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Sample records for decreased angiotensin ii

  1. Angiotensin-(1-7) decreases skeletal muscle atrophy induced by angiotensin II through a Mas receptor-dependent mechanism.

    PubMed

    Cisternas, Franco; Morales, María Gabriela; Meneses, Carla; Simon, Felipe; Brandan, Enrique; Abrigo, Johanna; Vazquez, Yaneisi; Cabello-Verrugio, Claudio

    2015-03-01

    Skeletal muscle atrophy is a pathological condition characterized by the loss of strength and muscle mass, an increase in myosin heavy chain (MHC) degradation and increase in the expression of two muscle-specific ubiquitin ligases: atrogin-1 and MuRF-1. Angiotensin II (AngII) induces muscle atrophy. Angiotensin-(1-7) [Ang-(1-7)], through its receptor Mas, produces the opposite effects than AngII. We assessed the effects of Ang-(1-7) on the skeletal muscle atrophy induced by AngII. Our results show that Ang-(1-7), through Mas, prevents the effects induced by AngII in muscle gastrocnemius: the decrease in the fibre diameter, muscle strength and MHC levels and the increase in atrogin-1 and MuRF-1. Ang-(1-7) also induces AKT phosphorylation. In addition, our analysis in vitro using C2C12 myotubes shows that Ang-(1-7), through a mechanism dependent on Mas, prevents the decrease in the levels of MHC and the increase in the expression of the atrogin-1 and MuRF-1, both induced by AngII. Ang-(1-7) induces AKT phosphorylation in myotubes; additionally, we demonstrated that the inhibition of AKT with MK-2206 decreases the anti-atrophic effects of Ang-(1-7). Thus, we demonstrate for the first time that Ang-(1-7) counteracts the skeletal muscle atrophy induced by AngII through a mechanism dependent on the Mas receptor, which involves AKT activity. Our study indicates that Ang-(1-7) is novel molecule with a potential therapeutical use to improve muscle wasting associated, at least, with pathologies that present high levels of AngII.

  2. Decrease in blood pressure and regression of cardiovascular complications by angiotensin II vaccine in mice.

    PubMed

    Nakagami, Futoshi; Koriyama, Hiroshi; Nakagami, Hironori; Osako, Mariana Kiomy; Shimamura, Munehisa; Kyutoku, Mariko; Miyake, Takashi; Katsuya, Tomohiro; Rakugi, Hiromi; Morishita, Ryuichi

    2013-01-01

    Vaccines have been recently developed to treat various diseases such as cancer, rheumatoid arthritis and Alzheimer's disease in addition to infectious diseases. However, before use in the clinical setting, vaccines targeting self-antigens must be demonstrated to be effective and safe, evoking an adequate humoral immune response from B cells while avoiding T cell activation in response to self. Although the vaccine targeting angiotensin II (Ang II) is efficient in rodents and humans, little is known regarding the immunological activation and safety of the vaccine. In this study, we evaluated the efficiency and safety of an Ang II peptide vaccine in mice. Immunization with Ang II conjugated to keyhole limpet hemocyanin (KLH) successfully induced the production of anti-Ang II antibody, which blocked Ang II signaling in human aortic smooth muscle cells. However, Ang II itself did not activate T cells, as assessed by the proliferation and lymphokine production of T cells in immunized mice, whereas KLH activated T cells. In an Ang II-infused model, the non-immunized mice showed high blood pressure (BP), whereas the immunized mice (Ang II-KLH) showed a significant decrease in systolic BP, accompanied by significant reductions in cardiac hypertrophy and fibrosis. Importantly, anti-Ang II antibody titer was not elevated even after the administration of large amounts of Ang II, indicating that Ang II itself boosted antibody production, most likely due to less activation of T cells. In addition, no accumulation of inflammatory cells was observed in immunized mice, because endogenous Ang II would not activate T cells after immunization with Ang II-KLH. Taken together, these data indicate that vaccines targeting Ang II might be effective to decrease high BP and prevent cardiovascular complications without severe side effects.

  3. Lead exposure, begun in utero, decreases renin and angiotensin II in adult rats

    SciTech Connect

    Victery, W.; Vander, A.J.; Markel, H.; Katzman, L.; Shulak, J.M.; Germain, C.

