nerve endings in the rat jejunum was investigated. The uptake of norepinephrine in rat jejunum was determined by incubating jejunal slices in Krebs buffer containing 0.01 {mu}M {sup 3}H-norepinephrine. The accumulation of label in the tissue after 10 min incubation was determined by liquid scintillation spectrometry. Intracellular uptake of {sup 3}H-norepinephrine was calculated and shown to be an active process.

  18. 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

  19. Reducing Disease Activity in Animal Models of MS by Activation of the Protective Arm of the Renin-Angiotensin System

    DTIC Science & Technology

    2015-10-01

    angiotensin metabolites. The regulatory arm of RAS was activated in an effort to stimulate repair once the immunological and pathological... immunological bias at the most efficacious dose of A(1-7). What was accomplished under these goals? Below is a summary of the statement of work that was...the regulatory arm of RAS there was a clear and dramatic loss of MAS receptor expression within 4 days of inoculation when innate components of the

  20. Effects of captopril on the renin angiotensin system, oxidative stress, and endothelin in normal and hypertensive rats.

    PubMed

    Bolterman, Rodney J; Manriquez, Melissa C; Ortiz Ruiz, M Clara; Juncos, Luis A; Romero, J Carlos

    2005-10-01

    There is substantial evidence suggesting that angiotensin II plays an important role in elevating blood pressure of spontaneously hypertensive rats, despite normal plasma renin activity, and that converting enzyme inhibitors (captopril) can effectively normalize blood pressure in the spontaneously hypertensive rats. One mechanism by which angiotensin II induces hypertension is via oxidative stress and endothelin, as seen in subpressor angiotensin II-induced hypertension. In fact, it has been shown that antioxidants lower mean arterial pressure in spontaneously hypertensive rats. However, the relationship between angiotensin II, oxidative stress, and endothelin in the spontaneously hypertensive rats is still relatively undefined. This study examines the relationship between mean arterial pressure, plasma renin activity, angiotensin II, oxidative stress, and endothelin in spontaneously hypertensive rats compared with normotensive Wistar Kyoto rats, and the effects of captopril on this association. Untreated spontaneously hypertensive rats had increased plasma angiotensin II levels despite normal plasma renin activity, oxidative stress, and endothelin. Captopril treatment in spontaneously hypertensive rats lowered mean arterial pressure, angiotensin II, oxidative stress, and endothelin, and increased plasma renin activity. In contrast, captopril increased plasma renin activity (suggesting effective captopril treatment) but did not significantly alter mean arterial pressure, angiotensin II, oxidative stress, or endothelin of Wistar Kyoto rats. These results suggest that in spontaneously hypertensive rats, angiotensin II is a primary instigator of hypertension, and that captopril selectively lowers angiotensin II, oxidant stress, and endothelin, which in turn may contribute to the blood pressure-lowering efficacy of captopril in spontaneously hypertensive rats.

  1. Responses of sympathoadrenal and renin angiotensin systems to stress stimuli in humans during real and simulated microgravity.

    PubMed

    Kvetnansky, R; Koska, J; Ksinantova, L; Noskov, V B; Blazicek, P; Marko, M; Macho, L; Grigoriev, A I; Vigas, M

    2002-07-01

    Changes of plasma hormone levels were investigated in human subjects after exposure to physical exercise (WL) and insulin induced hypoglycemia (ITT) during space flight or after head down bed rest (HDBR). Exaggerated responses of plasma epinephrine (EPI), norepinephrine (NE) and aldosterone (ALD) were observed after WL during space flight as compared to preflight response. Hypoglycemia during space flight induced attenuated responses of EPI, NE and augmented response of ALD. Exposure to WL during HDBR was followed by significantly exaggerated responses of plasma EPI, NE, ALD, PRA and cortisol. In HDBR the responses of plasma EPI, NE and cortisol were reduced and PRA response was exaggerated during ITT. These data indicate that hormonal responses to ITT and WL are similar at real and simulated microgravity.

  2. Molecular mechanism of vitamin D in the cardiovascular system.

    PubMed

    Li, Yan Chun

    2011-08-01

    Vitamin D deficiency is a global health problem that has various adverse consequences. Vitamin D is mainly synthesized in the skin by sunlight (UV light) irradiation; therefore, vitamin D status is influenced by geographic locations, seasonal changes, and skin pigmentations. The kidney is involved in the biosynthesis of 1,25-dihydroxyvitamin D and the reuptake of filtered 25-hydroxyvitamin D from the proximal tubules, thus, vitamin D deficiency is highly prevalent in patients with kidney disease who have renal insufficiency. There is a growing body of epidemiological and clinical evidence in the literature that links vitamin D deficiency to cardiovascular disease. The discovery of the vitamin D hormone functioning as an endocrine inhibitor of the renin-angiotensin system provides an explanation for this association. This review will discuss the mechanism underlying the connection between vitamin D and cardiovascular disease and its physiological and therapeutic implications.

  3. Renal function impairment induced by change in posture in patients with cirrhosis and ascites.

    PubMed Central

    Bernardi, M; Santini, C; Trevisani, F; Baraldini, M; Ligabue, A; Gasbarrini, G

    1985-01-01

    The assumption of upright posture by patients with liver cirrhosis leads to striking activation of adrenergic and renin-angiotensin systems. The tilting-induced modifications in renal function of eight healthy controls and 14 untreated patients with liver cirrhosis and ascites were related to plasma concentrations of noradrenaline, renin activity and aldosterone. All patients had preserved renal blood perfusion. All parameters were evaluated during bed rest for two hours and in the sitting posture for one hour. Basal plasma renin activity (0.1 greater than p greater than 0.05), aldosterone and noradrenaline concentrations (p less than or equal to 0.01) were raised in cirrhotics. The renal function tests (creatinine clearance, filtered sodium, tubular rejection fraction, urinary sodium excretion) were significantly reduced in cirrhosis. Under basal conditions, in cirrhotic patients tubular rejection fraction and urinary sodium excretion were inversely related to both noradrenaline and aldosterone concentrations. After tilting, the noradrenaline and aldosterone integrated outputs (sigma delta) were significantly greater in cirrhosis. All renal function tests significantly decreased in cirrhotics, whereas creatinine clearance only significantly decreased in controls. Patient's tubular rejection fraction of sodium and sodium excretion were related to sigma delta aldosteronaemia (r = -0.72; p less than 0.01), but no longer to sigma delta plasma noradrenaline. PMID:3891534

  4. Predisposition to essential hypertension and renal hemodynamics in recent-onset insulin-dependent diabetic patients.

    PubMed

    Hannedouche, T P; Marques, L P; Guicheney, P; Lacour, B; Boitard, C; Grünfeld, J P

    1992-10-01

    The offspring of essential hypertensive parents have been found to exhibit abnormalities in renal hemodynamics and sodium handling before the eventual occurrence of hypertension. The reported abnormalities represent a wide spectrum of changes including increased GFR, normal or decreased RPF, slight increase in blood pressure (although within the normal range), and an exaggerated natriuresis response to a sodium load. The heterogeneity of these abnormalities may reflect the specific conditions of the studies, the lability of the changes, or different subgroups of subjects with genetic predisposition to essential hypertension. Several lines of evidence have suggested a relationship between hypertension and the development of diabetic nephropathy in insulin-dependent diabetics. This laboratory has found that recent-onset insulin-dependent diabetics can exhibit renal hemodynamics abnormalities very early in the course of diabetes according to a positive or negative family history of essential hypertension. These changes include increased GFR and mean arterial pressure, but no differences in renal sodium and lithium handling in diabetics with a genetic predisposition to essential hypertension. In addition, diabetics with a positive family history of essential hypertension exhibited a more-marked vasodilative response to an acute interruption of the renin-angiotensin system, further suggesting inadequate angiotensin modulation of renal vascular tone. The significance of these abnormalities in relation to the development of diabetic nephropathy requires further investigation.

  5. Advances in renal (patho)physiology using multiphoton microscopy.

    PubMed

    Sipos, A; Toma, I; Kang, J J; Rosivall, L; Peti-Peterdi, J

    2007-11-01

    Multiphoton excitation fluorescence microscopy is a state-of-the-art confocal imaging technique ideal for deep optical sectioning of living tissues. It is capable of performing ultrasensitive, quantitative imaging of organ functions in health and disease with high spatial and temporal resolution which other imaging modalities cannot achieve. For more than a decade, multiphoton microscopy has been successfully used with various in vitro and in vivo experimental approaches to study many functions of different organs, including the kidney. This study focuses on recent advances in our knowledge of renal (patho)physiological processes made possible by the use of this imaging technology. Visualization of cellular variables like cytosolic calcium, pH, cell-to-cell communication and signal propagation, interstitial fluid flow in the juxtaglomerular apparatus (JGA), real-time imaging of tubuloglomerular feedback (TGF), and renin release mechanisms are reviewed. A brief summary is provided of kidney functions that can be measured by in vivo quantitative multiphoton imaging including glomerular filtration and permeability, concentration, dilution, and activity of the intrarenal renin-angiotensin system using this minimally invasive approach. New visual data challenge a number of existing paradigms in renal (patho)physiology. Also, quantitative imaging of kidney function with multiphoton microscopy has tremendous potential to eventually provide novel non-invasive diagnostic and therapeutic tools for future applications in clinical nephrology.

  6. Effects of reducing blood pressure on renal outcomes in patients with type 2 diabetes: Focus on SGLT2 inhibitors and EMPA-REG OUTCOME.

    PubMed

    Scheen, A J; Delanaye, P

    2017-01-30

    Empagliflozin, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, has enabled remarkable reductions in cardiovascular and all-cause mortality as well as in renal outcomes in patients with type 2 diabetes (T2D) and a history of cardiovascular disease in the EMPA-REG OUTCOME. These results have been attributed to haemodynamic rather than metabolic effects, in part due to the osmotic/diuretic action of empagliflozin and the reduction in arterial blood pressure (BP). The present narrative review includes the results of meta-analyses of trials evaluating the effects on renal outcomes of lowering BP in patients with T2D, with a special focus on the influence of baseline and achieved systolic BP, and compares the renal outcome results of the EMPA-REG OUTCOME with those of other major trials with inhibitors of the renin-angiotensin system in patients with T2D and the preliminary findings with other SGLT2 inhibitors, and also evaluates post hoc analyses from the EMPA-REG OUTCOME of special interest as regards the BP-lowering hypothesis and renal function. While systemic BP reduction associated to empagliflozin therapy may have contributed to the renal benefits reported in EMPA-REG OUTCOME, other local mechanisms related to kidney homoeostasis most probably also played a role in the overall protection observed in the trial.

  7. Nebivolol Reduces Proteinuria and Renal NADPH Oxidase-Generated Reactive Oxygen Species in the Transgenic Ren2 Rat

    PubMed Central

    Whaley-Connell, Adam; Habibi, Javad; Johnson, Megan; Tilmon, Roger; Rehmer, Nathan; Rehmer, Jenna; Wiedmeyer, Charles; Ferrario, Carlos M.; Sowers, James R.

    2009-01-01

    Background/Aims Renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system activation are crucial in the pathogenesis of hypertension, cardiovascular and renal disease. NADPH oxidase-mediated increases in reactive oxygen species (ROS) are an important mediator for RAAS-induced cardiovascular and renal injury. Increased levels of ROS can diminish the bioactivity of nitric oxide (NO), a critical modulator of RAAS effects on the kidney. Thereby, we hypothesized that in vivo nebivolol therapy in a rodent model of activated RAAS would attenuate glomerular damage and proteinuria through its actions to reduce NADPH oxidase activity/ROS and increase bioavailable NO. Methods We utilized the transgenic Ren2 rat which displays heightened tissue RAAS, hypertension, and proteinuria. Ren2 rats (6–9 weeks of age) and age-matched Sprague-Dawley littermates were treated with nebivolol 10 mg/kg/day (osmotic mini-pump) for 21 days. Results Ren2 rats exhibited increases in systolic blood pressure, proteinuria, kidney cortical tissue total NADPH oxidase activity and subunits (Rac1, p67phox, and p47phox), ROS and 3-nitrotyrosine, as well as reductions in podocyte protein markers; each of these parameters improved with nebivolol treatment along with increases in renal endothelial NO synthase expression. Conclusions Our data suggest that nebivolol improves proteinuria through reductions in renal RAAS-mediated increases in NADPH oxidase/ROS and increases in bioavailable NO. PMID:19609077

  8. [Case of distal renal tubular acidosis complicated with renal diabetes insipidus, showing aggravation of symptoms with occurrence of diabetes mellitus].

    PubMed

    Liu, Hexing; Tomoda, Fumihiro; Koike, Tsutomu; Ohara, Maiko; Nakagawa, Taizo; Kagitani, Satoshi; Inoue, Hiroshi

    2011-01-01

    We report herein a 27-year-old male case of inherited distal renal tubular acidosis complicated with renal diabetes insipidus, the symptoms of which were aggravated by the occurrence of diabetes mellitus. At 2 months after birth, he was diagnosed as having inherited distal renal tubular acidosis and thereafter supplementation of both potassium and alkali was started to treat his hypokalemia and metabolic acidosis. At the age of 4 years, calcification of the bilateral renal medulla was detected by computed tomography. Subsequently his urinary volume gradually increased and polyuria of approximately 4 L/day persisted. At the age of 27 years, he became fond of sugar-sweetened drinks and also often forgot to take the medicine. He was admitted to our hospital due to polyuria of more than 10 L day, muscle weakness and gait disturbance. Laboratory tests disclosed worsening of both hypokalemia and metabolic acidosis in addition to severe hyperglycemia. It seemed likely that occurrence of diabetes mellitus and cessation of medications can induce osmotic diuresis and aggravate hypokalemia and metabolic acidosis. Consequently, severe dehydration, hypokalemia-induced damage of his urinary concentration ability and enhancement of the renin angiotensin system occurred and thereby possibly worsened his hypokalemia and metabolic acidosis. As normalization of hyperglycemia and metabolic acidosis might have exacerbated hypokalemia further, dehydration and hypokalemia were treated first. Following intensive treatment, these abnormalities were improved, but polyuria persisted. Elevated plasma antidiuretic hormone (12.0 pg/mL) and deficit of renal responses to antidiuretic hormone suggested that the polyuria was attributable to the preexisting renal diabetes insipidus possibly caused by bilateral renal medulla calcification. Thiazide diuretic or nonsteroidal anti-inflammatory drugs were not effective for the treatment of diabetes insipidus in the present case.

  9. High risk of ESRD in type 1 diabetes: New strategies are needed to retard progressive renal function decline

    PubMed Central

    Krolewski, Andrzej S.; Bonventre, Joseph V.

    2012-01-01

    Care of patients with Type 1 diabetes (T1D) has changed during the last 30 years. Tools to control glycemia have improved and it was demonstrated that improvement in glycemic control diminished the risk of late diabetic complications, including nephropathy. Moreover, in patients with impaired renal function, aggressive treatment of hypertension and reno-protective blockade of the renin-angiotensin system were shown to postpone end-stage renal disease (ESRD), albeit for a short while. Despite these achievements, the incidence of ESRD due to T1D in the US population has not decreased but rather has increased over the last 20 years, although it now occurs at slightly older ages. This state of affairs is a call to action. This should begin with adopting a new model of diabetic nephropathy in humans. In that model, instead of microalbuminuria or proteinuria, the focus should be on diagnosis and treatment of progressive renal function decline that leads to ESRD. Such a model has received significant support in clinical and epidemiological studies. Investigation of mechanisms of such progressive renal function decline should help in the identification of new therapeutic targets and the development of new interventions. To evaluate these interventions, accurate diagnostic algorithms are needed so T1D patients will be stratified according to time to onset to ESRD. Consistent with concepts of personalized medicine, the new interventions should be tailored to and evaluated in patients predicted to have rapid, moderate or even slow progression to ESRD. PMID:23062980

  10. Vascular contractile reactivity in hypotension due to reduced renal reabsorption of Na(+) and restricted dietary Na().

    PubMed

    Alshahrani, Saeed; Rapoport, Robert M; Soleimani, Manoocher

    2017-03-01

    Reduced renal Na(+) reabsorption along with restricted dietary Na(+) depletes intravascular plasma volume which can then result in hypotension. Whether hypotension occurs and the magnitude of hypotension depends in part on compensatory angiotensin II-mediated increased vascular resistance. We investigated whether the ability of vascular resistance to mitigate the hypotension was compromised by decreased contractile reactivity. In vitro reactivity was investigated in aorta from mouse models of reduced renal Na(+) reabsorption and restricted dietary Na(+) associated with considerable hypotension and renin-angiotensin system activation: (1) the Na(+)-Cl(-)-Co-transporter (NCC) knockout (KO) with Na(+) restricted diet (0.1%, 2 weeks) and (2) the relatively more severe pendrin (apical chloride/bicarbonate exchanger) and NCC double KO. Contractile sensitivity to KCl, phenylephrine, and/or U46619 remained unaltered in aorta from both models. Maximal KCl and phenylephrine contraction expressed as force/aorta length from NCC KO with Na(+)-restricted diet remained unaltered, while in pendrin/NCC double KO were reduced to 49 and 64%, respectively. Wet weight of aorta from NCC KO with Na(+)-restricted diet remained unaltered, while pendrin/NCC double KO was reduced to 67%, consistent with decreased medial width determined with Verhoeff-Van Gieson stain. These findings suggest that hypotension associated with severe intravascular volume depletion, as the result of decreased renal Na(+) reabsorption, may in part be due to decreased contractile reactivity as a consequence of reduced vascular hypertrophy.

  11. Dissociation of renal blood flow and filtration rate autoregulation by renin depletion.

    PubMed

    Hall, J E; Guyton, A C; Cowley, A W

    1977-03-01

    Renal blood flow (RBF) and glomerular filtration rate (GFR) autoregulation during changes in renal artery pressure (RAP) were examined in dogs fed a "normal" diet (group 1, n = 10) and in renin-depleted dogs (group 2, n = 11) which received a high-sodium diet and deoxycorticosterone acetate (DOCA) injections for a minimum of 21 days prior to the study. Renal venous plasma renin activity was undetectable in group 2 by radioimmunoassay of angiotensin I and did not increase even when RAP was reduced to less than 70 mmHg. Autoregulation of RBF was not impaired by renin depletion. However, GFR autoregulation, which was very effective in group 1 dogs, was markedly impaired in group 2. Average GFR in group 2 decreased progressively to 58 +/- 7% of the control value as RAP was reduced in steps from the control value of 137 +/- 3 to 69 +/- 1 mmHg. In normal dogs, the filtration fraction either increased slightly or did not change when RAP was reduced in steps, whereas in renin-depleted dogs the filtration fraction decreased progressively during reductions in RAP. Thus, chronic sodium loading and DOCA administration causes renin depletion and dissociates the autoregulation of RBF and GFR. These data are consistent with the hypothesis that the renin-angiotensin system participates in the control of GFR, possibly by an efferent arteriolar mechanism.

  12. GENETIC INFLUENCE ON THE DEVELOPMENT OF RENAL HYPERTENSION IN PARABIOTIC RATS

    PubMed Central

    Iwai, J.; Knudsen, K. D.; Dahl, L. K.; Heine, M.; Leitl, G.

    1969-01-01

    The effects of several renal manipulations including uninephrectomy, unilateral renal artery constriction, and a combination of these two (Goldblatt procedure) were studied in two strains of rats with opposite constitutional predispositions to experimental hypertension. The protective value of intact renal tissue to protect against hypertension was shown to be genetically determined. The Goldblatt procedure carried out on only one member of a parabiotic pair induced hypertension in this operated rat but significant hypertension developed in the intact partner only when the operated animal belonged to the strain predisposed to hypertension. It was speculated that there were qualitative differences in the pressor signals of the two strains of rats. In the strain genetically predisposed to hypertension there are at least two pressor principles: (a) one which is common to both strains, not transmittable via the parabiosis junction and presumably related to the renin-angiotensin system; and (b) a second which is specific for the hypertension-prone strain and can be transmitted through the parabiosis junction. This transmittable agent is probably identical with the factor that produces salt hypertension and is associated with the salt-excreting mechanism. PMID:4304137

  13. Mesenchymal Stem Cells (MSC) Prevented the Progression of Renovascular Hypertension, Improved Renal Function and Architecture

    PubMed Central

    Oliveira-Sales, Elizabeth B.; Maquigussa, Edgar; Semedo, Patricia; Pereira, Luciana G.; Ferreira, Vanessa M.; Câmara, Niels O.; Bergamaschi, Cassia T.; Campos, Ruy R.; Boim, Mirian A.

    2013-01-01

    Renovascular hypertension induced by 2 Kidney-1 Clip (2K-1C) is a renin-angiotensin-system (RAS)-dependent model, leading to renal vascular rarefaction and renal failure. RAS inhibitors are not able to reduce arterial pressure (AP) and/or preserve the renal function, and thus, alternative therapies are needed. Three weeks after left renal artery occlusion, fluorescently tagged mesenchymal stem cells (MSC) (2×105 cells/animal) were injected weekly into the tail vein in 2K-1C hypertensive rats. Flow cytometry showed labeled MSC in the cortex and medulla of the clipped kidney. MSC prevented a further increase in the AP, significantly reduced proteinuria and decreased sympathetic hyperactivity in 2K-1C rats. Renal function parameters were unchanged, except for an increase in urinary volume observed in 2K-1C rats, which was not corrected by MSC. The treatment improved the morphology and decreased the fibrotic areas in the clipped kidney and also significantly reduced renal vascular rarefaction typical of 2K-1C model. Expression levels of IL-1β, TNF-α angiotensinogen, ACE, and Ang II receptor AT1 were elevated, whereas AT2 levels were decreased in the medulla of the clipped kidney. MSC normalized these expression levels. In conclusion, MSC therapy in the 2K-1C model (i) prevented the progressive increase of AP, (ii) improved renal morphology and microvascular rarefaction, (iii) reduced fibrosis, proteinuria and inflammatory cytokines, (iv) suppressed the intrarenal RAS, iv) decreased sympathetic hyperactivity in anesthetized animals and v) MSC were detected at the CNS suggesting that the cells crossed the blood-brain barrier. This therapy may be a promising strategy to treat renovascular hypertension and its renal consequences in the near future. PMID:24223811

  14. P2X7 receptor antagonism improves renal blood flow and oxygenation in angiotensin-II infused rats

    PubMed Central

    Menzies, Robert I.; Howarth, Amelia R.; Unwin, Robert J.; Tam, Frederick W.K.; Mullins, John J.; Bailey, Matthew A.

    2015-01-01

    Chronic activation of the renin angiotensin system promotes hypertension, renal microvascular dysfunction, tissue hypoxia and inflammation. We found previously that the injurious response to excess angiotensin II (ANGII) is greater in F344 rats, whereas Lewis rats are renoprotected, despite similar hypertension. We further identified p2rx7, encoding the P2X7 receptor (P2X7R), as a candidate gene for differential susceptibility and here we have tested the hypothesis that activation of P2X7R promotes vascular dysfunction under high ANGII tone. 14-day infusion of ANGII at 30ng/min into F344 rats increased blood pressure by ~15mmHg without inducing fibrosis or albuminuria. In vivo pressure natriuresis was suppressed, medullary perfusion reduced by ~50% and the cortico-medullary oxygenation gradient disrupted. Selective P2X7R antagonism restored pressure natriuresis, promoting a significant leftward shift in the intercept and increasing the slope. Sodium excretion was increased 6 fold and blood pressure normalized. The specific P2X7R antagonist AZ11657312 increased renal medullary perfusion, but only in ANGII-treated rats. Tissue oxygenation was improved by P2X7R blockade, particularly in poorly oxygenated regions of the kidney. Activation of P2X7R induces microvascular dysfunction and regional hypoxia when ANGII is elevated. These pro-inflammatory effects may contribute to progression of renal injury induced by chronic ANGII. PMID:26108066

  15. Renal denervation attenuates aldosterone expression and associated cardiovascular pathophysiology in angiotensin II-induced hypertension

    PubMed Central

    Chen, Dong-Rui; Ruan, Cheng-Chao; Xu, Jian-Zhong; Chen, Jing; Wu, Yong-Jie; Ma, Yu; Zhu, Ding-Liang; Gao, Ping-Jin

    2016-01-01

    The sympathetic nervous system interacts with the renin-angiotensin-aldosterone system (RAAS) contributing to cardiovascular diseases. In this study, we sought to determine if renal denervation (RDN) inhibits aldosterone expression and associated cardiovascular pathophysiological changes in angiotensin II (Ang II)-induced hypertension. Bilateral RDN or SHAM operation was performed before chronic 14-day Ang II subcutaneous infusion (200ng/kg/min) in male Sprague-Dawley rats. Bilateral RDN blunted Ang II-induced hypertension and ameliorated the mesenteric vascular dysfunction. Cardiovascular hypertrophy in response to Ang II was significantly attenuated by RDN as shown by histopathology and transthoracic echocardiography. Moreover, Ang II-induced vascular and myocardial inflammation and fibrosis were suppressed by RDN with concurrent decrease in fibronectin and collagen deposition, macrophage infiltration, and MCP-1 expression. Interestingly, RDN also inhibited Ang II-induced aldosterone expression in the plasma, kidney and heart. This was associated with the reduction of calcitonin gene-related peptide (CGRP) in the adrenal gland. Ang II promoted aldosterone secretion which was partly attenuated by CGRP in the adrenocortical cell line, suggesting a protective role of CGRP in this model. Activation of transforming growth factor-β (TGF-β)/Smad and mitogen-activated protein kinases (MAPKs) signaling pathway was both inhibited by RDN especially in the heart. These results suggest that the regulation of the renal sympathetic nerve in Ang II-induced hypertension and associated cardiovascular pathophysiological changes is likely mediated by aldosterone, with CGRP involvement. PMID:27661131

  16. Impairment of renal sodium excretion in tropical residents - phenomenological analysis

    NASA Astrophysics Data System (ADS)

    Arthur, S. K.; Aryee, P. A.; Amuasi, J.; Hesse, I. F. A.; Affram, R. K.

    There is evidence of impaired renal sodium excretion in salt-sensitive African Blacks. A decreased rate of renal sodium chloride (NaCl) excretion, low plasma renin activity and a tendency to elevated blood pressure are the hallmarks of salt sensitivity. Recent evidence indicates that increased proximal and distal tubular fluid reabsorption in some tropical residents may explain the impaired sodium excretion in these people. In this study of a cohort population, we speculated that subjects selected from that population might be salt-sensitive. We therefore measured the sodium balance in 10 normotensive male subjects over 10 consecutive days, after they had ingested a normal or a high amount of sodium, as NaCl (salt) in their diet. We quantified their renal sodium excretion rate by phenomenological analysis of their sodium balance data. We also measured plasma renin activity for 7 consecutive days in a separate group of 6 male and 4 female subjects in order to assess the state of their renin/angiotensin system. We selected all our subjects from a cohort population of 269 subjects randomly selected from a community known to have a high prevalence of primary hypertension. Our data on two separate groups of subjects from the same cohort population revealed delayed renal sodium excretion with t1/2 of about 5 days, compared to published data for normal individuals with t1/2 of less than 24 h. Also, plasma renin activity levels were low. Hence, our subjects are salt-sensitive. Quantification of their renal impairment is important for various reasons: it heightens one's appreciation of the problem of salt retention in African Blacks who are salt-sensitive and it also underlines the importance of the need for further research into the benefits of dietary salt restriction for reducing cardiovascular mortality in African populations, as has been done in some Western countries.

  17. The patterns of peripheral plasma renin concentration in the early post-renal-transplant period.

    PubMed

    Kornerup, H J

    1979-01-01

    Serial determinations of peripheral plasma renin concentration (PRC) were performed in 11 kidney transplant recipients during the early post-transplant period. In 5 recipients with late onset of graft function, PRC values were increased during the anuric phase and, subsequently, PRC values declined in every during restoration of graft function. In 4 recipients with an acute renal allograft reaction, PRC values were increased at the onset of the allograft reaction in 3 with hypertension whereas PRC values were normal in one normotensive recipient. Subsequently, PRC normalized in the hypertensives coincident with increasing body weights. In 2 recipients with an uncomplicated course and with a normal graft function immediately after transplantation and throughout the study period, PRC values were constantly normal. The results indicate that acute anuria in the early phase after kidney transplantation is associated with an increased release of renin. The results also suggest that an increased activity of the renin-angiotensin system may be counterbalanced by sodium and fluid retention in hypertension following an acute renal allograft reaction.

  18. The burden of hyperkalemia in patients with cardiovascular and renal disease.

    PubMed

    Dunn, Jeffrey D; Benton, Wade W; Orozco-Torrentera, Ernesto; Adamson, Robert T

    2015-11-01

    Hyperkalemia is a potentially serious condition that can result in life-threatening cardiac arrhythmias and is associated with an increased mortality risk. Patients older than 65 years who have an advanced stage of chronic kidney disease (stage 3 or higher), diabetes, and/or chronic heart failure are at higher risk for hyperkalemia. To reduce disease progression and improve outcomes in these groups of patients, modulation of the renin-angiotensin-aldosterone system (RAAS) is recommended by guidelines. One limiting factor of RAAS inhibitors at proven doses is the increased risk for hyperkalemia associated with their use. Although there are effective therapeutic options for the short-term, acute management of hyperkalemia, the available strategies for chronic control of high potassium levels have limited effectiveness. The management of high potassium in the long term often requires withdrawing or reducing the doses of drugs proven to reduce cardiovascular and renal outcomes (eg, RAAS inhibitors) or implementing excessive and often intolerable dietary restrictions. Furthermore, withholding RAAS inhibitors may lead to incremental healthcare costs associated with poor outcomes, such as end-stage renal disease, hospitalizations due to cardiovascular causes, and cardiovascular mortality. As such, there is an important unmet need for novel therapeutic options for the chronic management of patients at risk for hyperkalemia. Potential therapies in development may change the treatment landscape in the near future.

  19. Blood pressure and renal function during chronic changes in sodium intake: role of angiotensin.

    PubMed

    Hall, J E; Guyton, A C; Smith, M J; Coleman, T G

    1980-09-01

    The present study was designed to quantitate the role of the renin-angiotensin system (RAS) in determining the chronic relationships between arterial pressure (AP), renal hemodynamics, and Na excretion. In six control dogs, Na balance was achieved during chronic step increases in Na intake from 5 to 500 meq/day with small increases in AP (<7 mmHg), moderate increases in GFR (19%), and decreases in filtration fraction (FF) and plasma renin activity. Similar increases in Na intake in six dogs with angiotensin II (AII) fixed, due to constant intravenous infusion of 5 ng . kg-1 . min-1 AII, caused large increases in AP (42%), GFR (31%) FF, and calculated renal Na reabsorption (TNa) above control. In six dogs with AII formation blocked with SQ 14,225, Na balance at intakes of 5-80 meq/day occurred at reduced AP, GFR, FF, and TNa, although plasma aldosterone concentration (PAC) was not substantially different from that in control dogs. At Na intakes above 240 meq/day, AP was not altered by SQ 14,225. These data indicate that during chronic changes in Na intake the RAS plays a major role, independent of changes in PAC, in allowing Na balance without large changes in GFR or AP. The mechanism whereby AII conserves Na chronically is through increased TNa, since steady-state TNa was increased by AII and decreased by SQ 14,225.

  20. Urinary angiotensin II: a marker of renal tissue activity?

    PubMed

    Reams, G; Villarreal, D; Wu, Z; Bauer, J H

    1994-01-01

    The methodology for the collection, extraction, separation and measurement of urinary angiotensin II [the octapeptide, ANG(1-8)] is described. To determine the origin of urinary ANG(1-8), mean arterial pressure, renal hemodynamics and the arterial, renal venous and urinary concentrations of ANG(1-8) were examined prior to and following the constant intra-arterial infusion of tritiated angiotensin II [3H-ANG(1-8)] in graded doses of 0.5, 2.0 and 2.5 ng/kg/min in 5 uninephrectomized, anesthetized female dogs. The infusion of 3H-ANG-(1-8) had no significant effect on mean arterial pressure, glomerular filtration rate, renal blood flow or urine flow rate. The mean concentration of ANG(1-8) in the urine was 3.7 fmol/ml. None or only trace amounts of 3H-ANG(1-8) were detected in the urine in spite of marked increases in renal arterial 3H-ANG(1-8) concentrations. These observations suggest that urinary ANG(1-8) was derived de novo from the intrarenal generation of angiotensin II. In addition, plasma and urinary concentrations of ANG(1-8) were assessed in patients with essential hypertension undergoing treatment with either a diuretic (n = 14) or an angiotensin-converting enzyme inhibitor (n = 14). Although the concentrations of plasma ANG(1-8) responded appropriately to the respective therapies, the urinary excretion of ANG(1-8) was not different following either therapy. These data suggest that ANG(1-8) collected from the urinary bladder may not occur in adequate concentrations to accurately assess the activity of the intrarenal renin-angiotensin system.

  1. Perinatally administered losartan augments renal ACE2 expression but not cardiac or renal Mas receptor in spontaneously hypertensive rats.

    PubMed

    Klimas, Jan; Olvedy, Michael; Ochodnicka-Mackovicova, Katarina; Kruzliak, Peter; Cacanyiova, Sona; Kristek, Frantisek; Krenek, Peter; Ochodnicky, Peter

    2015-08-01

    Since the identification of the alternative angiotensin converting enzyme (ACE)2/Ang-(1-7)/Mas receptor axis, renin-angiotensin system (RAS) is a new complex target for a pharmacological intervention. We investigated the expression of RAS components in the heart and kidney during the development of hypertension and its perinatal treatment with losartan in young spontaneously hypertensive rats (SHR). Expressions of RAS genes were studied by the RT-PCR in the left ventricle and kidney of rats: normotensive Wistar, untreated SHR, SHR treated with losartan since perinatal period until week 9 of age (20 mg/kg/day) and SHR treated with losartan only until week 4 of age and discontinued until week 9. In the hypertrophied left ventricle of SHR, cardiac expressions of Ace and Mas were decreased while those of AT1 receptor (Agtr1a) and Ace2 were unchanged. Continuous losartan administration reduced LV weight (0.43 ± 0.02; P < 0.05 versus SHR) but did not influence altered cardiac RAS expression. Increased blood pressure in SHR (149 ± 2 in SHR versus 109 ± 2 mmHg in Wistar; P < 0.05) was associated with a lower renal expressions of renin, Agtr1a and Mas and with an increase in ACE2. Continuous losartan administration lowered blood pressure to control levels (105 ± 3 mmHg; P < 0.05 versus SHR), however, only renal renin and ACE2 were significantly up-regulated (for both P < 0.05 versus SHR). Conclusively, prevention of hypertension and LV hypertrophy development by losartan was unrelated to cardiac or renal expression of Mas. Increased renal Ace2, and its further increase by losartan suggests the influence of locally generated Ang-(1-7) in organ response to the developing hypertension in SHRs.

  2. Renal Involvement in Idiopathic Inflammatory Myopathies.

    PubMed

    Cucchiari, David; Angelini, Claudio

    2017-02-01

    Renal involvement in idiopathic inflammatory myopathies is not as uncommon as was previously thought, as it develops in about one fifth of patients. Clinical presentation includes either acute kidney injury or chronic glomerulonephritis. The former usually develops abruptly during acute phases of rhabdomyolysis: in this case, kidney injury is caused by the toxic effects that myoglobinuria has on the kidney tubules, including cast formation and iron-induced oxidative stress and the development of a third space into the injured muscles. The latter instead has an autoimmune nature, a pleomorphic histological picture, and a more indolent course, with the exception of crescentic glomerulonephritis. Accurate diagnosis and management is crucial for these patients, as timely evaluation and treatment can prevent most of the complications. In the setting of rhabdomyolysis-induced acute kidney injury, the necessity of dialysis can be avoided through aggressive hydration and alkalinization, in order to force diuresis and avoid acidosis and hyperkalemia. In immune-mediated glomerulonephritis, renal biopsy is of undoubtedly value in the diagnostic process and can add prognostic and therapeutic information. In these forms, the development of chronic kidney disease can be prevented or at least delayed by the institution or modification of immunosuppressive treatment. Moreover, the use of drugs that inhibit the renin-angiotensin-aldosterone system and some lifestyle modifications, such as smoking cessation, weight loss, and salt restriction have also value in reducing proteinuria and the progression of kidney damage. In this review, we have summarized the currently available evidence and the different case series in an attempt to provide the readers with the most complete and practical notions that are needed to handle these delicate patients.

  3. Gender differences in pressure-natriuresis and renal autoregulation: role of the Angiotensin type 2 receptor.

    PubMed

    Hilliard, Lucinda M; Nematbakhsh, Mehdi; Kett, Michelle M; Teichman, Elleesha; Sampson, Amanda K; Widdop, Robert E; Evans, Roger G; Denton, Kate M

    2011-02-01

    Sexual dimorphism in arterial pressure regulation has been observed in humans and animal models. The mechanisms underlying this gender difference are not fully known. Previous studies in rats have shown that females excrete more salt than males at a similar arterial pressure. The renin-angiotensin system is a powerful regulator of arterial pressure and body fluid volume. This study examined the role of the angiotensin type 2 receptor (AT₂R) in pressure-natriuresis in male and female rats because AT₂R expression has been reported to be enhanced in females. Renal function was examined at renal perfusion pressures of 120, 100, and 80 mm Hg in vehicle-treated and AT₂R antagonist-treated (PD123319; 1 mg/kg/h) groups. The pressure-natriuresis relationship was gender-dependent such that it was shifted upward in female vs male rats (P < 0.001). AT₂R blockade modulated the pressure-natriuresis relationship, shifting the curve downward in male (P < 0.01) and female (P < 0.01) rats to a similar extent. In females, AT₂R blockade also reduced the lower end of the autoregulatory range of renal blood flow (P < 0.05) and glomerular filtration rate (P < 0.01). Subsequently, the renal blood flow response to graded angiotensin II infusion was also measured with and without AT₂R blockade. We found that AT₂R blockade enhanced the renal vasoconstrictor response to angiotensin II in females but not in males (P < 0.05). In conclusion, the AT₂R modulates pressure-natriuresis, allowing the same level of sodium to be excreted at a lower pressure in both genders. However, a gender-specific role for the AT₂R in renal autoregulation was evident in females, which may be a direct vascular AT₂R effect.

  4. Serum aldosterone and death, end-stage renal disease, and cardiovascular events in blacks and whites: findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

    PubMed

    Deo, Rajat; Yang, Wei; Khan, Abigail M; Bansal, Nisha; Zhang, Xiaoming; Leonard, Mary B; Keane, Martin G; Soliman, Elsayed Z; Steigerwalt, Susan; Townsend, Raymond R; Shlipak, Michael G; Feldman, Harold I

    2014-07-01

    Prior studies have demonstrated that elevated aldosterone concentrations are an independent risk factor for death in patients with cardiovascular disease. Limited studies, however, have evaluated systematically the association between serum aldosterone and adverse events in the setting of chronic kidney disease. We investigated the association between serum aldosterone and death and end-stage renal disease in 3866 participants from the Chronic Renal Insufficiency Cohort. We also evaluated the association between aldosterone and incident congestive heart failure and atherosclerotic events in participants without baseline cardiovascular disease. Cox proportional hazards models were used to evaluate independent associations between elevated aldosterone concentrations and each outcome. Interactions were hypothesized and explored between aldosterone and sex, race, and the use of loop diuretics and renin-angiotensin-aldosterone system inhibitors. During a median follow-up period of 5.4 years, 587 participants died, 743 developed end-stage renal disease, 187 developed congestive heart failure, and 177 experienced an atherosclerotic event. Aldosterone concentrations (per SD of the log-transformed aldosterone) were not an independent risk factor for death (adjusted hazard ratio, 1.00; 95% confidence interval, 0.93-1.12), end-stage renal disease (adjusted hazard ratio, 1.07; 95% confidence interval, 0.99-1.17), or atherosclerotic events (adjusted hazard ratio, 1.04; 95% confidence interval, 0.85-1.18). Aldosterone was associated with congestive heart failure (adjusted hazard ratio, 1.21; 95% confidence interval, 1.02-1.35). Among participants with chronic kidney disease, higher aldosterone concentrations were independently associated with the development of congestive heart failure but not for death, end-stage renal disease, or atherosclerotic events. Further studies should evaluate whether mineralocorticoid receptor antagonists may reduce adverse events in individuals with

  5. Renal hemodynamic and morphological changes after 7 and 28 days of leptin treatment: the participation of angiotensin II via the AT1 receptor.

    PubMed

    Thieme, Karina; Oliveira-Souza, Maria

    2015-01-01

    The role of hyperleptinemia in cardiovascular diseases is well known; however, in the renal tissue, the exact site of leptin's action has not been established. This study was conducted to assess the effect of leptin treatment for 7 and 28 days on renal function and morphology and the participation of angiotensin II (Ang II), through its AT1 receptor. Rats were divided into four groups: sham, losartan (10 mg/kg/day, s.c.), leptin (0.5 mg/kg/day for the 7 days group and 0.25 mg/kg/day for the 28 days group) and leptin plus losartan. Plasma leptin, Ang II and endothelin 1 (ET-1) levels were measured using an enzymatic immuno assay. The systolic blood pressure (SBP) was evaluated using the tail-cuff method. The renal plasma flow (RPF) and the glomerular filtration rate (GFR) were determined by p-aminohippuric acid and inulin clearance, respectively. Urinary Na+ and K+ levels were also analyzed. Renal morphological analyses, desmin and ED-1 immunostaining were performed. Proteinuria was analyzed by silver staining. mRNA expression of renin-angiotensin system (RAS) components, TNF-α and collagen type III was analyzed by quantitative PCR. Our results showed that leptin treatment increased Ang II plasma levels and progressively increased the SBP, achieving a pre-hypertension state. Rats treated with leptin 7 days showed a normal RPF and GFR, but increased filtration fraction (FF) and natriuresis. However, rats treated with leptin for 28 showed a decrease in the RPF, an increase in the FF and no changes in the GFR or tubular function. Leptin treatment-induced renal injury was demonstrated by: glomerular hypertrophy, increased desmin staining, macrophage infiltration in the renal tissue, TNF-α and collagen type III mRNA expression and proteinuria. In conclusion, our study demonstrated the progressive renal morphological changes in experimental hyperleptinemia and the interaction between leptin and the RAS on these effects.

  6. Effect of exercise on plasma concentrations of arginine vasopressin, angiotensin II and aldosterone in hypertensive and normotensive renal transplant recipients.

    PubMed

    Pedersen, E B; Danielsen, H; Nielsen, A H; Knudsen, F; Jensen, T; Kornerup, H J; Madsen, M

    1986-04-01

    Plasma concentrations of angiotensin II (A II), aldosterone (Aldo) and arginine vasopressin (AVP), and serum osmolality (Sosm) were determined before and after gradually increasing exercise loads on a bicycle ergometer in 10 hypertensive (group I) and 10 normotensive renal transplant recipients (group II), and in 15 healthy control subjects (group III). Working capacity was reduced in groups I and II. The A II, Aldo, AVP, Sosm increased in all groups after exercise. The A II was higher in group I than II and the percentage changes were significantly lower in groups I and II than in group III. There were no significant differences in Aldo between the groups either before or after exercise. The AVP was the same in groups I and II, and AVP in these groups was higher than in group III. The Sosm and AVP were significantly correlated in all groups. Neither A II, Aldo nor AVP were significantly correlated to systolic blood pressure (BP). Alterations in AVP, but not in A II or Aldo, were correlated to the degree of exercise load. It can be concluded that the renin-angiotensin-aldosterone system and the osmoregulatory system are stimulated during exercise in renal transplant recipients. The A II is elevated in post-renal transplant hypertension, but the responsiveness is reduced in both hypertensive and normotensive recipients. The alterations in AVP are probably secondary to changes in Sosm, and the higher AVP levels in recipients could be due to a decreased responsiveness of the renal tubules to AVP. Our findings are in good agreement with the hypothesis that hypertension after renal transplantation is angiotensin II-dependent.

  7. Dietary sodium intake modulates renal excretory responses to intrarenal angiotensin (1-7) administration in anesthetized rats.

    PubMed

    O'Neill, Julie; Corbett, Alan; Johns, Edward J

    2013-02-01

    Angiotensin II at the kidney regulates renal hemodynamic and excretory function, but the actions of an alternative metabolite, angiotensin (1-7), are less clear. This study investigated how manipulation of dietary sodium intake influenced the renal hemodynamic and excretory responses to intrarenal administration of angiotensin (1-7). Renal interstitial infusion of angiotensin (1-7) in anesthetized rats fed a normal salt intake had minimal effects on glomerular filtration rate but caused dose-related increases in urine flow and absolute and fractional sodium excretions ranging from 150 to 200%. In rats maintained for 2 wk on a low-sodium diet angiotensin (1-7) increased glomerular filtration rate by some 45%, but the diuretic and natriuretic responses were enhanced compared with those in rats on a normal sodium intake. By contrast, renal interstitial infusion of angiotensin (1-7) in rats maintained on a high-sodium intake had no effect on glomerular filtration rate, whereas the diuresis and natriuresis was markedly attenuated compared with those in rats fed either a normal or low-sodium diet. Plasma renin and angiotensin (1-7) were highest in the rats on the low-sodium diet and depressed in the rats on a high-sodium diet. These findings demonstrate that the renal hemodynamic and excretory responses to locally administered angiotensin (1-7) is dependent on the level of sodium intake and indirectly on the degree of activation of the renin-angiotensin system. The exact way in which angiotensin (1-7) exerts its effects may be dependent on the prevailing levels of angiotensin II and its receptor expression.

  8. Role of Mas receptor in renal blood flow response to angiotensin (1-7) in male and female rats.

    PubMed

    Nematbakhsh, Mehdi; Safari, Tahereh

    2014-01-01

    Epidemiologic and clinical studies have shown that progression of renal disease in male is faster than that in female. However, the exact mechanisms are not well recognized. Angiotensin (1-7) (Ang 1-7) receptor, called "Mas", is an element in the depressor arm of renin angiotensin system (RAS), and its expression is enhanced in females. We test the hypothesis that Mas receptor (MasR) blockade (A779) attenuates renal blood flow (RBF) in response to infusion of graded doses of Ang 1-7 in female rats. Male and female Wistar rats were anesthetized and catheterized. Then, the mean arterial pressure (MAP), RBF, and controlled renal perfusion pressure (RPP) responses to infusion of graded doses of Ang 1-7 (100-1000 ng/kg/min i.v.) with and without A779 were measured in the animals. Basal MAP, RPP, RBF, and renal vascular resistance (RVR) were not significantly different between the two groups. After Ang 1-7 administration, RPP was controlled at a constant level. However, RBF increased in a dose-related manner in response to Ang 1-7 infusion in both male and female rats (Pdose<0.0001), but masR blockade significantly attenuated this response only in female (Pgroup=0.04) and not male (Pgroup=0.23). In addition, A779 increased the RBF response to Ang 1-7 to a greater extent. This is while the increase in male was not significant when compared with that in female (Pgender=0.08). RVR response to Ang 1-7 was insignificantly attenuated by A779 in both genders. The masR differently regulated RBF response to Ang 1-7 in the two genders, and the effect was greater in female rats. The masR may be a target for improvement of kidney circulation in renal diseases.

  9. Fluid compartment and renal function alterations in the rat during 7 and 14 day head down tilt

    NASA Technical Reports Server (NTRS)

    Tucker, Bryan J.

    1991-01-01

    Exposure to conditions of microgravity for any extended duration can modify the distribution of fluid within the vascular and interstitial spaces, and eventually intracellular volume. Whether the redistribution of fluid and resetting of volume homeostasis mechanisms is appropriate for the long term environmental requirements of the body in microgravity remains to be fully defined. The event that initiates the change in fluid volume homeostasis is the cephalad movement of fluid which potentially triggers volume sensors and stretch receptors (atrial stretch with the resulting release of atrial natriuretic peptide) and suppresses adrenergic activity via the carotid and aortic arch baroreceptors. All these events act in concert to reset blood and interstitial volume to new levels, which in turn modify the renin-angiotensin system. All these factors have an influence on the kidney, the end organ for fluid volume control. How the fluid compartment volume changes interrelate with alterations in renal functions under conditions of simulated microgravity is the focus of the present investigation which utilizes 25-30 deg head-down tilt in the rat.