    1982-05-01

    Male rats were exposed continously to Pb in utero and after birth by giving their mothers, during pregnancy and lactation, drinking water containing 0, 5, or 25 ppm Pb (as Pb acetate) and then continuing this regimen after weaning for approximately 5 months. At the time of sacrifice (5 months) the 5- and 25-ppm groups had mean blood Pb concentrations of 5.6 and 18.2 ..mu..g/dl, respectively. No differences in systolic blood pressure occurred between groups. Rats exposed to 25 ppm manifested a significant decrease in basal plasma renin activity (PRA) but a significant increase in PRA during stimulation of renin release by acute volume depletion. In this latter state, the ratio of angiotensin II to PRA was significantly reduced in the 25-ppm group. Groups exposed to 5 and 25 ppm both had significant decreases in renal renin concentration. We conclude that chronic exposure of rats to doses of Pb which produce blood Pb concentrations similar to those generally present in urban human populations does not induce hypertension but does inhibit renin synthesis and release, as well as reducing plasma angiotension II concentration at any given PRA, either by inhibiting conversion of AI to AII or by enhancing AII catabolism.

  4. Swimming training prevents fat deposition and decreases angiotensin II-induced coronary vasoconstriction in ovariectomized rats.

    PubMed

    Endlich, Patrick Wander; Claudio, Erick Roberto Gonçalves; da Silva Gonçalves, Washington Luiz; Gouvêa, Sonia Alves; Moysés, Margareth Ribeiro; de Abreu, Glaucia Rodrigues

    2013-09-01

    We investigated the effects of chronic swimming training (ST) on the deposition of abdominal fat and vasoconstriction in response to angiotensin II (ANG II) in the coronary arterial bed of estrogen deficient rats. Twenty-eight 3-month old Wistar female rats were divided into 4 groups: sedentary sham (SS), sedentary-ovariectomized (SO), swimming-trained sham (STS) and swimming-trained ovariectomized (STO). ST protocol consisted of a continuous 60-min session, with a 5% BW load attached to the tail, completed 5 days/week for 8-weeks. The retroperitoneal, parametrial, perirenal and inguinal fat pads were measured. The intrinsic heart rate (IHR), coronary perfusion pressure (CPP) and a concentration-response curve to ANG II in the coronary bed was constructed using the Langendorff preparation. Ovariectomy (OVX) significantly reduced 17-β-estradiol plasma levels in SO and STO groups (p<0.05). The STO group had a significantly reduced retroperitoneal and parametrial fat pad compared with the SO group (p<0.05). IHR values were similar in all groups; however, baseline CPP was significantly reduced in the SO, STS and STO groups compared with the SS group (p<0.05). ANG II caused vasoconstriction in the coronary bed in a concentration-dependent manner. The SO group had an increased response to ANG II when compared with all other experimental groups (p<0.05), which was prevented by 8-weeks of ST in the STO group (p<0.05). OVX increased ANG II-induced vasoconstriction in the coronary vascular bed and abdominal fat pad deposition. Eight weeks of swimming training improved these vasoconstrictor effects and decreased abdominal fat deposition in ovariectomized rats.

  5. GPR30 decreases cardiac chymase/angiotensin II by inhibiting local mast cell number

    SciTech Connect

    Zhao, Zhuo; Wang, Hao; Lin, Marina; Groban, Leanne

    2015-03-27

    Chronic activation of the novel estrogen receptor GPR30 by its agonist G1 mitigates the adverse effects of estrogen (E2) loss on cardiac structure and function. Using the ovariectomized (OVX) mRen2.Lewis rat, an E2-sensitive model of diastolic dysfunction, we found that E2 status is inversely correlated with local cardiac angiotensin II (Ang II) levels, likely via Ang I/chymase-mediated production. Since chymase is released from cardiac mast cells during stress (e.g., volume/pressure overload, inflammation), we hypothesized that GPR30-related cardioprotection after E2 loss might occur through its opposing actions on cardiac mast cell proliferation and chymase production. Using real-time quantitative PCR, immunohistochemistry, and immunoblot analysis, we found mast cell number, chymase expression, and cardiac Ang II levels were significantly increased in the hearts of OVX-compared to ovary-intact mRen2.Lewis rats and the GPR30 agonist G1 (50 mg/kg/day, s.c.) administered for 2 weeks limited the adverse effects of estrogen loss. In vitro studies revealed that GPR30 receptors are expressed in the RBL-2H3 mast cell line and G1 inhibits serum-induced cell proliferation in a dose-dependent manner, as determined by cell counting, BrdU incorporation assay, and Ki-67 staining. Using specific antagonists to estrogen receptors, blockage of GPR30, but not ERα or ERβ, attenuated the inhibitory effects of estrogen on BrdU incorporation in RBL-2H3 cells. Further study of the mechanism underlying the effect on cell proliferation showed that G1 inhibits cyclin-dependent kinase 1 (CDK1) mRNA and protein expression in RBL-2H3 cells in a dose-dependent manner. - Highlights: • GPR30 activation limits mast cell number in hearts from OVX mRen2.Lewis rats. • GPR30 activation decreases cardiac chymase/angiotensin II after estrogen loss. • GPR30 activation inhibits RBL-2H3 mast cell proliferation and CDK1 expression.

  6. Angiotensin II causes weight loss and decreases circulating insulin-like growth factor I in rats through a pressor-independent mechanism.

    PubMed Central

    Brink, M; Wellen, J; Delafontaine, P

    1996-01-01

    The renin-angiotensin system regulates normal cardiovascular homeostasis and is activated in certain forms of hypertension and in heart failure. Angiotensin II has multiple physiological effects and we have shown recently that its growth-promoting effects on vascular smooth muscle require autocrine activation of the IGF I receptor. To study the effect of angiotensin II on circulating IGF I, we infused rats with 500 ng/kg/min angiotensin II for up to 14 d. Angiotensin II markedly reduced plasma IGF I levels (56 and 41% decrease at 1 and 2 wk, respectively) and IGF binding protein-3 levels, and increased IGF binding protein-2 levels, a pattern suggestive of dietary restriction. Compared with sham, angiotensin II-infused hypertensive rats lost 18-26% of body weight by 1 wk, and pair-feeding experiments indicated that 74% of this loss was attributable to a reduction in food intake. The vasodilator hydralazine and the AT1 receptor antagonist losartan had comparable effects to reverse angiotensin II-induced hypertension, but only losartan blocked the changes in body weight and in circulating IGF I and its binding proteins produced by angiotensin II. Moreover, in Dahl rats that were hypertensive in response to a high-salt diet, none of these changes occurred. Thus, angiotensin II produces weight loss through a pressor-independent mechanism that includes a marked anorexigenic effect and an additional (likely metabolic) effect. These findings have profound implications for understanding the pathophysiology of conditions, such as congestive heart failure, in which the renin-angiotensin system is activated. PMID:8647943

  7. Decreased angiotensin II binding affinity and binding capacity in the anterior pituitary gland of adult spontaneously hypertensive rats

    SciTech Connect

    Gutkind, J.S.; Castren, E.; Saavedra, J.M.

    1988-01-01

    Angiotensin II (ANG) binding sites were quantified in single pituitary glands from 4-week-old and 14-week-old male spontaneously hypertensive rats (SHR) and age-matched male normotensive Wistar-Kyoto (WKY) control rats after incubation with /sup 125/I-(Sar/sup 1/)-ANG, autoradiography with computerized densitometry, and comparison to /sup 125/I-standards. The maximum binding capacity (B/sub max/) decreased while the dissociation constant (K/sub d/) for ANG increased in 14-week-old SHR when compared to age-matched WKY control rats. Conversely, no difference between rat strains was found in 4-week-old animals. Our results suggest that pituitary ANG binding sites may play a role in the pathophysiology of established genetic hypertension.

  8. Angiotensin II and angiotensin-(1-7) decrease sFlt1 release in normal but not preeclamptic chorionic villi: an in vitro study