  10. Renal and extrarenal mechanisms of perinatal programming after intrauterine growth restriction.

    PubMed

    Dötsch, Jörg

    2009-04-01

    The concept of fetal programming of disease in later life after intrauterine growth restriction (IUGR) has opened a potential new perspective on the treatment and prevention of arterial hypertension. Numerous large studies have recently confirmed the relationship between low birth weight and raised blood pressure. Hyperalimentation after birth appears to add to the risk of higher blood pressure later in life. However, there is still a controversy and clear intervention studies have not yet been possible. Therefore, the gain of knowledge about the underlying mechanisms of fetal programming is of utmost importance.Two major groups of mechanisms may be identified: renal and extrarenal mechanisms. Renal mechanisms include the reduction of nephron number, which is encountered in patients and animals with low birth weight. According to the so-called Brenner hypothesis, this may lead to increased arterial blood pressure. Another important renal system is the renin-angiotensin-aldosterone system, which appears to be more active on a number of levels in low birth weight individuals. Finally, there is the conversion of cortisol to inactive cortisone by the 11beta-hydroxysteroid dehydrogenase in distal tubule cells, which is reduced after intrauterine growth restriction. This enables a more powerful activation of mineralocorticoid receptors by cortisol. Extrarenal mechanisms include alterations in vascular structure (primary and secondary), increased activity of the sympathetic nerve system, and maybe most interestingly, an impairment of endothelial function. The latter is at least partially caused by an inactivation of nitric oxide by an excess of free oxygen radicals. In summary, mechanisms of fetal programming are only in the process of being revealed, and research has to focus on finding the key mechanism that might allow for successful intervention.

  11. Inhibition of soluble epoxide hydrolase counteracts the development of renal dysfunction and progression of congestive heart failure in Ren-2 transgenic hypertensive rats with aorto-caval fistula.

    PubMed

    Červenka, Luděk; Melenovský, Vojtěch; Husková, Zuzana; Škaroupková, Petra; Nishiyama, Akira; Sadowski, Janusz

    2015-07-01

    The detailed mechanisms determining the course of congestive heart failure (CHF) in hypertensive subjects with associated renal dysfunction remain unclear. In Ren-2 transgenic rats (TGR), a model of angiotensin II (ANG II)-dependent hypertension, CHF was induced by volume overload achieved by creation of the aorto-caval fistula (ACF). In these rats we investigated the putative pathophysiological contribution of epoxyeicosatrienoic acids (EETs) and compared it with the role of the renin-angiotensin system (RAS). We found that untreated ACF TGR exhibited marked intrarenal and myocardial deficiency of EETs and impairment of renal function. Chronic treatment of these rats with cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid (c-AUCB, 3 mg/L in drinking water), an inhibitor of soluble epoxide hydrolase (sEH) which normally degrades EETs, increased intrarenal and myocardial EETs, markedly improved survival rate, and increased renal blood flow, glomerular filtration rate and fractional sodium excretion, without altering RAS activity. Chronic angiotensin-converting enzyme inhibition (ACEi) with trandolapril, (6 mg/L in drinking water) improved survival rate even more, and also inhibited the development of renal dysfunction; these beneficial actions were associated with significant suppression of the vasoconstrictor/sodium retaining axis and further activation of the vasodilatory/natriuretic axis of the systemic and intrarenal RAS, without modifying tissue availability of biologically active fatty acid epoxides. In conclusion, these findings strongly suggest that chronic sEH inhibition and chronic treatment with ACEi, each of them altering a different vasoactive system, delay or even prevent the onset of decompensation of CHF in ACF TGR, probably by preventing the development of renal dysfunction.

  12. Effects of xanthine oxidase inhibitors on renal function and blood pressure in hypertensive patients with hyperuricemia.

    PubMed

    Kohagura, Kentaro; Tana, Takeshi; Higa, Akira; Yamazato, Masanobu; Ishida, Akio; Nagahama, Kazufumi; Sakima, Atsushi; Iseki, Kunitoshi; Ohya, Yusuke

    2016-08-01

    Hyperuricemia may promote the progression of hypertension and renal dysfunction. However, the effects of hyperuricemia treatment on blood pressure and renal function in adult hypertensive patients with hyperuricemia remain unclear. A total of 137 hypertensive patients with hyperuricemia (96 men and 41 women; mean age of 67 years) who recently started taking xanthine oxidase inhibitors (allopurinol or febuxostat) as outpatients were recruited. Serum uric acid level, estimated glomerular filtration rate (eGFR, ml min(-1) per 1.73 m(2)) and blood pressure (mm Hg) were retrospectively compared immediately before and shortly after starting treatment with xanthine oxidase inhibitors. The mean blood pressure and the eGFR immediately before starting treatment were 128/71 mm Hg and 44.6 ml min(-1) per 1.73 m(2), respectively. Although the eGFR decreased from 46.6 to 44.6 ml min(-1) per 1.73 m(2) before starting treatment with xanthine oxidase inhibitors, it increased to 46.2 ml min(-1) per 1.73 m(2) (P=0.001, compared with immediately before treatment) without any significant changes in blood pressure after the administration of xanthine oxidase inhibitors. Multiple regression analysis revealed that the increase in eGFR after starting xanthine oxidase inhibitor treatment positively correlated with the changes in systolic blood pressure and negatively correlated with the changes in uric acid levels and the use of renin-angiotensin system inhibitors. These results suggest that xanthine oxidase inhibitors may delay the progression of renal dysfunction in adult hypertensive patients with hyperuricemia.

  13. Aliskiren restores renal AQP2 expression during unilateral ureteral obstruction by inhibiting the inflammasome

    PubMed Central

    Wang, Weidong; Luo, Renfei; Lin, Yu; Wang, Feifei; Zheng, Peili; Levi, Moshe; Yang, Tianxin

    2015-01-01

    Ureteral obstruction is associated with reduced expression of renal aquaporins (AQPs), urinary concentrating defects, and an enhanced inflammatory response, in which the renin-angiotensin system (RAS) may play an important role. We evaluated whether RAS blockade by a direct renin inhibitor, aliskiren, would prevent the decreased renal protein expression of AQPs in a unilateral ureteral obstruction (UUO) model and what potential mechanisms may be involved. UUO was performed for 3 days (3UUO) and 7 days (7UUO) in C57BL/6 mice with or without aliskiren injection. In 3UUO and 7UUO mice, aliskiren abolished the reduction of AQP2 protein expression but not AQP1, AQP3, and AQP4. mRNA levels of renal AQP2 and vasopressin type 2 receptor were decreased in obstructed kidneys of 7UUO mice, which were prevented by aliskiren treatment. Aliskiren treatment was also associated with a reduced inflammatory response in obstructed kidneys of UUO mice. Aliskiren significantly decreased mRNA levels of several proinflammatory factors, such as transforming growth factor-β and tumor necrosis factor-α, seen in obstructed kidneys of UUO mice. Interestingly, mRNA and protein levels of the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome components apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, and IL-1β were dramatically increased in obstructed kidneys of 7UUO mice, which were significantly suppressed by aliskiren. In primary cultured inner medullary collecting duct cells, IL-1β significantly decreased AQP2 expression. In conclusions, RAS blockade with the direct renin inhibitor aliskiren increased water channel AQP2 expression in obstructed kidneys of UUO mice, at least partially by preventing NLRP3 inflammasome activation in association with ureteral obstruction. PMID:25694485

  14. [Vitamin D hormone system and diabetes mellitus: lessons from selective activators of vitamin D receptor and diabetes mellitus].

    PubMed

    Jódar-Gimeno, Esteban; Muñoz-Torres, Manuel

    2013-02-01

    The vitamin D hormone system has significant skeletal and extra-skeletal effects. Vitamin D receptor occurs in different tissues, and several cells other than renal cells are able to locally produce active vitamin D, which is responsible for transcriptional control of hundreds of genes related to its pleiotropic effects. There is increasing evidence relating vitamin D to development and course of type 1 and 2 diabetes mellitus. Specifically, influence of vitamin D on the renin-angiotensin-aldosterone system, inflammatory response, and urinary albumin excretion could explain the relevant impact of vitamin D status on diabetic nephropathy. Selective vitamin D receptor activators are molecules able to reproduce agonistic or antagonistic effects of active vitamin D depending on the tissue or even on the cell type. Specifically, paricalcitol has a beneficial profile because of its potency to reduce parathyroid hormone, with lower effects on serum calcium or phosphate levels. Moreover, in patients with diabetes and renal disease, paricalcitol decreases microalbuminuria, hospitalization rates, and cardiovascular mortality. Therefore, these molecules represent an attractive new option to improve prognosis of renal disease in patients with diabetes.

  15. Plasma renin, plasma aldosterone and exchangeable sodium in normotensive and hypertensive kidney transplant recipients with and without transplant renal artery stenosis.

    PubMed

    Kornerup, H J; Pedersen, E B

    1977-01-01

    Blood pressure (BP), plasma renin concentration (PRC), plasma aldosterone concentration (PAC) and exchangeable sodium (ES) were studied in 19 kidney recipients on different fixed levels of sodium intake after successful kidney transplantation. The following groups of kidney recipients were investigated: group 1: 7 normotensives, group 2:7 hypertensives without transplant renal artery stenosis (TRAS), group 3:5 hypertensives with angiographically verified TRAS. Hypertension in the recipients without TRAS (group 2) was characterized by a positive correlation between BP and ES and a normal response of PRC and PAC to a fixed low (10 mEQ/day) and high (150 mEq/day) sodium intake. In contrast, hypertension in the recipients with TRAS (group 3) was characterized by a normal or varyingly increased PRC on a liberal sodium intake and a reduced response of PRC to sodium restriction, whereas PAC did not differ from the other groups of recipients. In one recipient in group 3 who underwent surgical correction for TRAS, PRC and PAC decreased before operation during sodium restriction, but BP remained high until after operation, when it normalized simultaneously with a decrease in ES. The results indicate that sodium retention is involved in the pathogenesis of posttransplant hypertension and suggest that an increased activity of the renin--angiotensin system is counterbalanced by an accumulation of sodium in TRAS.

  16. Once daily administration of the SGLT2 inhibitor, empagliflozin, attenuates markers of renal fibrosis without improving albuminuria in diabetic db/db mice.

    PubMed

    Gallo, Linda A; Ward, Micheal S; Fotheringham, Amelia K; Zhuang, Aowen; Borg, Danielle J; Flemming, Nicole B; Harvie, Ben M; Kinneally, Toni L; Yeh, Shang-Ming; McCarthy, Domenica A; Koepsell, Hermann; Vallon, Volker; Pollock, Carol; Panchapakesan, Usha; Forbes, Josephine M

    2016-05-26

    Blood glucose control is the primary strategy to prevent complications in diabetes. At the onset of kidney disease, therapies that inhibit components of the renin angiotensin system (RAS) are also indicated, but these approaches are not wholly effective. Here, we show that once daily administration of the novel glucose lowering agent, empagliflozin, an SGLT2 inhibitor which targets the kidney to block glucose reabsorption, has the potential to improve kidney disease in type 2 diabetes. In male db/db mice, a 10-week treatment with empagliflozin attenuated the diabetes-induced upregulation of profibrotic gene markers, fibronectin and transforming-growth-factor-beta. Other molecular (collagen IV and connective tissue growth factor) and histological (tubulointerstitial total collagen and glomerular collagen IV accumulation) benefits were seen upon dual therapy with metformin. Albuminuria, urinary markers of tubule damage (kidney injury molecule-1, KIM-1 and neutrophil gelatinase-associated lipocalin, NGAL), kidney growth, and glomerulosclerosis, however, were not improved with empagliflozin or metformin, and plasma and intra-renal renin activity was enhanced with empagliflozin. In this model, blood glucose lowering with empagliflozin attenuated some molecular and histological markers of fibrosis but, as per treatment with metformin, did not provide complete renoprotection. Further research to refine the treatment regimen in type 2 diabetes and nephropathy is warranted.

  17. Effects of Add-on Fluvastatin Therapy in Patients with Chronic Proteinuric Nephropathy on Dual Renin-Angiotensin System Blockade: The ESPLANADE Trial

    PubMed Central

    Ruggenenti, Piero; Perna, Annalisa; Tonelli, Marcello; Loriga, Giacomina; Motterlini, Nicola; Rubis, Nadia; Ledda, Franca; Rota, Stefano; Satta, Andrea; Granata, Antonio; Battaglia, Giovanni; Cambareri, Francesco; David, Salvatore; Gaspari, Flavio; Stucchi, Nadia; Carminati, Sergio; Ene-Iordache, Bogdan; Cravedi, Paolo

    2010-01-01

    Background and objectives: This open, prospective, randomized trial aimed to assess the effects of statins in chronic kidney disease patients on optimized antiproteinuric treatment with combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade. Design, setting, participants, & measurements: After 1-month benazepril therapy followed by 1-month benazepril-valsartan combined therapy (run-in), 186 consenting patients with residual proteinuria >0.5 g/24 h were randomized to 6-month benazepril-valsartan therapy alone or combined with fluvastatin. Between-groups changes in proteinuria (primary outcome), serum lipids, and GFR were compared by ANCOVA. Analyses were blinded and by intention to treat. Results: During the run-in, proteinuria decreased more on benazepril-valsartan than on benazepril alone. Proteinuria reduction correlated with concomitant reduction in total, LDL, and HDL cholesterol, and apolipoprotein B and apolipoprotein A levels. After randomization, median proteinuria similarly decreased from 1.2 (0.6 to 2.2) to 1.1 (0.5 to 1.7) g/24 h on fluvastatin and from 1.5 (0.8 to 2.7) to 1.0 (0.5 to 2.4) g/24 h on benazapril-valsartan therapy alone. Fluvastatin further reduced total and LDL cholesterol and apolipoprotein B versus benazepril-valsartan alone, but did not affect serum triglycerides and GFR. Treatment was well tolerated. Conclusions: In chronic kidney disease patients with residual proteinuria despite combined angiotensin-converting enzyme inhibitor and angiotensin receptor blockade therapy, add-on fluvastatin does not affect urinary proteins, but further reduces serum lipids and is safe. Whether combined angiotensin-converting enzyme inhibitor, angiotensin receptor blockade, and statin therapy may improve cardiovascular outcomes in this high-risk population is worth investigating. PMID:20671225

  18. The kallikrein-kinin system in diabetic nephropathy

    PubMed Central

    Tomita, Hirofumi; Sanford, Ryan B.; Smithies, Oliver; Kakoki, Masao

    2012-01-01

    Diabetic nephropathy is the major cause of end-stage renal disease worldwide. Although the renin-angiotensin system has been implicated in the pathogenesis of diabetic nephropathy, angiotensin I-converting enzyme (ACE) inhibitors have a beneficial effect on diabetic nephropathy independently of their effects on blood pressure and plasma angiotensin II levels. This suggests that the kallikrein-kinin system (KKS) is also involved in the disease. To study the role of the KKS in diabetic nephropathy, mice lacking either the bradykinin B1 receptor (B1R) or the bradykinin B2 receptor (B2R) have been commonly used. However, because absence of either receptor causes enhanced expression of the other, it is difficult to determine the precise functions of each receptor. This difficulty has recently been overcome by comparing mice lacking both receptors with mice lacking each receptor. Deletion of both B1R and B2R reduces nitric oxide (NO) production and aggravates renal diabetic phenotypes, relevant to either lack of B1R or B2R, demonstrating that both B1R and B2R exert protective effects on diabetic nephropathy presumably via NO. Here, we review previous epidemiological and experimental studies, and discuss novel insights regarding the therapeutic implications of the importance of the KKS in averting diabetic nephropathy. PMID:22318421

  19. PTGER1 deletion attenuates renal injury in diabetic mouse models.

    PubMed

    Thibodeau, Jean-François; Nasrallah, Rania; Carter, Anthony; He, Ying; Touyz, Rhian; Hébert, Richard L; Kennedy, Christopher R J

    2013-12-01

    We hypothesized that the EP1 receptor promotes renal damage in diabetic nephropathy. We rendered EP1 (PTGER1, official symbol) knockout mice (EP1(-/-)) diabetic using the streptozotocin and OVE26 models. Albuminuria, mesangial matrix expansion, and glomerular hypertrophy were each blunted in EP1(-/-) streptozotocin and OVE26 cohorts compared with wild-type counterparts. Although diabetes-associated podocyte depletion was unaffected by EP1 deletion, EP1 antagonism with ONO-8711 in cultured podocytes decreased angiotensin II-mediated superoxide generation, suggesting that EP1-associated injury of remaining podocytes in vivo could contribute to filtration barrier dysfunction. Accordingly, EP1 deletion in OVE26 mice prevented nephrin mRNA expression down-regulation and ameliorated glomerular basement membrane thickening and foot process effacement. Moreover, EP1 deletion reduced diabetes-induced expression of fibrotic markers fibronectin and α-actin, whereas EP1 antagonism decreased fibronectin in cultured proximal tubule cells. Similarly, proximal tubule megalin expression was reduced by diabetes but was preserved in EP1(-/-) mice. Finally, the diabetes-associated increase in angiotensin II-mediated constriction of isolated mesenteric arteries was blunted in OVE26EP1(-/-) mice, demonstrating a role for EP1 receptors in the diabetic vasculature. These data suggest that EP1 activation contributes to diabetic nephropathy progression at several locations, including podocytes, proximal tubule, and the vasculature. The EP1 receptor facilitates the actions of angiotensin II, thereby suggesting that targeting of both the renin-angiotensin system and the EP1 receptor could be beneficial in diabetic nephropathy.

  20. Salt-induced renal injury in SHRs is mediated by AT1 receptor activation

    PubMed Central

    Susic, Dinko; Frohlich, Edward D.; Kobori, Hiroyuki; Shao, Weijian; Seth, Dale; Navar, L. Gabriel

    2011-01-01

    Objective This study aimed to examine the effects of salt loading, with or without simultaneous angiotensin receptor blocker (ARB) treatment, on the systemic and tissue renin-angiotensin system (RAS) in spontaneously hypertensive rats (SHRs). Method Evaluation was performed early (4 weeks) in the course of salt loading in order to examine initial mediating events of cardiovascular and renal damage produced by salt excess. Four groups of rats were studied. Group 1 received regular rat chow (normal-salt diet); group 2 received normal-salt diet and an ARB (losartan, 30 mg/kg per day); group 3 received high-salt (8%) chow; and group 4 received high-salt diet and losartan. Results High-salt diet increased systolic pressure to 193 ± 1 mmHg compared to 180 ± 2 in normal-salt diet group. Losartan reduced SBP in SHRs fed normal-salt diet but did not reduce SBP in the SHRs fed high-salt diet (192 ± 2 mmHg). High-salt diet markedly increased urinary protein excretion from 27 ± 4 to 64 ± 13 mg/day and this increase was ameliorated by losartan (40 ± 9 mg/day). In SHRs on high-salt diet, plasma angiotensin II concentration increased three to four-fold, whereas urinary angiotensinogen excretion increased 10-fold; and these changes were significantly reduced by losartan. High-salt diet accelerated glomerular injury and interstitial fibrosis in SHRs which were reduced by losartan. Conclusion These results demonstrate that the activity of RAS was either not suppressed or, even augmented, after 4 weeks of salt loading despite high salt intake and increased SBP. The data suggest that an augmented intrarenal RAS during high-salt diet may contribute to the development of renal injury in this experimental model. PMID:21346625

  1. ACE2 and vasoactive peptides: novel players in cardiovascular/renal remodeling and hypertension.

    PubMed

    Mendoza-Torres, Evelyn; Oyarzún, Alejandra; Mondaca-Ruff, David; Azocar, Andrés; Castro, Pablo F; Jalil, Jorge E; Chiong, Mario; Lavandero, Sergio; Ocaranza, María Paz

    2015-08-01

    The renin-angiotensin system (RAS) is a key component of cardiovascular physiology and homeostasis due to its influence on the regulation of electrolyte balance, blood pressure, vascular tone and cardiovascular remodeling. Deregulation of this system contributes significantly to the pathophysiology of cardiovascular and renal diseases. Numerous studies have generated new perspectives about a noncanonical and protective RAS pathway that counteracts the proliferative and hypertensive effects of the classical angiotensin-converting enzyme (ACE)/angiotensin (Ang) II/angiotensin type 1 receptor (AT1R) axis. The key components of this pathway are ACE2 and its products, Ang-(1-7) and Ang-(1-9). These two vasoactive peptides act through the Mas receptor (MasR) and AT2R, respectively. The ACE2/Ang-(1-7)/MasR and ACE2/Ang-(1-9)/AT2R axes have opposite effects to those of the ACE/Ang II/AT1R axis, such as decreased proliferation and cardiovascular remodeling, increased production of nitric oxide and vasodilation. A novel peptide from the noncanonical pathway, alamandine, was recently identified in rats, mice and humans. This heptapeptide is generated by catalytic action of ACE2 on Ang A or through a decarboxylation reaction on Ang-(1-7). Alamandine produces the same effects as Ang-(1-7), such as vasodilation and prevention of fibrosis, by interacting with Mas-related GPCR, member D (MrgD). In this article, we review the key roles of ACE2 and the vasoactive peptides Ang-(1-7), Ang-(1-9) and alamandine as counter-regulators of the ACE-Ang II axis as well as the biological properties that allow them to regulate blood pressure and cardiovascular and renal remodeling.

  2. Calcineurin-inhibition Results in Upregulation of Local Renin and Subsequent Vascular Endothelial Growth Factor Production in Renal Collecting Ducts

    PubMed Central

    Sziksz, Erna; Pap, Domonkos; Balicza-Himer, Leonóra; Boros, Szilvia; Magda, Balázs; Vannay, Ádám; Kis-Petik, Katalin; Fekete, Andrea; Peti-Peterdi, János; Szabó, Attila J.

    2016-01-01

    Background Tacrolimus (Tac) and Cyclosporine A (CyA) calcineurin inhibitors (CNIs) are 2 effective immunosuppressants which are essential to prevent allograft rejection. Calcineurin inhibitors are known to be nephrotoxic. However, the precise mechanism of nephrotoxicity is not fully understood. In this study, we investigated the in vivo effects of CNIs on the local renal renin-angiotensin system in the collecting duct (CD). Methods Three-week-old mice were treated with either vehicle, CyA (2 mg/kg per day), Tac (0.075 mg/kg per day), CyA + Aliskiren (25 mg/kg per day), or Tac + Aliskiren for 3 weeks. Serum creatinine was measured. Renin and vascular endothelial growth factor (VEGF) contents in CD were evaluated with flow cytometry and multiphoton microscopy. The diameter of vessels was assessed with multiphoton microscopy, and the amount of renal collagen was determined by real-time polymerase chain reaction and Masson staining. Results The elevated level of serum creatinine in CNI groups was abolished by Aliskiren. Flow cytometric analysis found elevated renin content in principal cells, which was prevented by Aliskiren. This result was further confirmed with multiphoton microscopy. The VEGF content in CD correlated with reduced capillary diameter and with the formation of fibrotic islands. Conclusions Calcineurin inhibitors induce production of renin in the CD that may contribute to decreased renal blood flow. In turn, CD responds with increased VEGF production, resulting in disproportional vessel growth, further worsening the local hypoxia and striped fibrosis surrounding the CDs. Aliskiren, a direct renin inhibitor blocks these effects and improves CNI-induced nephropathy by decreasing renin production in the CDs. Our data suggest that Aliskiren may be used for the prevention of CNI nephrotoxicity. PMID:26502369

  3. Garlic Attenuates Plasma and Kidney ACE-1 and AngII Modulations in Early Streptozotocin-Induced Diabetic Rats: Renal Clearance and Blood Pressure Implications

    PubMed Central

    Al-Qattan, Khaled K.; Jayasree, Divya; Ali, Muslim

    2016-01-01

    Raw garlic aqueous extract (GE) has ameliorative actions on the renin-angiotensin system in type-1 diabetes mellitus (DM); however its effects on plasma and kidney angiotensin I converting enzyme type-1 (ACE-1) and angiotensin II (AngII) require further elucidation. This study investigated the effect of GE on plasma and kidney ACE-1 and AngII concentrations and in relation to systemic and renal clearance indicators significant to blood pressure (BP) homeostasis in early streptozotocin- (STZ-) induced type-1 DM. Normal rats (n = 10) received 0.5 mL normal saline (NR/NS), diabetic rats (n = 10) received 0.5 mL NS (DR/NS), and treated diabetic rats (n = 10) received 50 mg/0.1 mL/100 g body weight GE (DR/GE) as daily intraperitoneal injections for 8 weeks. Compared to NR/NS, DR/NS showed a significant increase in plasma ACE-1 and AngII and conversely a decrease in kidney ACE-1 and AngII. These changes were associated with an increase in BP and clearance functions. Alternatively and compared to DR/NS, DR/GE showed normalization or attenuation in plasma and kidney ACE-1 and AngII. These GE induced rectifications were associated with moderation in BP elevation and renal clearance functions. Garlic attenuates modulations in plasma and kidney ACE-1 and AngII, in addition to BP and renal clearance function in type-1 DM. PMID:27293465

  4. Salt, aldosterone, and insulin resistance: impact on the cardiovascular system.

    PubMed

    Lastra, Guido; Dhuper, Sonal; Johnson, Megan S; Sowers, James R

    2010-10-01

    Hypertension and type 2 diabetes mellitus (T2DM) are powerful risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD), both of which are leading causes of morbidity and mortality worldwide. Research into the pathophysiology of CVD and CKD risk factors has identified salt sensitivity and insulin resistance as key elements underlying the relationship between hypertension and T2DM. Excess dietary salt and caloric intake, as commonly found in westernized diets, is linked not only to increased blood pressure, but also to defective insulin sensitivity and impaired glucose homeostasis. In this setting, activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS), as well as increased signaling through the mineralocorticoid receptor (MR), result in increased production of reactive oxygen species and oxidative stress, which in turn contribute to insulin resistance and impaired vascular function. In addition, insulin resistance is not limited to classic insulin-sensitive tissues such as skeletal muscle, but it also affects the cardiovascular system, where it participates in the development of CVD and CKD. Current clinical knowledge points towards an impact of salt restriction, RAAS blockade, and MR antagonism on cardiovascular and renal protection, but also on improved insulin sensitivity and glucose homeostasis.

  5. Novel mechanism of intra‑renal angiotensin II-induced sodium/proton exchanger 3 expression by losartan in spontaneously hypertensive rats.

    PubMed

    Fan, Xiaoqin; Liu, Kaishan; Cui, Wei; Huang, Jiongmei; Wang, Weina; Gao, Yuan

    2014-11-01

    The present study aimed to investigate the molecular pharmacodynamic mechanisms of losartan used in the treatment of hypertension. A total of 12 spontaneously hypertensive rats (SHR) were divided randomly into an SHR group treated with saline and LOS group treated with losartan. Six Wistar‑kyoto rats (WKY) were enrolled as the WKY group with saline in the study. The LOS group received 30 mg/kg/day losartan by intragastric injection, while the SHR and WKY were fed the same volume of saline. The dosage was modulated according to the weekly weight. Changes in blood pressure were measured by the indirect tail cuff method. Angiotensin (Ang) II production in the plasma and renal tissue was measured by an immunoradiometric method. Na+/H+ exchanger (NHE)3 and serum and glucocorticoid‑inducible kinase (SGK)1 were assessed by quantitative polymerase chain reaction (qPCR) and western blot analysis. When compared with the WKY group, the blood pressure of the SHR and LOS groups were higher prior to treatment with losartan. Following two weeks, blood pressure was reduced and the trend continued to decrease over the following six weeks. The plasma and renal tissue levels of Ang II in the SHR and LOS groups were significantly higher than those in the WKY group. NHE3 and SGK1 were increased at the mRNA and protein level in the SHR group, and losartan reduced the expression of both of them. The results suggested that in hypertensive rats, the circular and tissue renin angiotensin systems were activated, and the increased Ang II stimulated the expression of NHE3 and SGK1, which was reduced by losartan. Therefore, the effects of losartan in hypertension may be associated with the Ang II‑SGK1‑NHE3 of intra‑renal tissue.

  6. Evidence for tissue-specific activation of renal angiotensinogen mRNA expression in chronic stable experimental heart failure.

    PubMed Central

    Schunkert, H; Ingelfinger, J R; Hirsch, A T; Tang, S S; Litwin, S E; Talsness, C E; Dzau, V J

    1992-01-01

    The intrarenal renin-angiotensin system (RAS) may contribute to the pathophysiology of heart failure by the generation of angiotensin II at local sites within the kidneys. Angiotensin II may directly influence renal hemodynamics, glomerular contractility, and tubular sodium reabsorption, thereby promoting sodium and fluid retention in this syndrome. In the present study, we examined components of the circulating RAS as well as the intrarenal expressions of renin and angiotensinogen mRNA in rats with stable compensated heart failure (HF) 12 wk after experimental myocardial infarction. Renal angiotensinogen mRNA level in vehicle-treated HF rats increased 47%, as compared with sham control rats (P = 0.001). The increase in angiotensinogen mRNA levels was more pronounced in animals with medium (46%, P < 0.05) and large (66%, P < 0.05) infarcts than in those with small infarcts (31%, P = NS). There were no differences in liver angiotensinogen mRNA, circulating angiotensinogen, angiotensin II, plasma renin concentration (PRC), kidney renin content (KRC), and renal renin mRNA level between sham and HFv. In addition, in a separate group of rats with heart failure, we demonstrated that renal angiotensin II concentration increased twofold (P < 0.05) as compared with that of age-matched sham operated controls. A parallel group of heart failure rats (HFe, n = 11) was treated with enalapril (25 mg/kg per d) in drinking water for 6 wk before these measurements. Blood pressure decreased significantly during treatment (91 vs. 103 mm Hg, P < 0.05). Enalapril treatment in HF rats increased renin mRNA level (2.5-fold, P < 0.005), KRC (5.6-fold, P = 0.005), and PRC (15.5-fold, P < 0.005). The increase in renal angiotensinogen mRNA level observed in HFv rats was markedly attenuated in enalapril treated HF rats (P < 0.001), suggesting a positive feedback of angiotensin II on renal angiotensinogen synthesis. These findings demonstrate an activation of intrarenal RAS, but no changes in

  7. Renal and Cardio-Endocrine Responses in Humans to Simulated Microgravity

    NASA Technical Reports Server (NTRS)

    Williams, Gordon H.

    1999-01-01

    The volume regulating systems are integrated to produce an appropriate response to both acute and chronic volume changes. Their responses include changing the levels of the hormones and neural inputs of the involved systems and/or changing the responsiveness of their target tissues. Weightlessness during space travel produces a volume challenge that is unfamiliar to the organism. Thus, it is likely that these volume regulatory mechanisms may respond inappropriately, e.g., a decrease in total body volume in space and abnormal responses to upright posture and stress on return to Earth. A similar "inappropriateness" also can occur in disease states, e.g., congestive heart failure. While it is clear that weightlessness produces profound changes in sodium and volume homeostasis, the mechanisms responsible for these changes are incompletely understood. Confounding this analysis is sleep deprivation, common in space travel, which can also modify volume homeostatic mechanisms. The purpose of this project is to provide the required understanding and then to design appropriate countermeasures to reduce or eliminate the adverse effects of microgravity. To accomplish this we are addressing five Specific Aims: (1) To test the hypothesis that microgravity modifies the acute responsiveness of the renin-angiotensin-aldosterone system (RAAS) and renal blood flow; (2) Does simulated microgravity change the circadian rhythm of the volume- regulating hormones?; (3) Does simulated microgravity change the target tissue responsiveness to angiotensin 11 (AngII)?; (4) Does chronic sleep deprivation modify the circadian rhythm of the RAAS and change the acute responsiveness of this system to posture beyond what a microgravity environment alone does? and (5) What effect does salt restriction have on the volume homeostatic and neurohumoral responses to a microgravity environment? Because the RAAS plays a pivotal role in blood pressure control and volume homeostasis, it likely is a major

  8. The evolution of angiotensin blockade in the management of cardiovascular disease.

    PubMed

    Nantel, Pierre; René de Cotret, Paul

    2010-12-01

    Dysregulation of the renin-angiotensin system is implicated in many cardiovascular and renal pathologies. Discovery of the renin-angiotensin system represents a major advance in the understanding of hypertension and cardiovascular disease, leading to the development of the anti-angiotensin medications: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and direct renin inhibitors. Clinical trials have shown that drugs in each of these classes have a protective effect on vascular organs that surpass the protection associated with the lowering of blood pressure alone.

  9. Renal

    MedlinePlus

    ... term "renal" refers to the kidney. For example, renal failure means kidney failure. Related topics: Kidney disease Kidney disease - diet Kidney failure Kidney function tests Renal scan Kidney transplant

  10. What is a preferred angiotensin II receptor blocker-based combination therapy for blood pressure control in hypertensive patients with diabetic and non-diabetic renal impairment?

    PubMed Central

    2012-01-01

    Hypertension has a major associated risk for organ damage and mortality, which is further heightened in patients with prior cardiovascular (CV) events, comorbid diabetes mellitus, microalbuminuria and renal impairment. Given that most patients with hypertension require at least two antihypertensives to achieve blood pressure (BP) goals, identifying the most appropriate combination regimen based on individual risk factors and comorbidities is important for risk management. Single-pill combinations (SPCs) containing two or more antihypertensive agents with complementary mechanisms of action offer potential advantages over free-drug combinations, including simplification of treatment regimens, convenience and reduced costs. The improved adherence and convenience resulting from SPC use is recognised in updated hypertension guidelines. Despite a wide choice of SPCs for hypertension treatment, clinical evidence from direct head-to-head comparisons to guide selection for individual patients is lacking. However, in patients with evidence of renal disease or at greater risk of developing renal disease, such as those with diabetes mellitus, microalbuminura and high-normal BP or overt hypertension, guidelines recommend renin-angiotensin system (RAS) blocker-based combination therapy due to superior renoprotective effects compared with other antihypertensive classes. Furthermore, RAS inhibitors attenuate the oedema and renal hyperfiltration associated with calcium channel blocker (CCB) monotherapy, making them a good choice for combination therapy. The occurrence of angiotensin-converting enzyme (ACE) inhibitor-induced cough supports the use of angiotensin II receptor blockers (ARBs) for RAS blockade rather than ACE inhibitors. In this regard, ARB-based SPCs are available in combination with the diuretic, hydrochlorothiazide (HCTZ) or the calcium CCB, amlodipine. Telmisartan, a long-acting ARB with preferential pharmacodynamic profile compared with several other ARBs, and the

  11. Angiotensin II-independent upregulation of cyclooxygenase-2 by activation of the (Pro)renin receptor in rat renal inner medullary cells.

    PubMed

    Gonzalez, Alexis A; Luffman, Christina; Bourgeois, Camille R T; Vio, Carlos P; Prieto, Minolfa C

    2013-02-01

    During renin-angiotensin system activation, cyclooxygenase-2 (COX-2)-derived prostaglandins attenuate the pressor and antinatriuretic effects of angiotensin II (AngII) in the renal medulla. The (pro)renin receptor (PRR) is abundantly expressed in the collecting ducts (CD) and its expression is augmented by AngII. PRR overexpression upregulates COX-2 via mitogen-activated kinases/extracellular regulated kinases 1/2 in renal tissues; however, it is not clear whether this effect occurs independently or in concert with AngII type 1 receptor (AT1R) activation. We hypothesized that PRR activation stimulates COX-2 expression independently of AT(1)R in primary cultures of rat renal inner medullary cells. The use of different cell-specific immunomarkers (aquaporin-2 for principal cells, anion exchanger type 1 for intercalated type-A cells, and tenascin C for interstitial cells) and costaining for AT(1)R, COX-2, and PRR revealed that PRR and COX-2 were colocalized in intercalated and interstitial cells whereas principal cells did not express PRR or COX-2. In normal rat kidney sections, PRR and COX-2 were colocalized in intercalated and interstitial cells. In rat renal inner medullary cultured cells, treatment with AngII (100 nmol/L) increased COX-2 expression via AT(1)R. In addition, AngII and rat recombinant prorenin (100 nmol/L) treatments increased extracellular regulated kinases 1/2 phosphorylation, independently. Importantly, rat recombinant prorenin upregulated COX-2 expression in the presence of AT(1)R blockade. Inhibition of mitogen-activated kinases/extracellular regulated kinases 1/2 suppressed COX-2 upregulation mediated by either AngII or rat recombinant prorenin. Furthermore, PRR knockdown using PRR-short hairpin RNA blunted the rat recombinant prorenin-mediated upregulation of COX-2. These results indicate that COX-2 expression is upregulated by activation of either PRR or AT(1)R via mitogen-activated kinases/extracellular regulated kinases 1/2 in rat renal

  12. Unexpected Return for Follow-up During the First Year of Multidisciplinary Care May Be Predictive of Rapid Deterioration of Renal Function.

    PubMed

    Tsai, Ming-Hsien; Fang, Yu-Weil; Wang, Li Hui; You, Xiang Gin; Leu, Jyh-Gang

    2015-10-01

    Multidisciplinary predialysis education and team care (MDC) may slow the decline in renal function in patients with chronic kidney disease (CKD). However, associations between unexpected return during MDC and progression of renal dysfunction have not been characterized in patients with CKD. Our study aimed to determine the association between exacerbation of renal dysfunction and the frequency of unexpected return during follow-up.A total of 437 patients with CKD receiving multidisciplinary care between January 2009 and June 2013 at the Shin-Kong Wu Ho-Su Memorial Hospital were included in this retrospective observational cohort study, and multiple imputations were performed for missing data. The predictor was the frequency of unexpected return for follow-up during the first year after entering MDC. Main outcome was monthly declines in estimated glomerular filtration rates (eGFR). Moreover, the demographic data, comorbidities, history of medication, and routine laboratory data for patients with CKD were collected.Among all patients, 59.7% were male, the mean age at initiation of MDC was 69.4 ± 13.2 years, and the duration of follow-up was 21.4 ± 3.3 months. The subjects were divided into 2 groups according to frequencies of follow-up (≤4 and > 4 visits) during the 1st year of MDC. The patients with CKD were regularly followed up every 3 months as a part of MDC in our hospital, and patients who returned for more than 4 follow-up visits were included in the unexpected return group. In crude regression analyses, unexpected return was significantly associated with higher monthly declines of eGFR (β = 0.092, 95% confidence interval, 0.014-0.170). This association remained after adjustments for multiple variables, and subgroup analyses of unexpected return showed that male gender, older age, CKD stage 1 to 3, hypertension, history of coronary artery disease, and use of renin-angiotensin system blockade were significantly associated with declines in

  13. Treatment of the diabetic patient: focus on cardiovascular and renal risk reduction.

    PubMed

    Abbott, Kevin C; Bakris, George L

    2002-01-01

    Diabetes mellitus increases the risk for hypertension and associated cardiovascular diseases, including coronary, cerebrovascular, renal and peripheral vascular disease. The risk for developing cardiovascular disease is increased when both diabetes and hypertension co-exist; in fact, over 11 million Americans have both diabetes and hypertension. These numbers will continue to climb, internationally, since the leading associated risk for diabetes development, obesity, has reached epidemic proportions, globally. Moreover, the frequent association of diabetes with dyslipidemia, as well as coagulation, endothelial, and metabolic abnormalities also aggravates the underlying vascular disease process in patients who possess these comorbid conditions. The renin-angiotensin-aldosterone system (RAS) and arginine vasopressin (AVP) are overactivated in both hypertension and diabetes. Drugs that inhibit this system, such as ACE inhibitors and more recently angiotensin receptor antagonists (ARBs), have proven beneficial effects on the micro- and macrovascular complications of diabetes, especially the kidney. The BRILLIANT study showed that lisinopril reduces microalbuminuria better than CCB therapy. Numerous other long-term studies confirm this association with ACE inhibitors including the HOPE trial. Furthermore, the European Controlled trial of Lisinopril in Insulin-dependent Diabetes (EUCLID) study, showed that lisinopril slowed the progression of renal disease, even in individuals with mild albuminuria. In fact, there are now five appropriately powered randomized placebo-controlled trials to show that both ACE inhibitors and ARBs slow progression of diabetic nephropathy in people with type 2 diabetes. These effects were shown to be better than conventional blood pressure lowering therapy, including dihydropyridine CCBs. In patients with microalbuminuria, ACE inhibitors and ARBs reduce the progression of microalbuminuria to proteinuria and provide a risk reduction of between

  14. Renal vascular lesions in systemic lupus erythematosus.

    PubMed

    Katz, S M; Korn, S; Umlas, S L; DeHoratius, R J

    1990-01-01

    In the past, necrotizing vasculitis has been considered to be one of the dominant intrarenal vascular abnormalities in systemic lupus erythematosus (SLE). To test the validity of this statement, 70 consecutive renal biopsies from patients with SLE were reviewed. Light microscopy (LM) and immunofluorescence (IF) studies documented abnormalities, including thrombosis and nephrosclerosis, in 30 patients (43 percent), but no cellular infiltration of the vessel walls or other evidence of acute necrotizing vasculitis was seen. It is concluded that while intrarenal vasculopathy with thrombosis and nephrosclerosis is a common finding in SLE, our data and recently published studies suggest that acute necrotizing vasculitis occurs rarely, if at all, in SLE nephritis.

  15. Effects of T-Type Calcium Channel Blockers on Renal Function and Aldosterone in Patients with Hypertension: A Systematic Review and Meta-Analysis

    PubMed Central

    Li, Xue; Yang, Mao Sheng

    2014-01-01

    Background High blood pressure can cause kidney damage, which can increase blood pressure, leading to a vicious cycle. It is not clear whether the protective effects of T-type calcium channel blockers (T-type CCBs) on renal function are better than those of L-type CCBs or renin-angiotensin system (RAS) antagonists in patients with hypertension. Methods and Findings PUBMED, MEDLINE, EMBASE, OVID, Web of Science, Cochrane, CNKI, MEDCH, VIP, and WANFANG databases were searched for clinical trials published in English or Chinese from January 1, 1990, to December 31, 2013. The weighted mean difference (WMD) and 95% confidence interval (CI) were calculated and reported. A total of 1494 reports were collected, of which 24 studies with 1,696 participants (including 809 reports comparing T-type CCBs versus L-type CCBs and 887 reports comparing T-type CCB versus RAS antagonists) met the inclusion criteria. Compared with L-type CCBs, T-type CCBs resulted in a significant decline in aldosterone (mean difference = −15.19, 95% CI −19.65–−10.72, p<1×10−5), proteinuria (mean difference = −0.73, 95% CI −0.88–−0.57, p<1×10−5), protein to creatinine ratio (mean difference = −0.22, 95% CI −0.41–−0.03, p = 0.02), and urinary albumin to creatinine ratio (mean difference = −55.38, 95% CI −86.67–−24.09, p = 0.0005); no significant difference was noted for systolic blood pressure (SBP) (p = 0.76) and diastolic blood pressure (DBP) (p = 0.16). The effects of T-type CCBs did not significantly differ from those of RAS antagonists for SBP (p = 0.98), DBP (p = 0.86), glomerular filtration rate (p = 0.93), albuminuria (p = 0.97), creatinine clearance rate (p = 0.24), and serum creatinine (p = 0.27) in patients with hypertension. Conclusion In a pooled analysis of data from 24 studies measuring the effects of T-type CCBs on renal function and aldosterone, the protective effects of T-type CCBs on renal

  16. Renal Sympathetic Denervation in Rats Ameliorates Cardiac Dysfunction and Fibrosis Post-Myocardial Infarction Involving MicroRNAs.

    PubMed

    Zheng, Xiaoxin; Li, Xiaoyan; Lyu, Yongnan; He, Yiyu; Wan, Weiguo; Jiang, Xuejun

    2016-08-04

    BACKGROUND The role of renal sympathetic denervation (RSD) in ameliorating post-myocardial infarction (MI) left ventricular (LV) fibrosis via microRNA-dependent regulation of connective tissue growth factor (CTGF) remains unknown. MATERIAL AND METHODS MI and RSD were induced in Sprague-Dawley rats by ligating the left coronary artery and denervating the bilateral renal nerves, respectively. Norepinephrine, renin, angiotensin II and aldosterone in plasma, collagen, microRNA21, microRNA 101a, microRNA 133a and CTGF in heart tissue, as well as cardiac function were evaluated six weeks post-MI. RESULTS In the RSD group, parameters of cardiac function were significantly improved as evidenced by increased LV ejection fraction (p<0.01), LV end-systolic diameter (p<0.01), end-diastolic diameter (p<0.05), LV systolic pressure (p<0.05), maximal rate of pressure rise and decline (dP/dtmax and dP/dtmin, p<0.05), and decreased LV end-diastolic pressure (p<0.05) when compared with MI rats. Further, reduced collagen deposition in peri-infarct myocardium was observed in RSD-treated rats along with higher microRNA101a and microRNA133a (p<0.05) and lower microRNA21 expression (p<0.01) than in MI rats. CTGF mRNA and protein levels were decreased in LV following RSD (p<0.01), accompanied by decreased expression of norepinephrine, renin, angiotensin II and aldosterone in plasma (p<0.05) compared with untreated MI rats. CONCLUSIONS The potential therapeutic effects of RSD on post-MI LV fibrosis may be partly mediated by inhibition of CTGF expression via upregulation of microRNA 101a and microRNA 133a and downregulation of microRNA21.

  17. Renal dopaminergic system: Pathophysiological implications and clinical perspectives

    PubMed Central

    Choi, Marcelo Roberto; Kouyoumdzian, Nicolás Martín; Rukavina Mikusic, Natalia Lucía; Kravetz, María Cecilia; Rosón, María Inés; Rodríguez Fermepin, Martín; Fernández, Belisario Enrique

    2015-01-01

    Fluid homeostasis, blood pressure and redox balance in the kidney are regulated by an intricate interaction between local and systemic anti-natriuretic and natriuretic systems. Intrarenal dopamine plays a central role on this interactive network. By activating specific receptors, dopamine promotes sodium excretion and stimulates anti-oxidant and anti-inflammatory pathways. Different pathological scenarios where renal sodium excretion is dysregulated, as in nephrotic syndrome, hypertension and renal inflammation, can be associated with impaired action of renal dopamine including alteration in biosynthesis, dopamine receptor expression and signal transduction. Given its properties on the regulation of renal blood flow and sodium excretion, exogenous dopamine has been postulated as a potential therapeutic strategy to prevent renal failure in critically ill patients. The aim of this review is to update and discuss on the most recent findings about renal dopaminergic system and its role in several diseases involving the kidneys and the potential use of dopamine as a nephroprotective agent. PMID:25949933

  18. Magnetic resonance urography in evaluation of duplicated renal collecting systems.

    PubMed

    Adeb, Melkamu; Darge, Kassa; Dillman, Jonathan R; Carr, Michael; Epelman, Monica

    2013-11-01

    Duplex renal collecting systems are common congenital anomalies of the upper urinary tract. In most cases they are incidental findings and not associated with additional pathologies. They demonstrate, however, higher incidences of hydroureteronephrosis, ureteroceles, and ectopic ureters. The most comprehensive morphologic and functional evaluation of duplex systems can be achieved using magnetic resonance urography. Functional magnetic resonance urography allows better separation of the renal poles, thus more accurate calculation of the differential renal functions compared with renal scintigraphy. Magnetic resonance urography is the study of choice when upper urinary tract anatomy is complex or when functional evaluation is needed.

  19. Systemic lupus erythematosus accompanying with renal tuberculosis: a case report

    PubMed Central

    Li, Tao; Gao, Liang; Chen, Peng; Bu, Si-Yuan; Cao, De-Hong; Yang, Lu; Wei, Qiang

    2015-01-01

    A 26-year-old woman, with a six-year history of well-controlled systemic lupus erythematosus (SLE), complained of urinary frequency and urgency. After failure of commonly-used antibiotic therapy, mycobacterium tuberculosis was cultured from her urine and renal tuberculosis (TB) was diagnosed. However, she underwent right nephrectomy after the combination therapies of prednisone for SLE and anti-tuberculosis treatment for renal TB failed. To our knowledge, SLE accompanying renal TB is rare, and such a rapid deterioration in renal function has never been reported. PMID:26221395

  20. Systemic sarcoidosis complicated of acute renal failure: about 12 cases.

    PubMed

    Mahfoudhi, Madiha; Mamlouk, Habiba; Turki, Sami; Kheder, Adel

    2015-01-01

    The sarcoidosis is a systemic granulomatosis affecting most frequently the lungs and the mediastinum. An acute renal failure reveals exceptionally this disease. It's a retrospective study implicating 12 cases of sarcoidosis complicated of acute renal failure. The aim of this study is to determine epidemiological, clinical, biological and histological profile in these cases and then to indicate the interest to consider the diagnosis of sarcoidosis in cases of unexplained renal failure. Extra-renal complications, therapeutic modalities and the outcome were determined in all patients. Our series involved 12 women with an average age of 40 years. Biological investigations showed an abnormal normocalcemia in 7 cases, a hypercalcemia in 5 cases, a hypercalciuria in 10 cases and polyclonal hypergammaglobulinemia in 7 cases. An acute renal failure was found in all patients with a median creatinin of 520 umol/L. For all patients, the renal echography was normal however, the kidney biopsy showed tubulo-interstitial nephritis. The extra-renal signs highlighting pulmonary interstitial syndrome in 5 cases, a sicca syndrome in 4 cases, mediastinal lymph nodes in 2 cases, a lymphocytic alveolitis in 3 cases, an anterior granulomatous uveitis in 2 cases and a polyarthritis in 5 cases. Five patients benefited of hemodialysis. The treatment consisted of corticosteroid in all cases. The follow up was marked by complete resolution of clinical and biological signs. The diagnosis of renal sarcoidosis must be done quickly to prevent renal failure.