    PubMed Central

    2010-01-01

    Background During preeclampsia, placental angiogenesis is impaired. Factors released from the placenta including vascular endothelial growth factor (VEGF), placental growth factor (PLGF), soluble VEGF receptor 1 (sFlt1), and soluble endoglin (sEng) are regulatory molecules of placental development and function. While the renin angiotensin system has been shown to regulate angiogenic factors in other research fields, these mechanisms have not been extensively studied during pregnancy. Methods We evaluated the effects of angiotensin II (Ang II) and angiotensin-(1-7) [Ang-(1-7)] on the release of VEGF, PLGF, sFlt1, and sEng from placental chorionic villi (CV). CV were collected from nulliparous third-trimester normotensive and preeclamptic subjects. CV were incubated for 0, 2, 4, and 16 hours with or without Ang II (1 nM and 1 microM) or Ang-(1-7) (1 nM and 1 microM). The release of VEGF, PLGF, sFlt1, sEng, lactate dehydrogenase (LDH), and human placenta lactogen (HPL) was measured by ELISA. Results The release of sFlt1, PLGF, sEng from normal and preeclamptic CV increased over time. Release of sFlt1 and sEng was significantly higher from preeclamptic CV. VEGF was below the detectable level of the assay in normal and preeclamptic CV. After 2 hours, sFlt1 release from normal CV was significantly inhibited with Ang II (1 nM and 1 microM) and Ang-(1-7) (1 nM and 1 microM). There was a time-dependent increase in HPL indicating that the CV were functioning normally. Conclusions Our study demonstrates a critical inhibitory role of angiotensin peptides on sFlt1 in normal pregnancy. Loss of this regulation in preeclampsia may allow sFlt1 to increase resulting in anti-angiogenesis and end organ damage in the mother. PMID:21050477

  9. Angiotensin III as well as angiotensin II regulates water flow through aquaporins in a clam worm.

    PubMed

    Satou, Ryousuke; Nakagawa, Tsutomu; Ido, Hiroki; Tomomatsu, Masayuki; Suzuki, Fumiaki; Nakamura, Yukio

    2005-07-01

    Angiotensin III has been reported to exist in various animals and tissues. The physiological role, however, is still unclear except that brain angiotensin III is a central regulator of vasopressin release. In this study, angiotensin III as well as angiotensin II enhanced an increase in body weight of clam worms of Perinereis sp. under a hypo-osmotic condition and suppressed a decrease in body weight under a hyper-osmotic condition. When clam worms were treated with tetrachloroaurate (III) after angiotensin-treatment, these enhancing and suppressive effects of the angiotensins under hypo- and hyper-osmotic conditions were inhibited. In contrast, when clam worms were pretreated with tetrachloroaurate (III) before angiotensin-treatment, these effects of angiotensins were not inhibited. Since tetrachloroaurate (III) is a representative blocker of aquaporins, these results indicate that angiotensin III as well as angiotensin II regulates water flow through aquaporins in clam worms.

  10. Angiotensin II receptor heterogeneity

    SciTech Connect

    Herblin, W.F.; Chiu, A.T.; McCall, D.E.; Ardecky, R.J.; Carini, D.J.; Duncia, J.V.; Pease, L.J.; Wong, P.C.; Wexler, R.R.; Johnson, A.L. )

    1991-04-01

    The possibility of receptor heterogeneity in the angiotensin II (AII) system has been suggested previously, based on differences in Kd values or sensitivity to thiol reagents. One of the authors earliest indications was the frequent observation of incomplete inhibition of the binding of AII to adrenal cortical membranes. Autoradiographic studies demonstrated that all of the labeling of the rat adrenal was blocked by unlabeled AII or saralasin, but not by DuP 753. The predominant receptor in the rat adrenal cortex (80%) is sensitive to dithiothreitol (DTT) and DuP 753, and is designated AII-1. The residual sites in the adrenal cortex and almost all of the sites in the rat adrenal medulla are insensitive to both DTT and DuP 753, but were blocked by EXP655. These sites have been confirmed by ligand binding studies and are designated AII-2. The rabbit adrenal cortex is unique in yielding a nonuniform distribution of AII-2 sites around the outer layer of glomerulosa cells. In the rabbit kidney, the sites on the glomeruli are AII-1, but the sites on the kidney capsule are AII-2. Angiotensin III appears to have a higher affinity for AII-2 sites since it inhibits the binding to the rabbit kidney capsule but not the glomeruli. Elucidation of the distribution and function of these diverse sites should permit the development of more selective and specific therapeutic strategies.

  11. Selective C1 Lesioning Slightly Decreases Angiotensin II type I Receptor Expression in the Rat Rostral Ventrolateral Medulla (RVLM)

    PubMed Central

    Bourassa, Erick A.; Stedenfeld, Kristen A.; Sved, Alan F.; Speth, Robert C.