  1. Combined Therapy with Renin-Angiotensin System and Calcium Channel Blockers in Type 2 Diabetic Hypertensive Patients with Proteinuria: Effects on Soluble TWEAK, PTX3, and Flow-Mediated Dilation

    PubMed Central

    Yilmaz, Mahmut Ilker; Carrero, Juan Jesús; Martín-Ventura, Jose Luis; Sonmez, Alper; Saglam, Mutlu; Celik, Turgay; Yaman, Halil; Yenicesu, Mujdat; Eyileten, Tayfun; Moreno, Juan Antonio; Egido, Jesús

    2010-01-01

    Background and objectives: Soluble TNF-like weak inducer of apoptosis (sTWEAK) and long pentraxin-3 (PTX3) concentrations have been associated with endothelial function in patients with chronic kidney disease (CKD). This study tested the hypothesis that the improvement in endothelial function after initiation of angiotensin II receptor blocker (valsartan), calcium channel blocker (amlodipine) therapy, or a combination of both is directly linked to the normalization of sTWEAK and PTX3. Design, setting, participants, & measurements: One-hundred-eight diabetic CKD stage I patients with hypertension (56% men, 46.7 ± 5.3 years) were allocated to a 12-week intervention with amlodipine (10 mg/d), valsartan (160 mg/d), or their combination. Plasma levels of sTWEAK, PTX3, and flow-mediated dilation (FMD) were studied during the interventions. Results: All treatment strategies effectively increased FMD and reduced proteinuria, confirming a more prone reduction with the combined therapy. These improvements were followed by significant PTX3 reductions. Valsartan alone and in combination with amlodipine achieved significant incremental raises in sTWEAK plasma levels. More importantly, the changes observed in sTWEAK (β = 0.25, P = 0.006) or PTX3 (β = −0.24, P = 0.007) plasma levels were independently associated with the improvement in ultrasonographically measured FMD. Conclusions: This study shows that treatment with antihypertensive drugs improves FMD and normalizes proteinuria, PTX3, and sTWEAK in diabetic CKD stage I patients with hypertension. The improvement in FMD was independently associated with PTX3 and sTWEAK normalization. Two surrogate biomarkers of endothelial function are therefore identified with potential as therapeutic targets. The study was registered in clinicaltrials.gov as NCT00921570. PMID:20430947

  2. Short-term administration of GW501516 improves inflammatory state in white adipose tissue and liver damage in high-fructose-fed mice through modulation of the renin-angiotensin system.

    PubMed

    Magliano, D'Angelo C; Penna-de-Carvalho, Aline; Vazquez-Carrera, Manuel; Mandarim-de-Lacerda, Carlos A; Aguila, Marcia B

    2015-11-01

    High activation of the angiotensin-converting enzyme (ACE)/(angiotensin-II type 1 receptor) AT1r axis is closely linked to pro-inflammatory effects and liver damage. The aim of this study was to evaluate the effects of the short-term administration of GW501516 on pro-inflammatory markers in white adipose tissue (WAT) and hepatic stellate cells (HSCs), lipogenesis and insulin resistance in the liver upon high-fructose diet (HFru)-induced ACE/AT1r axis activation. Three-month-old male C57Bl/6 mice were fed a standard chow diet or a HFru for 8 weeks. Then, the animals were separated randomly into four groups and treated with GW501516 for 3 weeks. Morphological variables, systolic blood pressure, and plasma determinations were analyzed. In the WAT, the ACE/AT1r axis and pro-inflammatory cytokines were assessed, and in the liver, the ACE/AT1r axis, HSCs, fatty acid oxidation, insulin resistance, and AMPK activation were evaluated. The HFru group displayed a high activation of the ACE/AT1r axis in both the WAT and liver; consequently, we detected inflammation and liver damage. Although GW501516 abolished the increased activation of the ACE/AT1r axis in the WAT, no differences were found in the liver. GW501516 blunted the inflammatory state in the WAT and reduced HSC activation in the liver. In addition, GW501516 alleviates damage in the liver by increasing the expression of the genes that regulate beta-oxidation and decreasing the expression of the genes and proteins that are involved in lipogenesis and gluconeogenesis. We conclude that GW501516 may serve as a therapeutic option for the treatment of a highly activated ACE/AT1r axis in WAT and liver.

  3. Fixed-Dose Combinations of Renin-Angiotensin System Inhibitors and Calcium Channel Blockers in the Treatment of Hypertension: A Comparison of Angiotensin Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors.

    PubMed

    Hsiao, Fu-Chih; Tung, Ying-Chang; Chou, Shing-Hsien; Wu, Lung-Sheng; Lin, Chia-Pin; Wang, Chun-Li; Lin, Yu-Sheng; Chang, Chee-Jen; Chu, Pao-Hsien

    2015-12-01

    Fixed-dose combinations (FDCs) of different regimens are recommended in guidelines for the treatment of hypertension. However, clinical studies comparing FDCs of angiotensin receptor blocker (ARB)/calcium channel blocker (CCB) and angiotensin-converting enzyme inhibitor (ACE inhibitor)/CCB in hypertensive patients are lacking.Using a propensity score matching of 4:1 ratio, this retrospective claims database study compared 2 FDC regimens, ARB/CCB and ACE inhibitor/CCB, in treating hypertensive patients with no known atherosclerotic cardiovascular disease. All patients were followed for at least 3 years or until the development of major adverse cardiovascular events (MACEs) during the study period. In addition, the effect of medication adherence on clinical outcomes was evaluated in subgroup analysis based on different portions of days covered.There was no significant difference in MACE-free survival (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 0.98-1.50; P = 0.08) and survival free from hospitalization for heart failure (HR: 1.15; 95% CI: 082-1.61; P = 0.431), new diagnosis of chronic kidney disease (HR: 0.98; 95% CI: 071-1.36; P = 0.906), and initiation of dialysis (HR: 0.99; 95% CI: 050-1.92; P = 0.965) between the 2 study groups. The results remained the same within each subgroup of patients with different adherence statuses.ARBs in FDC regimens with CCBs in the present study were shown to be as effective as ACE inhibitors at reducing the risks of MACEs, hospitalization for heart failure, new diagnosis of chronic kidney disease, and new initiation of dialysis in hypertensive patients, regardless of the medication adherence status.

  4. Renal Denervation Suppresses the Inducibility of Atrial Fibrillation in a Rabbit Model for Atrial Fibrosis

    PubMed Central

    Zhou, Genqing; Chen, Songwen; Ouyang, Ping; Liu, Shaowen

    2016-01-01

    Renal denervation (RD) was reported to reduce the susceptibility of atrial fibrillation (AF), but the underlying mechanism has not been well understood. This study was performed to investigate the effect of RD on the inducibility of AF in a rabbit model for atrial fibrosis and to explore the potential mechanisms. Thirty-five rabbits were randomly assigned into sham-operated group (n = 12), abdominal aortic constriction (AAC) group (n = 12) and AAC with RD (AAC-RD) group (n = 11). The incidence of AF induced by burst pacing in atriums was determined. Blood was collected to measure the levels of rennin, angiotensin II and aldosterone. Atrial samples were preserved to evaluate protein and gene expression of collagen, connective tissue growth factor (CTGF) and transforming growth factor-β1 (TGF-β1). Our data suggested cardiac structure remodeling and atrial fibrosis were successfully induced by AAC. Compared with the AAC group, the AAC-RD rabbits had smaller ascending aortic diameter and left ventricular end-systolic diameter. For burst pacing at the left atrium (LA), AF was induced in two of the 12 rabbits in the sham-operated group, 10 of the 12 rabbits in the AAC group, and 2 of the 11 rabbits in the AAC-RD group, with great difference among the three groups (P = 0.001). The percentage of LA burst stimulations with induced AF achieved 47.2% in the AAC group, which was higher than those in both the AAC-RD (12.1%) and the Sham-operated (5.6%) groups. Significantly increasing intercellular space in the AAC group (P<0.001) compared with the sham-operated rabbits. RD clearly decreased the volume fraction of collagen in LA and right atrium compared with that of the AAC group (P< 0.01). AAC-induced elevation of collagen I, CTGF and TGF-β1 was suppressed by RD. In conclusion, RD suppressed the inducibility of AF in a rabbit model for pressure associated atrial fibrosis, potentially by modulating renin-angiotensin-aldosterone system and decreasing pro-fibrotic factors

  5. Association of systemic hypertension with renal injury in dogs with induced renal failure.

    PubMed

    Finco, Delmar R

    2004-01-01

    Systemic hypertension is hypothesized to cause renal injury to dogs. This study was performed on dogs with surgically induced renal failure to determine whether hypertension was associated with altered renal function or morphology. Mean arterial pressure (MAP), heart rate (HR), systolic arterial pressure (SAP), and diastolic arterial pressure (DAP) were measured before and after surgery. Glomerular filtration rate (GFR) and urine protein:creatinine ratios (UPC) were measured at 1, 12, 24, 36, and 56-69 weeks after surgery, and renal histology was evaluated terminally. The mean of weekly MAP, SAP, and DAP measurements for each dog over the 1st 26 weeks was used to rank dogs on the basis of MAP, SAP, or DAP values. A statistically significant association was found between systemic arterial pressure ranking and ranked measures of adverse renal responses. When dogs were divided into higher pressure and lower pressure groups on the basis of SAP, group 1 (higher pressure, n = 9) compared with group 2 (lower pressure, n = 10) had significantly lower GFR values at 36 and 56-69 weeks; higher UPC values at 12 and 56-69 weeks; and higher kidney lesion scores for mesangial matrix, tubule damage, and fibrosis. When dogs were divided on MAP and DAP values, group 1 compared with group 2 had significantly lower GFR values at 12, 24, 36, and 56-69 weeks; higher UPC values at 12 and 56-69 weeks; and higher kidney lesion scores for mesangial matrix, tubule damage, fibrosis, and cell infiltrate. These results demonstrate an association between increased systemic arterial pressure and renal injury. Results from this study might apply to dogs with some types of naturally occurring renal failure.

  6. Bioartificial Renal Epithelial Cell System (BRECS): A Compact, Cryopreservable Extracorporeal Renal Replacement Device

    PubMed Central

    Buffington, Deborah A.; Pino, Christopher J.; Chen, Lijun; Westover, Angela J.; Hageman, Gretchen; Humes, H. David

    2012-01-01

    Renal cell therapy has shown clinical efficacy in the treatment of acute renal failure (ARF) and promise for treatment of end-stage renal disease (ESRD) by supplementing conventional small solute clearance (hemodialysis or hemofiltration) with endocrine and metabolic function provided by cells maintained in an extracorporeal circuit. A major obstacle in the widespread adoption of this therapeutic approach is the lack of a cryopreservable system to enable distribution, storage, and therapeutic use at point of care facilities. This report details the design, fabrication, and assessment of a Bioartificial Renal Epithelial Cell System (BRECS), the first all-in-one culture vessel, cryostorage device, and cell therapy delivery system. The BRECS was loaded with up to 20 cell-seeded porous disks, which were maintained by perfusion culture. Once cells reached over 5×106 cells/disk for a total therapeutic dose of approximately 108 cells, the BRECS was cryopreserved for storage at −80°C or −140°C. The BRECS was rapidly thawed, and perfusion culture was resumed. Near precryopreservation values of cell viability, metabolic activity, and differentiated phenotype of functional renal cells were confirmed postreconstitution. This technology could be extended to administer other cell-based therapies where metabolic, regulatory, or secretion functions can be leveraged in an immunoisolated extracorporeal circuit. PMID:24575327

  7. The impact of age-related dysregulation of the angiotensin system on mitochondrial redox balance

    PubMed Central

    Vajapey, Ramya; Rini, David; Walston, Jeremy; Abadir, Peter

    2014-01-01

    Aging is associated with the accumulation of various deleterious changes in cells. According to the free radical and mitochondrial theory of aging, mitochondria initiate most of the deleterious changes in aging and govern life span. The failure of mitochondrial reduction-oxidation (redox) homeostasis and the formation of excessive free radicals are tightly linked to dysregulation in the Renin Angiotensin System (RAS). A main rate-controlling step in RAS is renin, an enzyme that hydrolyzes angiotensinogen to generate angiotensin I. Angiotensin I is further converted to Angiotensin II (Ang II) by angiotensin-converting enzyme (ACE). Ang II binds with equal affinity to two main angiotensin receptors—type 1 (AT1R) and type 2 (AT2R). The binding of Ang II to AT1R activates NADPH oxidase, which leads to increased generation of cytoplasmic reactive oxygen species (ROS). This Ang II-AT1R–NADPH-ROS signal triggers the opening of mitochondrial KATP channels and mitochondrial ROS production in a positive feedback loop. Furthermore, RAS has been implicated in the decrease of many of ROS scavenging enzymes, thereby leading to detrimental levels of free radicals in the cell. AT2R is less understood, but evidence supports an anti-oxidative and mitochondria-protective function for AT2R. The overlap between age related changes in RAS and mitochondria, and the consequences of this overlap on age-related diseases are quite complex. RAS dysregulation has been implicated in many pathological conditions due to its contribution to mitochondrial dysfunction. Decreased age-related, renal and cardiac mitochondrial dysfunction was seen in patients treated with angiotensin receptor blockers. The aim of this review is to: (a) report the most recent information elucidating the role of RAS in mitochondrial redox hemostasis and (b) discuss the effect of age-related activation of RAS on generation of free radicals. PMID:25505418

  8. AT1A Angiotensin Receptors in the Renal Proximal Tubule Regulate Blood Pressure

    PubMed Central

    Gurley, Susan B.; Riquier, Anne D. M.; Schnermann, Jurgen; Sparks, Matthew A.; Allen, Andrew M.; Haase, Volker H.; Snouwaert, John N.; Le, Thu H.; McDonough, Alicia A.; Koller, Beverley H.; Coffman, Thomas M.

    2011-01-01

    Summary Hypertension affects more than 1.5 billion people worldwide but the precise cause of elevated blood pressure (BP) cannot be determined in most affected individuals. Nonetheless, blockade of the renin-angiotensin system (RAS) lowers BP in the majority of patients with hypertension. Despite its apparent role in hypertension pathogenesis, the key cellular targets of the RAS that control BP have not been clearly identified. Here we demonstrate that RAS actions in the epithelium of the proximal tubule have a critical and non-redundant role in determining the level of BP. Abrogation of AT1 angiotensin receptor signaling in the proximal tubule alone is sufficient to lower BP, despite intact vascular responses. Elimination of this pathway reduces proximal fluid reabsorption and alters expression of key sodium transporters, modifying pressure-natriuresis and providing substantial protection against hypertension. Thus, effectively targeting epithelial functions of the proximal tubule of the kidney should be a useful therapeutic strategy in hypertension. PMID:21459331

  9. Inclusion of renal vascular lesions in the 2003 ISN/RPS system for classifying lupus nephritis improves renal outcome predictions.

    PubMed

    Wu, Li-Hua; Yu, Feng; Tan, Ying; Qu, Zhen; Chen, Meng-Hua; Wang, Su-Xia; Liu, Gang; Zhao, Ming-Hui

    2013-04-01

    The 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) pathological classification system of lupus nephritis specified the importance of vascular damage and indicated this should be included in the diagnostic summary. Few pathological studies of lupus nephritis, however, focus on the patterns of renal vascular involvement. Here we assessed renal vascular lesions in lupus nephritis based on the 2003 ISN/RPS classification system and evaluated their association with clinical and pathological data in a large cohort from a single center in China. Among 341 patients with lupus nephritis, 279 were diagnosed with single or multiple renal vascular lesions that included 253 with vascular immune complex deposits, 82 with atherosclerosis, 60 with thrombotic microangiopathy, 13 with noninflammatory necrotizing vasculopathy, and 2 with true renal vasculitis. Patients with thrombotic microangiopathy had the poorest renal outcome. In multivariate Cox hazard analysis after inclusion of renal vascular lesions, the new chronicity index score became a significantly better independent risk factor for renal outcome (hazard ratio 2.32). Thus, renal vascular lesions are common in lupus nephritis and closely correlate with clinical disease activity and renal outcome. Inclusion of a detailed description of renal vascular lesions in the ISN/RPS classification of lupus nephritis may strengthen its predictive value for renal outcome.

  10. High Na intake increases renal angiotensin II levels and reduces expression of the ACE2-AT2R-MasR axis in obese Zucker rats

    PubMed Central

    Samuel, Preethi; Ali, Quaisar; Sabuhi, Rifat; Wu, Yonnie

    2012-01-01

    High sodium intake is known to regulate the renal renin-angiotensin system (RAS) and is a risk factor for the pathogenesis of obesity-related hypertension. The complex nature of the RAS reveals that its various components may have opposing effects on natriuresis and blood pressure regulation. We hypothesized that high sodium intake differentially regulates and shifts a balance between opposing components of the renal RAS, namely, angiotensin-converting enzyme (ACE)-ANG II-type 1 ANG II receptor (AT1R) vs. AT2-ACE2-angiotensinogen (Ang) (1–7)-Mas receptor (MasR), in obesity. In the present study, we evaluated protein and/or mRNA expression of angiotensinogen, renin, AT1A/BR, ACE, AT2R, ACE2, and MasR in the kidney cortex following 2 wk of a 8% high-sodium (HS) diet in lean and obese Zucker rats. The expression data showed that the relative expression pattern of ACE and AT1BR increased, renin decreased, and ACE2, AT2R, and MasR remained unaltered in HS-fed lean rats. On the other hand, HS intake in obese rats caused an increase in the cortical expression of ACE, a decrease in ACE2, AT2R, and MasR, and no changes in renin and AT1R. The cortical levels of ANG II increased by threefold in obese rats on HS compared with obese rats on normal salt (NS), which was not different than in lean rats. The HS intake elevated mean arterial pressure in obese rats (27 mmHg) more than in lean rats (16 mmHg). This study suggests that HS intake causes a pronounced increase in ANG II levels and a reduction in the expression of the ACE2-AT2R-MasR axis in the kidney cortex of obese rats. We conclude that such changes may lead to the potentially unopposed function of AT1R, with its various cellular and physiological roles, including the contribution to the pathogenesis of obesity-related hypertension. PMID:22592638

  11. High Na intake increases renal angiotensin II levels and reduces expression of the ACE2-AT(2)R-MasR axis in obese Zucker rats.

    PubMed

    Samuel, Preethi; Ali, Quaisar; Sabuhi, Rifat; Wu, Yonnie; Hussain, Tahir

    2012-08-01

    High sodium intake is known to regulate the renal renin-angiotensin system (RAS) and is a risk factor for the pathogenesis of obesity-related hypertension. The complex nature of the RAS reveals that its various components may have opposing effects on natriuresis and blood pressure regulation. We hypothesized that high sodium intake differentially regulates and shifts a balance between opposing components of the renal RAS, namely, angiotensin-converting enzyme (ACE)-ANG II-type 1 ANG II receptor (AT(1)R) vs. AT(2)-ACE2-angiotensinogen (Ang) (1-7)-Mas receptor (MasR), in obesity. In the present study, we evaluated protein and/or mRNA expression of angiotensinogen, renin, AT(1A/B)R, ACE, AT(2)R, ACE2, and MasR in the kidney cortex following 2 wk of a 8% high-sodium (HS) diet in lean and obese Zucker rats. The expression data showed that the relative expression pattern of ACE and AT(1B)R increased, renin decreased, and ACE2, AT(2)R, and MasR remained unaltered in HS-fed lean rats. On the other hand, HS intake in obese rats caused an increase in the cortical expression of ACE, a decrease in ACE2, AT(2)R, and MasR, and no changes in renin and AT(1)R. The cortical levels of ANG II increased by threefold in obese rats on HS compared with obese rats on normal salt (NS), which was not different than in lean rats. The HS intake elevated mean arterial pressure in obese rats (27 mmHg) more than in lean rats (16 mmHg). This study suggests that HS intake causes a pronounced increase in ANG II levels and a reduction in the expression of the ACE2-AT(2)R-MasR axis in the kidney cortex of obese rats. We conclude that such changes may lead to the potentially unopposed function of AT(1)R, with its various cellular and physiological roles, including the contribution to the pathogenesis of obesity-related hypertension.

  12. Competition by meperidine for the organic cation renal excretory system.

    PubMed

    Acara, M; Gessner, T; Trudnowski, R J

    1981-07-01

    Renal tubular excretory transport of meperidine was studied using the Sperber preparation in chickens. When urine samples from infused and uninfused kidneys were analyzed for meperidine by gas chromatography, meperidine was always present in greater amounts in the urine from the infused kidney, demonstrating active tubular excretion. Meperidine at an infusion rate of 1 mumole/min, also inhibited the excretion of the organic cations choline and acetylcholine, indicating occupation of the renal organic cation excretory system in the chicken.

  13. Effect of Pentoxifylline on Renal Function and Urinary Albumin Excretion in Patients with Diabetic Kidney Disease: The PREDIAN Trial

    PubMed Central

    Mora-Fernández, Carmen; Muros de Fuentes, Mercedes; Chahin, Jesús; Méndez, María L.; Gallego, Eduardo; Macía, Manuel; del Castillo, Nieves; Rivero, Antonio; Getino, María A.; García, Patricia; Jarque, Ana; García, Javier

    2015-01-01

    Diabetic kidney disease (DKD) is the leading cause of ESRD. We conducted an open-label, prospective, randomized trial to determine whether pentoxifylline (PTF), which reduces albuminuria, in addition to renin-angiotensin system (RAS) blockade, can slow progression of renal disease in patients with type 2 diabetes and stages 3–4 CKD. Participants were assigned to receive PTF (1200 mg/d) (n=82) or to a control group (n=87) for 2 years. All patients received similar doses of RAS inhibitors. At study end, eGFR had decreased by a mean±SEM of 2.1±0.4 ml/min per 1.73 m2 in the PTF group compared with 6.5±0.4 ml/min per 1.73 m2 in the control group, with a between-group difference of 4.3 ml/min per 1.73 m2 (95% confidence interval [95% CI], 3.1 to 5.5 ml/min per 1.73 m2; P<0.001) in favor of PTF. The proportion of patients with a rate of eGFR decline greater than the median rate of decline (0.16 ml/min per 1.73 m2 per month) was lower in the PTF group than in the control group (33.3% versus 68.2%; P<0.001). Percentage change in urinary albumin excretion was 5.7% (95% CI, −0.3% to 11.1%) in the control group and −14.9% (95% CI, −20.4% to −9.4%) in the PTF group (P=0.001). Urine TNF-α decreased from a median 16 ng/g (interquartile range, 11–20.1 ng/g) to 14.3 ng/g (interquartile range, 9.2–18.4 ng/g) in the PTF group (P<0.01), with no changes in the control group. In this population, addition of PTF to RAS inhibitors resulted in a smaller decrease in eGFR and a greater reduction of residual albuminuria. PMID:24970885

  14. The Role of Hydrogen Sulfide in Renal System

    PubMed Central

    Cao, Xu; Bian, Jin-Song

    2016-01-01

    Hydrogen sulfide has gained recognition as the third gaseous signaling molecule after nitric oxide and carbon monoxide. This review surveys the emerging role of H2S in mammalian renal system, with emphasis on both renal physiology and diseases. H2S is produced redundantly by four pathways in kidney, indicating the abundance of this gaseous molecule in the organ. In physiological conditions, H2S was found to regulate the excretory function of the kidney possibly by the inhibitory effect on sodium transporters on renal tubular cells. Likewise, it also influences the release of renin from juxtaglomerular cells and thereby modulates blood pressure. A possible role of H2S as an oxygen sensor has also been discussed, especially at renal medulla. Alternation of H2S level has been implicated in various pathological conditions such as renal ischemia/reperfusion, obstructive nephropathy, diabetic nephropathy, and hypertensive nephropathy. Moreover, H2S donors exhibit broad beneficial effects in renal diseases although a few conflicts need to be resolved. Further research reveals that multiple mechanisms are underlying the protective effects of H2S, including anti-inflammation, anti-oxidation, and anti-apoptosis. In the review, several research directions are also proposed including the role of mitochondrial H2S in renal diseases, H2S delivery to kidney by targeting D-amino acid oxidase/3-mercaptopyruvate sulfurtransferase (DAO/3-MST) pathway, effect of drug-like H2S donors in kidney diseases and understanding the molecular mechanism of H2S. The completion of the studies in these directions will not only improves our understanding of renal H2S functions but may also be critical to translate H2S to be a new therapy for renal diseases. PMID:27803669

  15. Chronic renal insufficiency among Asian Indians with type 2 diabetes: I. Role of RAAS gene polymorphisms

    PubMed Central

    Prasad, Pushplata; Tiwari, Arun K; Kumar, KM Prasanna; Ammini, AC; Gupta, Arvind; Gupta, Rajeev; Sharma, AK; Rao, AR; Nagendra, R; Chandra, T Satish; Tiwari, SC; Rastogi, Priyanka; Gupta, B Lal; Thelma, BK

    2006-01-01

    Background Renal failure in diabetes is mediated by multiple pathways. Experimental and clinical evidences suggest that renin-angiotensin-aldosterone system (RAAS) has a crucial role in diabetic kidney disease. A relationship between the RAAS genotypes and chronic renal insufficiency (CRI) among type 2 diabetes subjects has therefore been speculated. We investigated the contribution of selected RAAS gene polymorphisms to CRI among type 2 diabetic Asian Indian subjects. Methods Twelve single nucleotide polymorphisms (SNPs) from six genes namely-renin (REN), angiotensinogen (ATG), angiotensin converting enzyme I (ACE), angiotensin II type 1 receptor (AT1) and aldosterone synthase (CYP11B2) gene from the RAAS pathway and one from chymase pathway were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and tested for their association with diabetic CRI using a case-control approach. Successive cases presenting to study centres with type 2 diabetes of ≥2 years duration and moderate CRI diagnosed by serum creatinine ≥3 mg/dl after exclusion of non-diabetic causes of CRI (n = 196) were compared with diabetes subjects with no evidence of renal disease (n = 225). Logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study pair wise interactions between SNPs of different genes. Results Of the 12 SNPs genotyped, Glu53Stop in AGT and A>T (-777) in AT1 genes, were monomorphic and not included for further analysis. We observed a highly significant association of Met235Thr SNP in angiotensinogen gene with CRI (O.R. 2.68, 95%CI: 2.01–3.57 for Thr allele, O.R. 2.94, 95%CI: 1.88–4.59 for Thr/Thr genotype and O.R. 2.68, 95%CI: 1.97–3.64 for ACC haplotype). A significant allelic and genotypic association of T>C (-344) SNP in aldosterone synthase gene (O.R. 1.57, 95%CI: 1.16–2.14 and O.R. 1.81, 95%CI: 1.21–2.71 respectively), and genotypic association of GA genotype of

  16. Evalution of Renal Involvement in Patients with Behçet Disease: Need to be Aware About Potential Hypertension in Long Term Follow Up?