    2015-01-01

    Cardiovascular homeostasis is regulated in large part by the rostral ventrolateral medulla (RVLM) in mammals. Projections from the RVLM to the intermediolateral column of the thoracolumbar spinal cord innervate preganglionic neurons of the sympathetic nervous system causing elevation of blood pressure and heart rate. A large proportion, but not all, of the neurons in the RVLM contain the enzymes necessary for the production of epinephrine and are identified as the C1 cell group. Angiotensin II (Ang II) activates the RVLM acting upon AT1 receptors. To assess the proportion of AT1 receptors that are located on C1 neurons in the rat RVLM this study employed an antibody to dopamine-beta-hydroxylase conjugated to saporin, to selectively destroy C1 neurons in the RVLM. Expression of tyrosine hydroxylase immunoreactive neurons in the RVLM was reduced by 57 % in the toxin injected RVLM compared to the contralateral RVLM. In contrast, densitometric analysis of autoradiographic images of 125I-sarcosine1, isoleucine8 Ang II binding to AT1 receptors of the injected side RVLM revealed a small (10%) reduction in AT1 receptor expression compared to the contralateral RVLM. These results suggest that the majority of AT1 receptors in the rat RVLM are located on non-C1 neurons or glia. PMID:26138553

  12. A forskolin derivative, colforsin daropate hydrochloride, inhibits the decrease in cortical renal blood flow induced by noradrenaline or angiotensin II in anesthetized rats.

    PubMed

    Ogata, Junichi; Minami, Kouichiro; Segawa, Kayoko; Uezono, Yasuhito; Shiraishi, Munehiro; Yamamoto, Chikako; Sata, Takeyoshi; Sung-Teh, Kim; Shigematsu, Akio

    2004-01-01

    A forskolin derivative, colforsin daropate hydrochloride (CDH), acts directly on adenylate cyclase to increase the intracellular cyclic adenosine monophosphate levels which produce a positive inotropic effect and a lower blood pressure. However, little is known about the effects of CDH on the renal function. We used laser Doppler flowmetry to measure the cortical renal blood flow (RBF) in male Wistar rats given a continuous intravenous infusion of CDH and evaluated the effects of CDH on the noradrenaline (NA) and angiotensin II (AngII) induced increases in blood pressure and reductions in RBF. Continuous intravenous administration of CDH at 0.25 microg/kg/min did not affect the mean arterial pressure (MAP), but increased heart rate and RBF. Continuous intravenous administration of CDH at high doses (0.5-0.75 microg/kg/min) decreased the MAP, with little effect on the RBF. The administration of exogenous NA (1.7 microg/kg) increased the MAP and decreased the RBF. However, a bolus injection of NA did not decrease the RBF during continuous intravenous administration of CDH, and CDH did not affect the NA-induced increase in MAP. The administration of exogenous AngII (100 ng/kg) increased MAP and decreased RBF and heart rate, but a bolus injection of AngII did not decrease RBF during continuous intravenous administration of CDH. These results suggest that CDH plays a protective role against the pressor effects and the decrease in RBF induced by NA or AngII.

  13. Decreased insulin sensitivity during dietary sodium restriction is not mediated by effects of angiotensin II on insulin action.

    PubMed

    Perry, Colin G; Palmer, Tim; Cleland, Steven J; Morton, Ian J; Salt, Ian P; Petrie, John R; Gould, Gwyn W; Connell, John M C

    2003-08-01

    We have previously reported that modest dietary sodium restriction, as advocated in management guidelines for diabetes, may reduce insulin sensitivity. It has since been suggested that this effect may be mediated via cross-talk between insulin and angiotensin II (AII)-stimulated intracellular second messengers. In order to assess the effect of 5 days of modest sodium restriction (to <80 mmol/day target sodium intake) on insulin sensitivity, 15 healthy males underwent a double-blind, placebo-controlled, randomized, cross-over euglycaemic hyperinsulinaemic clamp study. One phase was supplemented with sodium tablets and the other with matched placebo. Insulin sensitivity (M) was reduced during dietary sodium restriction [median M value, 10.2 mg/kg per min (interquartile range 9.50-13.85) versus 12.8 mg/kg per min (interquartile range 9.60-14.30), P <0.05]. To elucidate potential mechanisms that may explain this observation, we investigated the effect of AII on insulin action in isolated adipocytes obtained from healthy females. No effect of AII on insulin-mediated glucose transport or suppression of lipolysis was observed. In conclusion, despite the observation that dietary sodium restriction was associated with a median 15% reduction in insulin sensitivity, we found no evidence of a direct effect of AII on insulin action in human adipocytes.