    PubMed Central

    Ozel, Deniz; Ozel, Betul Duran; Ozkan, Fuat; Kutlu, Ramazan

    2016-01-01

    Summary Backround The aim of this study was to evaluate frequency and severity of kidney involvement with some clinical, ultrasonography and color Doppler measurements in patients with Behçet disease. Material/Methods This study was including 32 patients with Behçet disease and 32 healthy sex and age-matched control subjects. Patients were divided into two groups as period of disease 0–6 years and 7 years and above to evaluate effect of duration of disease. We evaluated some biochemical tests in both blood and urine related to renal functions, blood pressure values. Gray scale and color Doppler findings were noted. Results Renal artery volume flow in patients with a duration of 7 years or above was significantly decreased compared to control group (p<0.05). However, gray scale ultrasound and color Doppler measurements reveal there was not statistically significant change compared to control group. There was no biochemical abnormalities in any patient. Four patients had elevated blood pressure but mean blood pressure values were not statistically different compared to volunteers. Conclusions Renal involvement ratios varies in different studies but not common. End stage renal failure can be seen very rare. Furthermore, vasculitic changes can lead renal artery narrowness and can result to decrease in renal blood flow. It has a potential to activate renin angiotensin aldosterone cascade to elevate blood pressure. We must be aware about blood pressure of patients with Behçet disease, especially with long term follow up. PMID:26937259

  17. A new microcontroller supervised thermoelectric renal hypothermia system.

    PubMed

    Işik, Hakan

    2005-10-01

    In the present study, a thermoelectric system controlled by a microcontroller is developed to induce renal hypothermia. Temperature value was managed by 8-byte microcontroller, PIC16F877, and was programmed using microcontroller MPASM package. In order to ensure hypothermia in the kidney 1-4 modules and sensors perceiving temperature of the area can be selected. Temperature values are arranged proportionately for the selected area and the determined temperature values can be monitored from an Liquid Crystal Display (LCD) screen. The temperature range of the system is between -50 and +50 degrees C. Renal hypothermia system was tried under in vivo conditions on the kidney of a dog.

  18. New registry and tracking system for renal transplantation in Japan.

    PubMed

    Yuzawa, K; Takahara, S; Kanmochi, T; Takahashi, K; Teraoka, S

    2010-12-01

    Following The Declaration of Istanbul 2008, a registration committees of The Japan Society for Transplantation and The Japanese Society for Clinical Renal Transplantation planned to establish a new registry and tracking system for renal transplant recipients and donors supported by a Health Labor Sciences Research Grant by The Ministry of Health Labour and Welfare. In place of the previous paper-based system, we established the new registry and tracking system, JARTRE (Japan Renal Transplantation Registry), using USB memory in 2009. Recipient and donor data were inputted into the USB memory at the transplantation centers. The memory was reviewed a yearly by committees. The recipient and donor registration included details from both. The tracking is performed centrally 3 months, 1 year, and every year after the operation. The advantages of this system are the ease of input, adequacy of the data, and rapid statistical processing. In 2009, we registered 97.9% of new renal transplantation recipients and donors; in 2008 it was more than 81.9% of all past renal transplantation recipients in Japan.

  19. Low-grade proteinuria and microalbuminuria in renal transplantation.

    PubMed

    Halimi, Jean-Michel

    2013-07-27

    Nephrotic-range proteinuria has been known for years to be associated with poor renal outcome. Newer evidence indicates that early (1-3 months after transplantation) low-grade proteinuria and microalbuminuria (1) provide information on the graft in terms of donor characteristics and ischemia/reperfusion injury, (2) may occur before the development of donor-specific antibodies, (3) predict the development of diabetes and cardiovascular events, and (4) are associated with reduced long-term graft and patient survivals. Low-grade proteinuria and microalbuminuria are also predictive of diabetes, cardiovascular morbidity, and death in nontransplanted populations, which may help us to understand the pathophysiology of low-grade proteinuria or microalbuminuria in renal transplantation. The impact of immunosuppressive medications, including mammalian target of rapamycin inhibitors, on graft survival is still discussed, and the effect on proteinuria is crucial to the debate. The fact that chronic allograft rejection may exist as early as 3 months after renal transplantation indicates that optimal management of low-grade proteinuria or microalbuminuria should occur very early after transplantation to improve long-term renal function and the overall outcome of renal transplant recipients. The presence of low-grade proteinuria or microalbuminuria early after transplantation must be taken into account to choose adequate immunosuppressive and antihypertensive medications. Limited information exists regarding the benefit of therapeutic interventions to reduce low-grade proteinuria or microalbuminuria. Whether renin angiotensin blockade results in optimal nephroprotection in patients with low-grade proteinuria or microalbuminuria is not proven, especially in the absence of chronic allograft nephropathy. Observational studies and randomized clinical trials yield conflicting results. Finally, randomized clinical trials are urgently needed.

  20. 74 FR 49921 - Medicare Programs; End-Stage Renal Disease Prospective Payment System

    Federal Register 2010, 2011, 2012, 2013, 2014

    2009-09-29

    ... Programs; End-Stage Renal Disease Prospective Payment System; Town Hall Meeting on End-Stage Renal Disease... & Medicaid Services 42 CFR Parts 410, 413 and 414 RIN 0938-AP57 Medicare Programs; End-Stage Renal Disease...) for Medicare outpatient end-stage renal disease (ESRD) dialysis facilities beginning January 1,...

  1. Bringing together components of the fly renal system.

    PubMed

    Denholm, Barry; Skaer, Helen

    2009-10-01

    The function of all animal excretory systems is to rid the body of toxins and to maintain homeostatic balance. Although excretory organs in diverse animal species appear superficially different they are often built on two common principals: filtration and tubular secretion/reabsorbtion. The Drosophila excretory system is composed of filtration nephrocytes and Malpighian (renal) tubules. Here we review recent molecular genetic data on the development and differentiation of nephrocytes and renal tubules. We focus in particular on the molecular mechanisms that underpin key cell and tissue behaviours during morphogenesis, drawing parallels with other species where they exist. Finally we assess the implications of patterned tissue differentiation for the subsequent regulation of renal function. These studies highlight the continuing usefulness of the fly to provide fundamental insights into the complexities of organ formation.

  2. [The WHO/ISUP grading system for renal carcinoma].

    PubMed

    Moch, H

    2016-07-01

    Histological tumor grading is an accepted prognostic parameter of renal cell carcinoma (RCC). In 2012, the International Society of Urologic Pathologists (ISUP) proposed a novel grading system for RCC, mainly based on the evaluation of nucleoli: grade 1 tumors have nucleoli that are inconspicuous and basophilic at ×400 magnification; grade 2 tumors have nucleoli that are clearly visible at ×400 magnification and eosinophilic; grade 3 tumors have clearly visible nucleoli at ×100 magnification; and grade 4 tumors have extreme pleomorphism or rhabdoid and/or sarcomatoid morphology. This grading system was validated for clear cell renal cell carcinoma and papillary renal cell carcinoma. At the same time, the ISUP proposed not grading chromophobe renal cell carcinomas according to this system. At a consensus conference in Zurich the World Health Organization (WHO) recommended the ISUP grading system; thus, the WHO/ISUP grading system is now going to be implemented internationally. The ISUP/WHO grading system has not been validated as a prognostic parameter for other tumor subtypes, but can be used for descriptive purposes.

  3. Transcription factor avian erythroblastosis virus E26 oncogen homolog-1 is a novel mediator of renal injury in salt-sensitive hypertension.

    PubMed

    Feng, Wenguang; Chumley, Phillip; Prieto, Minolfa C; Miyada, Kayoko; Seth, Dale M; Fatima, Huma; Hua, Ping; Rezonzew, Gabriel; Sanders, Paul W; Jaimes, Edgar A

    2015-04-01

    Transcription factor E26 transformation-specific sequence-1 (ETS-1) is a transcription factor that regulates the expression of a variety of genes, including growth factors, chemokines, and adhesion molecules. We recently demonstrated that angiotensin II increases the glomerular expression of ETS-1 and that blockade of ETS-1 ameliorates the profibrotic and proinflammatory effects of angiotensin II. The Dahl salt-sensitive rat is a paradigm of salt-sensitive hypertension associated with local activation of the renin-angiotensin system. In these studies, we determined whether: (1) salt-sensitive hypertension is associated with renal expression of ETS-1 and (2) ETS-1 participates in the development of end-organ injury in salt-sensitive hypertension. Dahl salt-sensitive rats were fed a normal-salt diet (0.5% NaCl diet) or a high-salt diet (4% NaCl) for 4 weeks. Separate groups on high-salt diet received an ETS-1 dominant-negative peptide (10 mg/kg/d), an inactive ETS-1 mutant peptide (10 mg/kg/d), the angiotensin II type 1 receptor blocker candesartan (10 mg/kg/d), or the combination high-salt diet/dominant-negative peptide/angiotensin II type 1 receptor blocker for 4 weeks. High-salt diet rats had a significant increase in the glomerular expression of the phosphorylated ETS-1 that was prevented by angiotensin II type 1 receptor blocker. ETS-1 blockade reduced proteinuria, glomerular injury score, fibronectin expression, urinary transforming growth factor-β excretion, and macrophage infiltration. Angiotensin II type 1 receptor blocker reduced proteinuria, glomerular injury score, and macrophage infiltration, whereas concomitant ETS-1 blockade and angiotensin II type 1 receptor blocker had additive effects and reduced interstitial fibrosis. Our studies demonstrated that salt-sensitive hypertension results in increased glomerular expression of phosphorylated ETS-1 and suggested that ETS-1 plays an important role in the pathogenesis of end-organ injury in salt

  4. Endothelin and endothelin receptors in the renal and cardiovascular systems.

    PubMed

    Vignon-Zellweger, Nicolas; Heiden, Susi; Miyauchi, Takashi; Emoto, Noriaki

    2012-10-15

    Endothelin-1 (ET-1) is a multifunctional hormone which regulates the physiology of the cardiovascular and renal systems. ET-1 modulates cardiac contractility, systemic and renal vascular resistance, salt and water renal reabsorption, and glomerular function. ET-1 is responsible for a variety of cellular events: contraction, proliferation, apoptosis, etc. These effects take place after the activation of the two endothelin receptors ET(A) and ET(B), which are present - among others - on cardiomyocytes, fibroblasts, smooth muscle and endothelial cells, glomerular and tubular cells of the kidney. The complex and numerous intracellular pathways, which can be contradictory in term of functional response depending on the receptor type, cell type and physiological situation, are described in this review. Many diseases share an enhanced ET-1 expression as part of the pathophysiology. However, the use of endothelin blockers is currently restricted to pulmonary arterial hypertension, and more recently to digital ulcer. The complexity of the endothelin system does not facilitate the translation of the molecular knowledge to clinical applications. Endothelin antagonists can prevent disease development but secondary undesirable effects limit their usage. Nevertheless, the increasing understanding of the effects of ET-1 on the cardiac and renal physiology maintains the endothelin system as a promising therapeutic target.

  5. Serum protease activity in chronic kidney disease patients: The GANI_MED renal cohort.

    PubMed

    Wolke, Carmen; Teumer, Alexander; Endlich, Karlhans; Endlich, Nicole; Rettig, Rainer; Stracke, Sylvia; Fiene, Beate; Aymanns, Simone; Felix, Stephan B; Hannemann, Anke; Lendeckel, Uwe

    2017-03-01

    , resulting in increased morbidity and mortality. Understanding of molecular mechanisms linking both diseases is limited, available fragmentary data point to a role of the renin-angiotensin system (RAS) and, in particular, Ras-related peptidases. • Here, a comprehensive analysis of serum peptidase activities in patients with different stages of chronic kidney disease (CKD) is presented, with special emphasis given to RAS peptidases • The serum activities of the peptidases angiotensin I-converting enzyme 2 and dipeptidyl peptidase 4 were identified as closely associated with kidney function, specifically with the estimated glomerular filtration rate. The findings are discussed in the context of available data suggesting protective roles for both enzymes in reno-cardiac diseases. • The data add to our understanding of pathomechanisms underlying development and progression of CKD and indicate that both enzymes might represent potential pharmacological targets for the preservation of renal function.

  6. System for renal movement elimination and renal diagnosis supported by vague knowledge

    NASA Astrophysics Data System (ADS)

    Martin, Jens; Hiltner, Jens; Fathi, Madjid; Reusch, Bernd; Stattaus, Joerg; Hacklaender, Thomas

    2000-06-01

    For the analysis of renal function, sequences of 90 magnet resonance images of the abdominal region showing both kidneys are taken in intervals of two seconds after a contrast medium was applied. Respiration of the patients during the acquisition of the images leads to organ movements throughout the series. These displacements are corrected by using an extended cepstral technique. To minimize registration errors caused by inhomogeneous movements of organs and tissues during respiration, the cepstrum-relevant part of the images is limited to small regions of interest around both kidneys. Even organ movements of sub-pixel range can be detected. After correction, the kidneys are the same position throughout the sequence. The regions of interest marked in one image are projected to all other images. To archive diagnostic results, dynamic contrast medium evaluations for different tissues of the kidneys are computed with signal-intensity-time graphs. Using a-priori knowledge about parameters of the SIT-graph for a whole kidney and about organ shape and structure, pixels of the kidney-segment are divided into the three classes renal cortex, medulla and pelvis. As a result, precise graphs can be computed for each tissue. The evaluation of the system is in progress, time save is more than one hour per patient.

  7. Zebrafish mesonephric renin cells are functionally conserved and comprise two distinct morphological populations.

    PubMed

    Rider, Sebastien A; Christian, Helen C; Mullins, Linda J; Howarth, Amelia R; MacRae, Calum A; Mullins, John J

    2017-04-01

    Zebrafish provide an excellent model in which to assess the role of the renin-angiotensin system in renal development, injury, and repair. In contrast to mammals, zebrafish kidney organogenesis terminates with the mesonephros. Despite this, the basic functional structure of the nephron is conserved across vertebrates. The relevance of teleosts for studies relating to the regulation of the renin-angiotensin system was established by assessing the phenotype and functional regulation of renin-expressing cells in zebrafish. Transgenic fluorescent reporters for renin (ren), smooth muscle actin (acta2), and platelet-derived growth factor receptor-beta (pdgfrb) were studied to determine the phenotype and secretory ultrastructure of perivascular renin-expressing cells. Whole kidney ren transcription responded to altered salinity, pharmacological renin-angiotensin system inhibition, and renal injury. Mesonephric ren-expressing cells occupied niches at the preglomerular arteries and afferent arterioles, forming intermittent epithelioid-like multicellular clusters exhibiting a granular secretory ultrastructure. In contrast, renin cells of the efferent arterioles were thin bodied and lacked secretory granules. Renin cells expressed the perivascular cell markers acta2 and pdgfrb Transcriptional responses of ren to physiological challenge support the presence of a functional renin-angiotensin system and are consistent with the production of active renin. The reparative capability of the zebrafish kidney was harnessed to demonstrate that ren transcription is a marker for renal injury and repair. Our studies demonstrate substantive conservation of renin regulation across vertebrates, and ultrastructural studies of renin cells reveal at least two distinct morphologies of mesonephric perivascular ren-expressing cells.

  8. 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

  9. Present and Future in the Treatment of Diabetic Kidney Disease

    PubMed Central

    de Arriba, Gabriel

    2015-01-01

    Diabetic kidney disease is the leading cause of end-stage renal disease. Albuminuria is recognized as the most important prognostic factor for chronic kidney disease progression. For this reason, blockade of renin-angiotensin system remains the main recommended strategy, with either angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. However, other antiproteinuric treatments have begun to be studied, such as direct renin inhibitors or aldosterone blockers. Beyond antiproteinuric treatments, other drugs such as pentoxifylline or bardoxolone have yielded conflicting results. Finally, alternative pathogenic pathways are being explored, and emerging therapies including antifibrotic agents, endothelin receptor antagonists, or transcription factors show promising results. The aim of this review is to explain the advances in newer agents to treat diabetic kidney disease, along with the background of the renin-angiotensin system blockade. PMID:25945357

  10. [Hypertension and arteriosclerosis].

    PubMed

    Sasamura, Hiroyuki; Itoh, Hiroshi

    2011-01-01

    Hypertension is a known risk factor for arteriosclerosis, and causes both atherosclero= sis of medium-large arteries and arteriolosclerosis of the arterioles. Elevated blood pressure causes damage to the endothelium and vascular wall through both mechanical and humoral factors. We and others have shown that inhibition of the renin-angiotensin system at a 'critical period' during the development of hypertension results in a permanent suppression of hypertension in animal models. We have also reported that high-dose renin-angiotensin inhibition results in regression of hypertension, possibly by regression of renal arteriolar hypertrophy. These results suggest that understanding the process of arterial remodeling may play a key role in the development of new strategies for prevention and regression of hypertension and arteriosclerosis.

  11. How does obesity affect the endocrine system? A narrative review.

    PubMed

    Poddar, M; Chetty, Y; Chetty, V T

    2017-03-15

    Obesity is a chronic, relapsing medical condition that results from an imbalance of energy expenditure and consumption. It is a leading cause of preventable illness, disability and premature death. The causes of obesity are multifactorial and include behavioural, socioeconomic, genetic, environmental and psychosocial factors. Rarely are endocrine diseases, e.g., hypothyroidism or Cushing's syndrome, the cause of obesity. What is less understood is how obesity affects the endocrine system. In this review, we will discuss the impact of obesity on multiple endocrine systems, including the hypothalamic-pituitary axis, changes in vitamin D homeostasis, gender steroids and thyroid hormones. We will also examine the renin angiotensin aldosterone system and insulin pathophysiology associated with obesity. We will provide a general overview of the biochemical changes that can be seen in patients with obesity, review possible aetiologies of these changes and briefly consider current guidelines on their management. This review will not discuss endocrine causes of obesity.

  12. Kidney scintigraphy after ACE inhibition in the diagnosis of renovascular hypertension

    SciTech Connect

    Ghione, S.; Fommei, E.; Palombo, C.; Giaconi, S.; Mantovanelli, A.; Ragazzini, A.; Palla, L.

    1986-01-01

    Suppression of the renin-angiotensin system (RAS) by angiotensin converting enzyme (ACE) inhibition may induce renal failure in patients with bilateral renal artery stenosis. Recent scintigraphic studies with the glomerular tracer technetium-99m-diethylenetriaminepenta-acetate (99m-Tc DTPA) indicate that in patients with unilateral renal artery stenosis, glomerular filtration rate (GFR) may be markedly reduced in the affected kidney after inhibition of ACE. This finding reflects the important role of the RAS in maintaining GFR (by increasing postglomerular resistance) in states of low renal perfusion pressure. Preliminary observations suggest that this scintigraphic test might be useful in the detection of renovascular hypertension.

  13. Associations between proteinuria, systemic hypertension and glomerular filtration rate in dogs with renal and non-renal diseases.

    PubMed

    Wehner, A; Hartmann, K; Hirschberger, J

    2008-02-02

    Proteinuria and systemic hypertension are well recognised risk factors in chronic renal failure (CRF). They are consequences of renal disease but also lead to a further loss of functional kidney tissue. The objectives of this study were to investigate the associations between proteinuria, systemic hypertension and glomerular filtration rate (GFR) in dogs with naturally occurring renal and non-renal diseases, and to determine whether proteinuria and hypertension were associated with shorter survival times in dogs with CRF. Measurements of exogenous creatinine plasma clearance (ECPC), urine protein:creatinine ratio (UPC), and Doppler sonographic measurements of systolic blood pressure (SBP) were made in 60 dogs with various diseases. There was a weak but significant inverse correlation between UPC and ECPC, a significant inverse correlation between SBP and ECPC and a weak but significant positive correlation between UPC and SBP. Some of the dogs with CRF were proteinuric and almost all were hypertensive. Neoplasia was commonly associated with proteinuria in the dogs with a normal ECPC. CRF was the most common cause leading to hypertension. In the dogs with CRF, hypertension and marked proteinuria were associated with significantly shorter survival times.

  14. Association of Renal Resistive Index, Renal Pulsatility Index, Systemic Hypertension, and Albuminuria with Survival in Dogs with Pituitary-Dependent Hyperadrenocorticism

    PubMed Central

    Chen, Hung-Yin; Lien, Yu-Hsin

    2016-01-01

    An increased renal resistive index (RI) and albuminuria are markers of target organ damage secondary to systemic hypertension. This study evaluated associations between systemic blood pressure (SBP), renal RI, pulsatility index (PI), and albuminuria in dogs with pituitary-dependent hyperadrenocorticism (PDH). Predictors of overall mortality were investigated. Twenty client-owned dogs with PDH and 20 clinically healthy client-owned dogs as matched controls were included. Incidence rates of systemic hypertension (SBP ≥ 160 mmHg), albuminuria, and increased renal RI (≥ 0.70) and PI (≥ 1.45) in the control group were 5%, 0%, 5%, and 0%, respectively, compared to 35%, 40%, 50%, and 35%, respectively, in the PDH group (P = 0.001, P < 0.001, P < 0.001, and P = 0.001, resp.). No association between systemic hypertension, renal RI, renal PI, and albuminuria was observed. PDH was the only predictor of albuminuria and increased renal RI. Survival was not affected by increased renal PI, systemic hypertension, or albuminuria. Increased renal RI (≥ 0.70) was the only predictor of overall mortality in dogs with PDH. PMID:27340403

  15. Experimental models of renal disease and the cardiovascular system.

    PubMed

    Grossman, Rebecca C

    2010-11-26

    Cardiovascular disease is a leading cause of death among patients with end stage renal failure. Animal models have played a crucial role in teasing apart the complex pathological processes involved. This review discusses the principles of using animal models, the history of their use in the study of renal hypertension, the controversies arising from experimental models of non-hypertensive uraemic cardiomyopathy and the lessons learned from these models, and highlights important areas of future research in this field, including de novo cardiomyopathy secondary to renal transplantation.

  16. Targeting brain angiotensin and corticotrophin-releasing hormone systems interaction for the treatment of mood and alcohol use disorders.

    PubMed

    Sommer, Wolfgang H; Saavedra, Juan M

    2008-06-01

    The brain renin-angiotensin system (RAS) participates importantly in the regulation of endocrine, autonomic, and behavioral response to stress. Recent data indicate that central action of AT(1) receptor antagonists can reduce anxiety symptoms in experimental animals. Furthermore, central inhibition of RAS activity decreases ethanol intake in an animal model of alcoholism. Pathological anxiety responses and the development of substance dependence are both critically mediated through corticotrophin-releasing hormone (CRH) systems, and the RAS is positioned to interact both with hypothalamic as well as extrahypothalamic CRH systems. The thesis of this paper is that the RAS is part of the neurochemical dysregulation underlying negative affective states, anxiety disorders, and ethanol dependence and that medications targeting the RAS should be considered to augment the treatment of these disorders.

  17. The ins and outs of angiotensin processing within the kidney

    PubMed Central

    Wilson, Bryan A.; Marshall, Allyson C.; Alzayadneh, Ebaa M.

    2014-01-01

    The kidney is a key target organ for bioactive components of the renin-angiotensin system (RAS); however, various renal cells such as the tubular epithelium contain an intrinsic RAS. The renal RAS can be functionally divided into ANG II-AT1 receptor and ANG-(1–7)-AT7/Mas receptor arms that functionally oppose one another. The current review considers both extracellular and intracellular pathways that potentially govern the formation and metabolism of angiotensin peptides within the renal proximal tubules. PMID:24944244

  18. Atrial Natriuretic Peptide and Renal Dopaminergic System: A Positive Friendly Relationship?

    PubMed Central

    Choi, Marcelo Roberto; Rukavina Mikusic, Natalia Lucía; Kouyoumdzian, Nicolás Martín; Kravetz, María Cecilia; Fernández, Belisario Enrique

    2014-01-01

    Sodium metabolism by the kidney is accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Renal dopamine plays a central role in this interactive network. The natriuretic hormones, such as the atrial natriuretic peptide, mediate some of their effects by affecting the renal dopaminergic system. Renal dopaminergic tonus can be modulated at different steps of dopamine metabolism (synthesis, uptake, release, catabolism, and receptor sensitization) which can be regulated by the atrial natriuretic peptide. At tubular level, dopamine and atrial natriuretic peptide act together in a concerted manner to promote sodium excretion, especially through the overinhibition of Na+, K+-ATPase activity. In this way, different pathological scenarios where renal sodium excretion is dysregulated, as in nephrotic syndrome or hypertension, are associated with impaired action of renal dopamine and/or atrial natriuretic peptide, or as a result of impaired interaction between these two natriuretic systems. The aim of this review is to update and comment on the most recent evidences demonstrating how the renal dopaminergic system interacts with atrial natriuretic peptide to control renal physiology and blood pressure through different regulatory pathways. PMID:25013796

  19. Health delivery system for renal disease care in bangladesh.

    PubMed

    Ur Rashid, Harun

    2004-01-01

    Bangladesh is one of the densely populated countries, a nation of 128 million people, 75% of whom lives in rural areas and the annual per capita gross national product (GNP) is US$ 380.00. The health care budget is 1.2% of GNP and the priority areas are population control, provision of clean drinking water and eradication of communicable diseases. The country has a small number of nephrologists and renal care is available in large cities only. The causes of renal diseases include glomerulonephritis, diabetes, hypertension, nephrolithiasis, obstructive uropathy and interstitial nephropathy. The incidence of end-stage renal disease is not known, but would be much higher than in developed countries because of high incidence of infection and environmental pollution. The treatment of ESRD has low priority in Bangladesh because of the government health policy and high cost of treatment. As a result, less than 10% of ESRD patients are able to maintain dialysis in private hospitals and governmental dialysis centers that are already overcrowded. The vast majority of patients who are started on dialysis die or stop treatment within the first three months. Renal transplantation is not as expensive as dialysis and is less costly in the university hospital than in private hospitals. Cyclosporine is usually replaced by azathioprine after six months of transplantation. Although organ act law is effective since 1998, cadaveric transplant has not picked up due to lack of infrastructure, facility and orientation regarding cadaveric transplantation. Preventive measures of renal disease can not be overemphasized.

  20. Role of aliskiren in cardio-renal protection and use in hypertensives with multiple risk factors

    PubMed Central

    Pimenta, Eduardo; Oparil, Suzanne

    2009-01-01

    The renin-angiotensin-aldosterone system (RAAS) is an important mediator of blood pressure (BP) and volume regulation in both normotensive and hypertensive persons and is a major contributor to hypertension-related target organ damage. The concept of renin inhibition for managing hypertension by blocking the RAAS pathway at its point of activation is very attractive since the renin-angiotensinogen reaction is the first and rate-limiting step in the generation of angiotensin II (Ang II). Aliskiren, the first in a new class of orally effective direct renin inhibitors (DRIs), is approved for the treatment of hypertension. It is effective in reducing BP in the general population of hypertensive patients and in special patient groups such as obese persons, and has a tolerability and safety profile similar to placebo. Aliskiren has renoprotective, cardioprotective and anti-atherosclerotic effects in animal models that appear to be independent of BP lowering. It reduces proteinuria in diabetic patients and has favorable neurohumoral effects in patients with symptomatic heart failure. Additional outcome trials are needed to establish the role of this novel class of antihypertensive medication in the therapeutic armamentarium. PMID:19475781

  1. The ISUP system of staging, grading and classification of renal cell neoplasia

    PubMed Central

    Gianduzzo, Troy; Delahunt, Brett

    2014-01-01

    There have been significant changes in the staging, classification and grading of renal cell neoplasia in recent times. Major changes have occurred in our understanding of extra-renal extension by renal cell cancer and how gross specimens must be handled to optimally display extra-renal spread. Since the 1981 World Health Organization (WHO) classification of renal tumors, in which only a handful of different entities were reported, many new morphological types have been described in the literature, resulting in 50 different entities reported in the 2004 WHO classification. Since 2004, further new entities have been recognized and reported necessitating an update of the renal tumor classification. There have also been numerous grading systems for renal cell carcinoma with Fuhrman grading, the most widely used system. In recent times, the prognostic value and the applicability of the Fuhrman grading system in practice has been shown to be, at best, suboptimal. To address these issues and to recommend reporting guidelines, the International Society of Urological Pathology (ISUP) undertook a review of adult renal neoplasia through an international consensus conference in Vancouver in 2012. The conduct of the conference was based upon evidence from the literature and the current practice amongst recognized experts in the field. Working groups selected to deal with key topics evaluated current data and identified points of controversy. A pre-meeting survey of the ISUP membership was followed by the consensus conference at which a formal ballot was taken on each key issue. A 65% majority vote was taken as consensus. This review summarizes the outcome and recommendations of this conference with regards to staging, classification and grading of renal cell neoplasia. PMID:28326247

  2. Hepcidin Mitigates Renal Ischemia-Reperfusion Injury by Modulating Systemic Iron Homeostasis.

    PubMed

    Scindia, Yogesh; Dey, Paromita; Thirunagari, Abhinav; Liping, Huang; Rosin, Diane L; Floris, Matteo; Okusa, Mark D; Swaminathan, Sundararaman

    2015-11-01

    Iron-mediated oxidative stress is implicated in the pathogenesis of renal ischemia-reperfusion injury. Hepcidin is an endogenous acute phase hepatic hormone that prevents iron export from cells by inducing degradation of the only known iron export protein, ferroportin. In this study, we used a mouse model to investigate the effect of renal ischemia-reperfusion injury on systemic iron homeostasis and determine if dynamic modulation of iron homeostasis with hepcidin has therapeutic benefit in the treatment of AKI. Renal ischemia-reperfusion injury induced hepatosplenic iron export through increased ferroportin expression, which resulted in hepatosplenic iron depletion and an increase in serum and kidney nonheme iron levels. Exogenous hepcidin treatment prevented renal ischemia-reperfusion-induced changes in iron homeostasis. Hepcidin also decreased kidney ferroportin expression and increased the expression of cytoprotective H-ferritin. Hepcidin-induced restoration of iron homeostasis was accompanied by a significant reduction in ischemia-reperfusion-induced tubular injury, apoptosis, renal oxidative stress, and inflammatory cell infiltration. Hepcidin -: deficient mice demonstrated increased susceptibility to ischemia-reperfusion injury compared with wild-type mice. Reconstituting hepcidin-deficient mice with exogenous hepcidin induced hepatic iron sequestration, attenuated the reduction in renal H-ferritin and reduced renal oxidative stress, apoptosis, inflammation, and tubular injury. Hepcidin-mediated protection was associated with reduced serum IL-6 levels. In summary, renal ischemia-reperfusion injury results in profound alterations in systemic iron homeostasis. Hepcidin treatment restores iron homeostasis and reduces inflammation to mediate protection in renal ischemia-reperfusion injury, suggesting that hepcidin-ferroportin pathway holds promise as a novel therapeutic target in the treatment of AKI.

  3. Hepcidin Mitigates Renal Ischemia-Reperfusion Injury by Modulating Systemic Iron Homeostasis

    PubMed Central

    Scindia, Yogesh; Dey, Paromita; Thirunagari, Abhinav; Liping, Huang; Rosin, Diane L.; Floris, Matteo; Okusa, Mark D.

    2015-01-01

    Iron-mediated oxidative stress is implicated in the pathogenesis of renal ischemia–reperfusion injury. Hepcidin is an endogenous acute phase hepatic hormone that prevents iron export from cells by inducing degradation of the only known iron export protein, ferroportin. In this study, we used a mouse model to investigate the effect of renal ischemia–reperfusion injury on systemic iron homeostasis and determine if dynamic modulation of iron homeostasis with hepcidin has therapeutic benefit in the treatment of AKI. Renal ischemia–reperfusion injury induced hepatosplenic iron export through increased ferroportin expression, which resulted in hepatosplenic iron depletion and an increase in serum and kidney nonheme iron levels. Exogenous hepcidin treatment prevented renal ischemia-reperfusion–induced changes in iron homeostasis. Hepcidin also decreased kidney ferroportin expression and increased the expression of cytoprotective H-ferritin. Hepcidin-induced restoration of iron homeostasis was accompanied by a significant reduction in ischemia-reperfusion–induced tubular injury, apoptosis, renal oxidative stress, and inflammatory cell infiltration. Hepcidin–deficient mice demonstrated increased susceptibility to ischemia-reperfusion injury compared with wild-type mice. Reconstituting hepcidin-deficient mice with exogenous hepcidin induced hepatic iron sequestration, attenuated the reduction in renal H-ferritin and reduced renal oxidative stress, apoptosis, inflammation, and tubular injury. Hepcidin-mediated protection was associated with reduced serum IL-6 levels. In summary, renal ischemia–reperfusion injury results in profound alterations in systemic iron homeostasis. Hepcidin treatment restores iron homeostasis and reduces inflammation to mediate protection in renal ischemia–reperfusion injury, suggesting that hepcidin-ferroportin pathway holds promise as a novel therapeutic target in the treatment of AKI. PMID:25788528

  4. Surgical Clips Migration up to Renal Collecting System from Ileal Conduit Postcystectomy

    PubMed Central

    Albadawi, Hani; Sener, Tarik Emre

    2016-01-01

    Abstract This is a 49-year-old female known to have had cystectomy and ileal conduit 4 years ago presented to our hospital complaining of left flank pain with recurrent urinary tract infection. Radiologic investigations showed left lower pole renal stone. She underwent left laser flexible ureterorenoscopy. Renal collection system was fully explored that showed stone occupying the lower calix, laser disintegration of the stone revealed what we assumed are surgical clips. PMID:28078327

  5. Renal biopsy in patients with systemic lupus erythematosus: Not just lupus glomerulonephritis!

    PubMed

    Howell, David N

    2017-01-01

    Kidney biopsy is a mainstay in the diagnosis and management of renal disease in patients with systemic lupus erythematosus. Though biopsies from patients with lupus typically show various forms of immune complex glomerulonephritis, other pathologies are occasionally encountered, including unusual lupus-related nephropathies, other forms of autoimmune disease, and occasional renal disorders without any direct connection with lupus or autoimmunity. Electron microscopy is a powerful tool for detecting and classifying these unusual conditions, which frequently have important therapeutic and prognostic implications.

  6. Renal arteriography

    MedlinePlus

    Renal angiogram; Angiography - kidney; Renal angiography; Renal artery stenosis - arteriography ... an artery by a blood clot Renal artery stenosis Renal cell cancer Angiomyolipomas (noncancerous tumors of the ...

  7. Renal disease in pregnancy.

    PubMed

    Thorsen, Martha S; Poole, Judith H

    2002-03-01

    Anatomic and physiologic adaptations within the renal system during pregnancy are significant. Alterations are seen in renal blood flow and glomerular filtration, resulting in changes in normal renal laboratory values. When these normal renal adaptations are coupled with pregnancy-induced complications or preexisting renal dysfunction, the woman may demonstrate a reduction of renal function leading to an increased risk of perinatal morbidity and mortality. This article will review normal pregnancy adaptations of the renal system and discuss common pregnancy-related renal complications.

  8. [A consensus of the Chilean Nephrology and Rheumatology Societies on renal involvement in systemic lupus erythematosus].

    PubMed

    Aguirre, Verónica; Alvo, Miriam; Ardiles, Leopoldo; Carpio, J Daniel; Foster, Carolina; Goecke, Annelise; Jalil, Roberto; Massardo, Loreto; Palma, Sergio; Roessler, Emilio; Wurgaft, Andrés

    2015-12-01

    Renal involvement affects over one half of patients with Systemic Lupus Erythematosus increasing their mortality and morbidity, including chronic renal disease and the need of renal replacement therapies. Aiming to achieve a consensus in the most relevant topics on diagnosis, therapy and follow-up of patients with lupus renal disease, the Chilean Societies of Nephrology and Rheumatology constituted a workgroup that, based on a critical review of the available literature and their experience, raised and answered by consensus a set of relevant questions. This document includes aspects related to the clinical diagnosis, the importance of a suitable histological classification, therapeutic alternatives to induce and maintain disease remission, strategies for follow-up, additional therapies and gynecological-obstetric issues.

  9. Mechanisms and management of hypertension in autosomal dominant polycystic kidney disease.

    PubMed

    Rahbari-Oskoui, Frederic; Williams, Olubunmi; Chapman, Arlene

    2014-12-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited kidney disease, characterized by progressive cyst growth and renal enlargement, resulting in renal failure. Hypertension is common and occurs early, prior to loss of kidney function. Whether hypertension in ADPKD is a primary vasculopathy secondary to mutations in the polycystin genes or secondary to activation of the renin-angiotensin-aldosterone system by cyst expansion and intrarenal ischemia is unclear. Dysregulation of the primary cilium causing endothelial and vascular smooth muscle cell dysfunction is a component of ADPKD. In this article, we review the epidemiology, pathophysiology and clinical characteristics of hypertension in ADPKD and give specific recommendations for its treatment.

  10. Diagnostic biomarkers for renal cell carcinoma: selection using novel bioinformatics systems for microarray data analysis

    PubMed Central

    Osunkoya, Adeboye O; Yin-Goen, Qiqin; Phan, John H; Moffitt, Richard A; Stokes, Todd H; Wang, May D; Young, Andrew N

    2009-01-01

    Summary The differential diagnosis of clear cell, papillary and chromophobe renal cell carcinoma is clinically important, because these tumor subtypes are associated with different pathobiology and clinical behavior. For cases in which histopathology is equivocal, immunohistochemistry and quantitative RT-PCR can assist in the differential diagnosis by measuring expression of subtype-specific biomarkers. Several renal tumor biomarkers have been discovered in expression microarray studies. However, due to heterogeneity of gene and protein expression, additional biomarkers are needed for reliable diagnostic classification. We developed novel bioinformatics systems to identify candidate renal tumor biomarkers from the microarray profiles of 45 clear cell, 16 papillary and 10 chromophobe renal cell carcinoma; the microarray data was derived from two independent published studies. The ArrayWiki biocomputing system merged the microarray datasets into a single file, so gene expression could be analyzed from a larger number of tumors. The caCORRECT system removed non-random sources of error from the microarray data, and the omniBioMarker system analyzed data with several gene-ranking algorithms, in order to identify algorithms effective at recognizing previously described renal tumor biomarkers. We predicted these algorithms would also be effective at identifying unknown biomarkers that could be verified by independent methods. We selected six novel candidate biomakers from the omniBioMarker analysis, and verified their differential expression in formalin-fixed paraffin-embedded tissues by quantitative RT-PCR and immunohistochemistry. The candidate biomarkers were carbonic anhydrase IX, ceruloplasmin, schwannomin-interacting protein 1, E74-like factor 3, cytochrome c oxidase subunit 5a and acetyl-CoA acetyltransferase 1. Quantitative RT-PCR was performed on 17 clear cell, 13 papillary and 7 chromophobe renal cell carcinoma. Carbonic anhydrase IX and ceruloplasmin were

  11. Catheter-directed therapy for acute renal vein thrombosis in systemic lupus erythematosus: A case report.

    PubMed

    Jong, Chien-Boon; Lo, Wei-Yung; Hsieh, Mu-Yang

    2017-02-15

    We report our experience using catheter-directed thrombectomy/thrombolysis (CDT) to treat a patient with acute renal vein thrombosis (RVT) associated with systemic lupus erythematosus (SLE). A 34-year-old woman presented with persistent left flank pain, and a renal ultrasonography examination revealed an enlarged left kidney. Contrast-enhanced computed tomography confirmed the presence of acute left RVT. Because medical treatment failed to relieve her pain and the renal function was deteriorating, we attempted to salvage the occluded left renal vein using an endovascular approach. The pain was completely relieved after a CDT and an overnight urokinase infusion. A follow-up computed tomography examination revealed the complete resolution of the thrombus. The creatinine level returned to normal (1.7-0.4 mg/dL), along with contrast enhancement in the left kidney, and this suggested the preservation of renal function. To our knowledge, this is the first report utilizing CDT to treat SLE-associated RVT. When the renal function is deteriorating, CDT is worth considering for RVT if conventional medical treatment has failed. © 2016 Wiley Periodicals, Inc.

  12. Renal involvement in childhood-onset systemic lupus erythematosus in Egypt.

    PubMed

    Mahmoud, Samia Salah-El-Din; Bazaraa, Hafez Mahmoud; Lotfy, Hala Mohamed; Abd-El-Aziz, Doaa Mohamed

    2012-01-01

    Lupus nephritis has been described as the most serious complication of systemic lupus erythematosus (SLE) and the strongest predictor of poor outcome. While the incidence of childhood SLE is relatively low, renal involvement appears to be more common and more severe in childhood SLE. This study aims to characterize the features and outcome of renal involvement in childhood-onset SLE based on a study of 100 Egyptian patients (mean age at diagnosis 10.1 years, range 2-17 years). Initial data regarding disease manifestations and biopsy findings were reviewed. Disease activity was assessed using SLEDAI scores. Follow-up data (mean duration 6 years) were noted regarding specific treatment, response, complications and renal survival. Initial renal involvement was present in 78 patients, including 66 with hypertension and 23 with renal impairment. Pathologically, class IV nephropathy was found in 18 patients, class V in 9 and low-grade lesions (class II-III) in 49. Twenty patients required follow-up biopsy, and all transformations were observed. SLEDAI scores significantly decreased from initial (mean ± SD) of 21.4 ± 7.3 to 13.4 ± 7.8, in association with response to therapy (P < 0.0001). Poor response was associated with initial hypertension and renal impairment but not with initial SLEDAI score or pathological class. The projected renal survival was 82.4 and 64.7% 5 and 10 years from diagnosis. Early renal involvement in childhood SLE is common, serious and requires proper evaluation and management.

  13. Renal thrombotic microangiopathy in patients with systemic lupus erythematosus and the antiphospholipid syndrome.

    PubMed

    Hughson, M D; Nadasdy, T; McCarty, G A; Sholer, C; Min, K W; Silva, F

    1992-08-01

    Current studies indicate that a thrombotic microangiopathy (TMA) identifies patients with systemic lupus erythematosus (SLE) who are at high risk of progressing to end-stage renal disease. We have observed two patients with SLE and one patient with a primary antiphospholipid syndrome (APS) who developed acute renal insufficiency with thrombocytopenia. Renal biopsies showed a TMA characterized by thrombi or by cellular and mucoid intimal hyperplasia of small arteries and arterioles. No arterial or arteriolar immune-complex deposits were detected by immunofluorescent or electron microscopy. Biopsies from one SLE patient and the APS patient showed no immune-complex glomerular disease. Both had serum antiphospholipid antibodies (aPL). aPL were not detected in the serum of the other SLE patient who had an active lupus nephritis. Acute renal failure and thrombocytopenia resolved in each case following treatment by plasmapheresis or prednisone and heparin. None of the patients were initially treated with cytotoxic drugs. As more knowledge is gained, the accurate identification of renal vascular lesions in SLE or related diseases could influence renal prognosis and choice of therapy. The cases reported here provide further evidence that a TMA can cause acute renal failure independent of lupus nephritis. TMA should be distinguished from other forms of renal vascular disease, particularly a noninflammatory lupus microangiopathy, which is probably mediated by subendothelial immune-complex deposits. The absence of immunoglobulin deposits in vessels involved by a TMA indicates that microvascular thrombosis is promoted by mechanisms other than those usually attributed to immune-complex disease. Phospholipid reactive antibodies may be pathogenetic in some cases.

  14. United States Renal Data System public health surveillance of chronic kidney disease and end-stage renal disease

    PubMed Central

    Collins, Allan J; Foley, Robert N; Gilbertson, David T; Chen, Shu-Cheng

    2015-01-01

    The United States Renal Data System (USRDS) began in 1989 through US Congressional authorization under National Institutes of Health competitive contracting. Its history includes five contract periods, two of 5 years, two of 7.5 years, and the fifth, awarded in February 2014, of 5 years. Over these 25 years, USRDS reporting transitioned from basic incidence and prevalence of end-stage renal disease (ESRD), modalities, and overall survival, as well as focused special studies on dialysis, in the first two contract periods to a comprehensive assessment of aspects of care that affect morbidity and mortality in the second two periods. Beginning in 1999, the Minneapolis Medical Research Foundation investigative team transformed the USRDS into a total care reporting system including disease severity, hospitalizations, pediatric populations, prescription drug use, and chronic kidney disease and the transition to ESRD. Areas of focus included issues related to death rates in the first 4 months of treatment, sudden cardiac death, ischemic and valvular heart disease, congestive heart failure, atrial fibrillation, and infectious complications (particularly related to dialysis catheters) in hemodialysis and peritoneal dialysis patients; the burden of congestive heart failure and infectious complications in pediatric dialysis and transplant populations; and morbidity and access to care. The team documented a plateau and decline in incidence rates, a 28% decline in death rates since 2001, and changes under the 2011 Prospective Payment System with expanded bundled payments for each dialysis treatment. The team reported on Bayesian methods to calculate mortality ratios, which reduce the challenges of traditional methods, and introduced objectives under the Health People 2010 and 2020 national health care goals for kidney disease. PMID:26097778

  15. United States Renal Data System public health surveillance of chronic kidney disease and end-stage renal disease.

    PubMed

    Collins, Allan J; Foley, Robert N; Gilbertson, David T; Chen, Shu-Cheng

    2015-06-01

    The United States Renal Data System (USRDS) began in 1989 through US Congressional authorization under National Institutes of Health competitive contracting. Its history includes five contract periods, two of 5 years, two of 7.5 years, and the fifth, awarded in February 2014, of 5 years. Over these 25 years, USRDS reporting transitioned from basic incidence and prevalence of end-stage renal disease (ESRD), modalities, and overall survival, as well as focused special studies on dialysis, in the first two contract periods to a comprehensive assessment of aspects of care that affect morbidity and mortality in the second two periods. Beginning in 1999, the Minneapolis Medical Research Foundation investigative team transformed the USRDS into a total care reporting system including disease severity, hospitalizations, pediatric populations, prescription drug use, and chronic kidney disease and the transition to ESRD. Areas of focus included issues related to death rates in the first 4 months of treatment, sudden cardiac death, ischemic and valvular heart disease, congestive heart failure, atrial fibrillation, and infectious complications (particularly related to dialysis catheters) in hemodialysis and peritoneal dialysis patients; the burden of congestive heart failure and infectious complications in pediatric dialysis and transplant populations; and morbidity and access to care. The team documented a plateau and decline in incidence rates, a 28% decline in death rates since 2001, and changes under the 2011 Prospective Payment System with expanded bundled payments for each dialysis treatment. The team reported on Bayesian methods to calculate mortality ratios, which reduce the challenges of traditional methods, and introduced objectives under the Health People 2010 and 2020 national health care goals for kidney disease.

  16. Markers of Renal Disease and Function Are Associated with Systemic Inflammation in HIV

    PubMed Central

    Gupta, Samir K; Kitch, Douglas; Tierney, Camlin; Melbourne, Kathleen; Ha, Belinda; McComsey, Grace A

    2015-01-01

    Objectives Both renal disease and systemic inflammation predict non-AIDS events and overall mortality in HIV-infected patients. Here we sought to determine the relationships between renal disease and circulating inflammation markers. Methods We performed a secondary analysis of AIDS Clinical Trials Group study A5224s to determine if markers of renal disease [urine protein/creatinine (uPCR); urine albumin/creatinine (uACR); estimated glomerular filtration rate, eGFR, using CKD-EPI creatinine and cystatin C-creatinine] were associated with markers of systemic inflammation [high sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, soluble receptors of TNF-α (sTNFRI and II), soluble vascular cellular and intercellular adhesion molecules]. We correlated these renal and inflammatory markers prior to antiretroviral initiation and at 96 weeks of therapy. Results We found that estimated eGFR (using CKD-EPI cystatin C-creatinine), uPCR, and uACR were significantly correlated with most assessed markers of systemic inflammation prior to antiretroviral initiation. uPCR and eGFR (using CKD-EPI cystatin C-creatinine), but not uACR, remained significantly correlated with most of the assessed inflammatory markers after 96 weeks of ART. Most of these correlations, although statistically significant, were under 0.50. eGFR using CKD-EPI creatinine was much less frequently associated with inflammation markers and only significantly correlated with sTNFR1 at Week 0 and with sTNFRI and II at Week 96. Conclusions Renal disease and function are associated with systemic inflammation in HIV both before and after ART. Systemic inflammation may partially explain the relationships between proteinuria, albuminuria, and reduced renal function and future adverse outcomes. PMID:25990642

  17. Systemic and renal lipids in kidney disease development and progression

    PubMed Central

    Wahl, Patricia; Ducasa, Gloria Michelle

    2015-01-01

    Altered lipid metabolism characterizes proteinuria and chronic kidney diseases. While it is thought that dyslipidemia is a consequence of kidney disease, a large body of clinical and experimental studies support that altered lipid metabolism may contribute to the pathogenesis and progression of kidney disease. In fact, accumulation of renal lipids has been observed in several conditions of genetic and nongenetic origins, linking local fat to the pathogenesis of kidney disease. Statins, which target cholesterol synthesis, have not been proven beneficial to slow the progression of chronic kidney disease. Therefore, other therapeutic strategies to reduce cholesterol accumulation in peripheral organs, such as the kidney, warrant further investigation. Recent advances in the understanding of the biology of high-density lipoprotein (HDL) have revealed that functional HDL, rather than total HDL per se, may protect from both cardiovascular and kidney diseases, strongly supporting a role for altered cholesterol efflux in the pathogenesis of kidney disease. Although the underlying pathophysiological mechanisms responsible for lipid-induced renal damage have yet to be uncovered, several studies suggest novel mechanisms by which cholesterol, free fatty acids, and sphingolipids may affect glomerular and tubular cell function. This review will focus on the clinical and experimental evidence supporting a causative role of lipids in the pathogenesis of proteinuria and kidney disease, with a primary focus on podocytes. PMID:26697982

  18. Serum uric acid levels contribute to new renal damage in systemic lupus erythematosus patients.

    PubMed

    Reátegui-Sokolova, C; Ugarte-Gil, Manuel F; Gamboa-Cárdenas, Rocío V; Zevallos, Francisco; Cucho-Venegas, Jorge M; Alfaro-Lozano, José L; Medina, Mariela; Rodriguez-Bellido, Zoila; Pastor-Asurza, Cesar A; Alarcón, Graciela S; Perich-Campos, Risto A

    2017-04-01

    This study aims to determine whether uric acid levels contribute to new renal damage in systemic lupus erythematosus (SLE) patients. This prospective study was conducted in consecutive patients seen since 2012. Patients had a baseline visit and follow-up visits every 6 months. Patients with ≥2 visits were included; those with end-stage renal disease (regardless of dialysis or transplantation) were excluded. Renal damage was ascertained using the SLICC/ACR damage index (SDI). Univariable and multivariable Cox-regression models were performed to determine the risk of new renal damage. Uric acid was included as a continuous and dichotomous (per receiving operating characteristic curve) variable. Multivariable models were adjusted for age at diagnosis, disease duration, socioeconomic status, SLEDAI, SDI, serum creatinine, baseline use of prednisone, antimalarials, and immunosuppressive drugs. One hundred and eighty-six patients were evaluated; their mean (SD) age at diagnosis was 36.8 (13.7) years; nearly all patients were mestizo. Disease duration was 7.7 (6.8) years. Follow-up time was 2.3 (1.1) years. The SLEDAI was 5.2 (4.3) and the SDI 0.8 (1.1). Uric acid levels were 4.5 (1.3) mg/dl. During follow-up, 16 (8.6%) patients developed at least one new point in the renal domain of the SDI. In multivariable analyses, uric acid levels (continuous and dichotomous) at baseline predicted the development of new renal damage (HR 3.21 (1.39-7.42), p 0.006; HR 18.28 (2.80-119.48), p 0.002; respectively). Higher uric acid levels contribute to the development of new renal damage in SLE patients independent of other well-known risk factors for such occurrence.

  19. Renal functional reserve is impaired in patients with systemic sclerosis without clinical signs of kidney involvement

    PubMed Central

    Livi, R; Teghini, L; Pignone, A; Generini, S; Matucci-Cerinic, M; Cagnoni, M

    2002-01-01

    Objective: To evaluate the functional response of the kidney to an amino acid challenge (the so called renal functional reserve (RFR)) in patients with systemic sclerosis (SSc) with no clinical sign of renal involvement. Methods: Before and after an intravenous amino acid load (Freamine III Baxter, 8.5% solution, 4.16 ml/min for two hours), glomerular filtration rate (GFR, as creatinine clearance), effective renal plasma flow (ERPF, as para-aminohyppurate clearance), and calculated total renal vascular resistance (TRVR) were measured in 21 patients with SSc with apparently normal renal function and 10 normal controls. Results: In basal conditions, patients had lower ERPF (403.5 (SD 43.8) v 496.4 (SD 71.3) ml/min, p<0.0002) and higher TRVR (10 822 (SD 2044) v 8874 (SD 1639) dyne/sxcm-5, p<0.014) than controls. The RFR, evaluated as the percentage increase of GFR after the amino acid load, was significantly reduced in patients with SSc (SSc +1.9 (SD18.6)%, controls +34.8 (SD 13.9)%; p<0.0002). However, the response of patients was not uniform. Multiple regression analysis showed that the RFR was inversely dependent on the patients' mean arterial pressure at admission and basal GFR (R2=65%, p<0.0001). Conclusions: Most patients with SSc cannot increase renal filtration under the challenge of a protein overload. This defective renal response to the amino acid load test sustains the concept of the prevalence of vasoconstrictor over vasodilating factors in the kidney of these patients. PMID:12117672

  20. Image-based retrieval system and computer-aided diagnosis system for renal cortical scintigraphy images

    NASA Astrophysics Data System (ADS)

    Mumcuoğlu, Erkan; Nar, Fatih; Uğur, Omer; Bozkurt, M. Fani; Aslan, Mehmet

    2008-03-01

    Cortical renal (kidney) scintigraphy images are 2D images (256x256) acquired in three projection angles (posterior, right-posterior-oblique and left-posterior-oblique). These images are used by nuclear medicine specialists to examine the functional morphology of kidney parenchyma. The main visual features examined in reading the images are: size, location, shape and activity distribution (pixel intensity distribution within the boundary of each kidney). Among the above features, activity distribution (in finding scars if any) was found to have the least interobserver reproducibility. Therefore, in this study, we developed an image-based retrieval (IBR) and a computer-based diagnosis (CAD) system, focused on this feature in particular. The developed IBR and CAD algorithms start with automatic segmentation, boundary and landmark detection. Then, shape and activity distribution features are computed. Activity distribution feature is obtained using the acquired image and image set statistics of the normal patients. Active Shape Model (ASM) technique is used for more accurate kidney segmentation. In the training step of ASM, normal patient images are used. Retrieval performance is evaluated by calculating precision and recall. CAD performance is evaluated by specificity and sensitivity. To our knowledge, this paper is the first IBR or CAD system reported in the literature on renal cortical scintigraphy images.

  1. [Clinical decision-making support systems in renal failure].

    PubMed

    Martínez Bernabé, E; Paluzie-Ávila, G; Terre Ohme, S; Ruiz Poza, D; Parada Aradilla, M A; González Martínez, J; Albertí Valmaña, R; Castellvi Gordo, M

    2014-05-01

    Introducción: Los sistemas de soporte a la toma de decisiones clínicas utilizan característicasindividuales del paciente para generar recomendaciones a los clínicos.Objetivo: Evaluar el impacto de una herramienta de ajuste de fármacos en insuficienciarenal como sistema de soporte en la toma de decisiones clínicas encuanto al grado de aceptación de las intervenciones y el tiempo invertido por elfarmacéutico.Método: Estudio cuasi-experimental del tipo antes y después realizado en dos hospitalescomarcales. La intervención consistía en la incorporación de una alerta automatizadade función renal en la orden médica. Antes de la intervención (2007) semonitorizaron 40 fármacos. Se revisaron las analíticas de pacientes cuyo tratamientocontenía alguno de ellos. En caso de función renal alterada, se insertabauna recomendación de ajuste en la orden médica. Si el médico aceptaba, se considerabaéxito. El tiempo medio empleado fue 1 minuto/analítica consultada y 3minutos/recomendación. En 2008 se incorporó un sistema de recomendación automáticade ajuste según función renal de 100 fármacos con mensajes emergentes.En una fase posterior (2009) se evaluó y comparó el número de intervenciones y elporcentaje de éxito con la herramienta.Resultados: Fase previa: Se validaron 28.234 Ordenes Médicas Electrónicas, correspondientesa un promedio de 205 pacientes hospitalizados/día, y se revisaron 4.035analíticas. Se realizaron 121 intervenciones farmacéuticas (0,43% del total de órdenesmédicas). Se obtuvo éxito en el 33,06% de las intervenciones. El tiempo invertidopor el farmacéutico en consultar analíticas y realizar recomendaciones fue 73,3horas (67,25 horas correspondían a pacientes sin alteración de la función renal y enlos que no se realizó ninguna intervención). Fase posterior: Se validaron 26.584Ordenes Médicas Electrónicas, correspondientes a un promedio de 193 pacienteshospitalizados/día, y se realizaron 1.737 intervenciones

  2. Urinary neutrophil gelatinase-associated lipocalin is a potential biomarker for renal damage in patients with systemic lupus erythematosus.

    PubMed

    Yang, Chun-Chen; Hsieh, Song-Chou; Li, Ko-Jen; Wu, Cheng-Han; Lu, Ming-Chi; Tsai, Chang-Youh; Yu, Chia-Li

    2012-01-01

    Neutrophil gelatinase-associated lipocalin (NGAL) has been demonstrated to be a novel biomarker in acute and chronic kidney disease. We hypothesized that 24-hour urinary NGAL excretion may be a predictor for renal damage in patients with systemic lupus erythematosus (SLE). Thirty-four SLE patients with renal involvement (SLE-renal group), 8 SLE patients without renal involvement (SLE-nonrenal group), 14 patients with non-SLE autoimmune diseases (disease control or DC group), and 12 healthy volunteers (normal control or NC group) were compared for 24-hour urinary excretion of NGAL and different cytokines. We found that the 24-hour urinary NGAL excretion in the SLE-renal group was higher than that in the SLE-non-renal, DC, and NC groups. However, the excretion of interleukin-10, transforming growth factor-β1, and tumor necrosis factor-α was not different between the SLE-renal and SLE-non-renal groups. Furthermore, NGAL excretion in the SLE-renal group was correlated with serum creatinine levels and creatinine clearance, but not with the SLE Disease Activity Index score. Multivariate logistic regression analysis and receiver operating characteristic curve analysis revealed that 24-hour urinary NGAL excretion is a potential biomarker for renal damage in SLE patients, with higher sensitivity and specificity than anti-dsDNA antibody titers.

  3. Nephrogenic systemic fibrosis in a patient with renal failure demonstrating a "reverse superscan" on bone scintigraphy.

    PubMed

    Khor, Lih Kin; Tan, Kong Bing; Loi, Hoi Yin; Lu, Suat-Jin

    2013-03-01

    Nephrogenic systemic fibrosis (NSF) has been linked to utilization of gadolinium-based contrast agents in patients with renal impairment. We present a 19-year-old female patient with end-stage renal failure presenting with joint pains and subcutaneous nodules. She had a prior gadolinium-enhanced magnetic resonance angiography when she was 14 years old. Clinical findings revealed firm subcutaneous nodules in both thighs. Whole-body bone scan demonstrates tracer uptake predominantly in the soft tissues and muscles of the extremities with minimal bony uptake. Incisional biopsy of the left thigh nodule revealed features of NSF with a total pathological score of 4, highly consistent with NSF.

  4. Recurrent urinary tract infections in an adult with a duplicated renal collecting system.

    PubMed

    Raja, Junaid; Mohareb, Amir M; Bilori, Bilori

    2016-12-01

    Because of advancements in fetal imaging, anatomic variants of the genitourinary tract are most often discovered in the antenatal period. As such, general internists are less likely to encounter adult patients with previously undiagnosed anatomic abnormalities of the renal collecting system, such as duplicated kidneys. These abnormalities put patients at risk for urinary obstruction and recurrent infections of the urinary tract. We report the case of a 40-year-old diabetic patient with a previously undiagnosed duplex kidney who had recurrent episodes of diabetic ketoacidosis triggered by urinary tract infections. She was ultimately found to have abscess formation in the duplicated renal moiety. We reviewed the epidemiology, diagnosis, and management of duplex kidneys. We also reviewed the indications for renal imaging in adult patients with similar clinical presentations.

  5. Percutaneous Management of Systemic Fungal Infection Presenting As Bilateral Renal Fungal Ball

    PubMed Central

    Shukla, Abhishek; Shrivastava, Nitin; Singh, Chirom Amit

    2016-01-01

    Abstract Background: Zygomycoses are uncommon, frequently fatal diseases caused by fungi of the class Zygomycetes. The majority of human cases are caused by Mucorales (genus—rhizopus, mucor, and absidia) fungi. Renal involvement is uncommon and urine microscopy, pottasium hydroxide mount, and fungal cultures are frequently negative. Case Presentation: A twenty-one-year-old young unmarried lady presented to our emergency department with bilateral flank pain, fever, nausea, and decreased urine output of one-month duration. She was found to have azotemia with sepsis with bilateral hydronephrosis with a left renal pelvic obstructing stone. Even after nephrostomy drainage and broad spectrum antibiotics, her condition worsened. She developed disseminated fungal infection, and timely systemic antifungal followed by bilateral nephroscopic clearance saved the patient. Conclusion: Although renal fungal infections are uncommon, a high index of suspicion and early antifungal and surgical intervention can give favorable outcomes. PMID:27704055

  6. 75 FR 49029 - Medicare Program; End-Stage Renal Disease Prospective Payment System

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-12

    ...This final rule implements a case-mix adjusted bundled prospective payment system (PPS) for Medicare outpatient end-stage renal disease (ESRD) dialysis facilities beginning January 1, 2011 (ESRD PPS), in compliance with the statutory requirement of the Medicare Improvements for Patients and Providers Act (MIPPA), enacted July 15, 2008. This ESRD PPS also replaces the current basic case-mix......

  7. 77 FR 67449 - Medicare Program; End-Stage Renal Disease Prospective Payment System, Quality Incentive Program...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-09

    ...This final rule updates and makes revisions to the end-stage renal disease (ESRD) prospective payment system (PPS) for calendar year (CY) 2013. This rule also sets forth requirements for the ESRD quality incentive program (QIP), including for payment year (PY) 2015 and beyond. In addition, this rule implements changes to bad debt reimbursement for all Medicare providers, suppliers, and other......

  8. Indapamide is superior to thiazide in the preservation of renal function in patients with renal insufficiency and systemic hypertension.

    PubMed

    Madkour, H; Gadallah, M; Riveline, B; Plante, G E; Massry, S G

    1996-02-22

    The long-term effects of indapamide or hydrochlorothiazide on blood presssure and renal function were examined in patents with impaired renal function and moderate hypertension. Both drugs controlled hypertension and blood pressure remained normal during the 2 years of the study. Despite this comparable control of hypertension, indapamide therapy was associated with a 28.5 +/- 4.4% increase in creatinine clearance, whereas treatment with hydrochlorothiazide was associated with a 17.4 +/- 3.0% decrease in creatinine clearance. The results of the study indicate that indapamide is superior to hydrochlorothiazide in the treatment of patients with impaired renal function and moderate hypertension.

  9. Internet based expert system for the management of gallstones, renal, ureteric and bladder calculi.

    PubMed

    Sridhar, S; Kumaravel, N

    2003-01-01

    An Internet based expert system for the management of gallstones, Renal, Ureteric and bladder calculi based on ultrasound images is presented in this paper. Calculi are due to abnormal collection of certain chemicals like oxalate, phosphate and Uric acid. These calculi can be present in kidney, Ureter or in Urinary bladder and also in gall bladder. The expert system is designed to assist the physician to detect, extract, classify and diagnose calculi with greater accuracy. It also helps physicians in the management of calculi based on the etiological analysis of calculi. The Expert system takes an ultrasound image as input along with the symptoms of the patients. The expert system extracts the renal calculi and analyzes it using different image processing techniques to extract the image features like size, location and texture. These image features along with the clinical data of the patient enable the expert system to provide the decisions to decide the future course of treatment with more accuracy.

  10. Systemic Therapies for Metastatic Renal Cell Carcinoma in Older Adults

    PubMed Central

    Pal, Sumanta K.; Vanderwalde, Ari; Hurria, Arti; Figlin, Robert A.

    2016-01-01

    The introduction of targeted therapies has radically changed the treatment paradigm for metastatic renal cell carcinoma (mRCC). However, multiple clinical dilemmas have emerged. For instance, limited data are available to juxtapose the safety and efficacy profile of targeted therapies between older and younger adults. Herein, pivotal trials of vascular endothelial growth factor (VEGF)- and mammalian target of rapamycin (mTOR)-directed therapies are assessed in the context of their implications in treating older adults with mRCC. In general, subset analyses from these pivotal studies suggest similar efficacy of targeted therapies amongst older adults. Aging is accompanied by a multitude of physiological changes, as well as an increased prevalence of co-morbidities. The age-related toxicity profiles of targeted agents for mRCC are detailed to provide a framework for the risks and benefits of these therapies in older adults. Ultimately, tools such as the Comprehensive Geriatric Assessment (CGA) that account for physiological (as opposed to chronological) age may prove useful in the evaluation and treatment of older adults with mRCC. PMID:21812499

  11. Lupus anticoagulant in systemic lupus erythematosus: a clinical and renal pathological study.

    PubMed

    Farrugia, E; Torres, V E; Gastineau, D; Michet, C J; Holley, K E

    1992-11-01

    Circulating lupus anticoagulant (LA) is associated with thrombosis in large and small vessels. To determine how often the presence of LA is associated with thrombosis within the renal microcirculation, 33 patients with systemic lupus erythematosus (SLE), renal dysfunction, and LA were identified over a 25-year period (LA group) and 32 patients with renal SLE but with normal gross coagulation screen were matched for age, sex, and biopsy timing (C group). Prevalences of serositis, neuropsychiatric illness, leukopenia, thrombocytopenia, hemolysis, anti-DS-DNA elevation, and complement reduction were similar. Arthritis was less and biologic false-positive (BFP) syphilis serology more common in LA. More LA patients had thrombotic events (LA 39% v C 13%; P = 0.014); bleeding episodes, including postbiopsy, were similar. At biopsy, hypertension (LA 55%, C 41%), serum creatinine (mean +/- SD: LA 186 +/- 168 mumol/L [2.1 +/- 1.9 mg/dL] v C 150 +/- 168 mumol/L [1.7 +/- 1.9 mg/dL]) and proteinuria (LA 2.6 +/- 3.1 g/24 h v C 3.1 +/- 2.7) were similar. Lesions by World Health Organization (WHO) class, activity, and chronicity indices, as well as immunofluorescence (IF) and electron microscopy (EM) findings, were not significantly different. Occlusive glomerular, arteriolar, and arterial fibrin thrombi, along with varying degrees of renal thrombotic microangiopathy, were seen in five of 33 patients with LA, but zero of 32 C patients (P = 0.053); three of these five patients died soon after biopsy. Overall, mortality was not different between LA and C. We conclude that the majority of patients with SLE, renal dysfunction, and LA exhibit renal morphologic findings indistinguishable from patients without LA. However, a significant minority of LA patients have thrombotic microangiopathy in their biopsy, which is accompanied by a worse prognosis.

  12. Pre-stimulation of the kallikrein system in cisplatin-induced acute renal injury: An approach to renoprotection

    SciTech Connect

    Aburto, Andrés; Barría, Agustín; Cárdenas, Areli; Carpio, Daniel; Figueroa, Carlos D.; Burgos, Maria E.; Ardiles, Leopoldo

    2014-10-15

    Antineoplastic treatment with cisplatin is frequently complicated by nephrotoxicity. Although oxidative stress may be involved, the pathogenic mechanisms responsible for renal damage have not been completely clarified. In order to investigate the role of the renal kinin system in this condition, a group of rats was submitted to high potassium diet to stimulate the synthesis and excretion of tissue kallikrein 1 (rKLK1) previous to an intraperitoneal injection of 7 mg/kg cisplatin. A significant reduction in lipoperoxidation, evidenced by urinary excretion of malondialdehyde and renal immunostaining of hidroxy-nonenal, was accompanied by a decline in apoptosis. Coincident with these findings we observed a reduction in the expression of renal KIM-1 suggesting that renoprotection may be occurring. Stimulation or indemnity of the renal kinin system deserves to be evaluated as a complementary pharmacological measure to diminish cisplatin nephrotoxicity. - Highlights: • Mechanisms of cisplatin-induced-renal damage have not been completely clarified. • Cisplatin induces oxidative stress and apoptosis. • The renal kallikrein-kinin system is protective in experimental acute renal damage. • Kallikrein stimulation reduces oxidative stress and apoptosis induced by cisplatin. • Protection of the kallikrein-kinin system may reduce cisplatin toxicity.

  13. 42 CFR 413.210 - Conditions for payment under the end-stage renal disease (ESRD) prospective payment system.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... disease (ESRD) prospective payment system. 413.210 Section 413.210 Public Health CENTERS FOR MEDICARE... SKILLED NURSING FACILITIES Payment for End-Stage Renal Disease (ESRD) Services and Organ Procurement Costs § 413.210 Conditions for payment under the end-stage renal disease (ESRD) prospective payment...

  14. 42 CFR 413.210 - Conditions for payment under the end-stage renal disease (ESRD) prospective payment system.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... disease (ESRD) prospective payment system. 413.210 Section 413.210 Public Health CENTERS FOR MEDICARE... SKILLED NURSING FACILITIES Payment for End-Stage Renal Disease (ESRD) Services and Organ Procurement Costs § 413.210 Conditions for payment under the end-stage renal disease (ESRD) prospective payment...

  15. Systemic and renal effects of an ETA receptor subtype-specific antagonist in healthy subjects

    PubMed Central

    Schmetterer, Leopold; Dallinger, Susanne; Bobr, Barbara; Selenko, Nicole; Eichler, Hans-Georg; Wolzt, Michael

    1998-01-01

    Endothelins (ETs) might play a pathophysiological role in a variety of vascular diseases. The aim of the present study was to characterize the effects of BQ-123, a specific ETA receptor antagonist on systemic and renal haemodynamics in healthy subjects. This was done at baseline and during infusion of exogenous ET-1.The study was performed in a balanced, randomized, placebo-controlled, double blind 4 way cross-over design in 10 healthy male subjects. Subjects received co-infusions of ET-1 (2.5 ng kg−1 min−1 for 120 min) or placebo and BQ-123 (15 μg min−1 for 60 min and subsequently 60 μg min−1 for 60 min) or placebo. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed by the para-aminohippurate (PAH) and the inulin plasma clearance method, respectively.BQ-123 alone had no renal or