  14. Angiotensin II, sympathetic nerve activity and chronic heart failure.

    PubMed

    Wang, Yutang; Seto, Sai-Wang; Golledge, Jonathan

    2014-03-01

    Sympathetic nerve activity has been reported to be increased in both humans and animals with chronic heart failure. One of the mechanisms believed to be responsible for this phenomenon is increased systemic and cerebral angiotensin II signaling. Plasma angiotensin II is increased in humans and animals with chronic heart failure. The increase in angiotensin II signaling enhances sympathetic nerve activity through actions on both central and peripheral sites during chronic heart failure. Angiotensin II signaling is enhanced in different brain sites such as the paraventricular nucleus, the rostral ventrolateral medulla and the area postrema. Blocking angiotensin II type 1 receptors decreases sympathetic nerve activity and cardiac sympathetic afferent reflex when therapy is administered to the paraventricular nucleus. Injection of an angiotensin receptor blocker into the area postrema activates the sympathoinhibitory baroreflex. In peripheral regions, angiotensin II elevates both norepinephrine release and synthesis and inhibits norepinephrine uptake at nerve endings, which may contribute to the increase in sympathetic nerve activity seen in chronic heart failure. Increased circulating angiotensin II during chronic heart failure may enhance the sympathoexcitatory chemoreflex and inhibit the sympathoinhibitory baroreflex. In addition, increased circulating angiotensin II can directly act on the central nervous system via the subfornical organ and the area postrema to increase sympathetic outflow. Inhibition of angiotensin II formation and its type 1 receptor has been shown to have beneficial effects in chronic heart failure patients.

  15. 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

  16. Angiotensin II receptors in testes

    SciTech Connect

    Millan, M.A.; Aguilera, G.

    1988-05-01

    Receptors for angiotensin II (AII) were identified and characterized in testes of rats and several primate species. Autoradiographic analysis of the binding of 125I-labeled (Sar1,Ile8)AII to rat, rhesus monkey, cebus monkey, and human testicular slide-mounted frozen sections indicated specific binding to Leydig cells in the interstitium. In rat collagenase-dispersed interstitial cells fractionated by Percoll gradient, AII receptor content was parallel to that of hCG receptors, confirming that the AII receptors are in the Leydig cells. In rat dispersed Leydig cells, binding was specific for AII and its analogs and of high affinity (Kd, 4.8 nM), with a receptor concentration of 15 fmol/10(6) cells. Studies of AII receptors in rat testes during development reveals the presence of high receptor density in newborn rats which decreases toward the adult age (4934 +/- 309, 1460 +/- 228, 772 +/- 169, and 82 +/- 12 fmol/mg protein at 5, 15, 20, and 30 days of age, respectively) with no change in affinity. At all ages receptors were located in the interstitium, and the decrease in binding was parallel to the decrease in the interstitial to tubular ratio observed with age. AII receptor properties in membrane-rich fractions from prepuberal testes were similar in the rat and rhesus monkey. Binding was time and temperature dependent, reaching a plateau at 60 min at 37 C, and was increased by divalent cations, EGTA, and dithiothreitol up to 0.5 mM. In membranes from prepuberal monkey testes, AII receptors were specific for AII analogs and of high affinity (Kd, 4.2 nM) with a receptor concentration of 7599 +/- 1342 fmol/mg protein. The presence of AII receptors in Leydig cells in rat and primate testes in conjunction with reports of the presence of other components of the renin-angiotensin system in the testes suggests that the peptide has a physiological role in testicular function.

  17. Documentation of angiotensin II receptors in glomerular epithelial cells

    NASA Technical Reports Server (NTRS)

    Sharma, M.; Sharma, R.; Greene, A. S.; McCarthy, E. T.; Savin, V. J.; Cowley, A. W. (Principal Investigator)

    1998-01-01

    Angiotensin II decreases glomerular filtration rate, renal plasma flow, and glomerular capillary hydraulic conductivity. Although angiotensin II receptors have been demonstrated in mesangial cells and proximal tubule cells, the presence of angiotensin II receptors in glomerular epithelial cells has not previously been shown. Previously, we have reported that angiotensin II caused an accumulation of cAMP and a reorganization of the actin cytoskeleton in cultured glomerular epithelial cells. Current studies were conducted to verify the presence of angiotensin II receptors by immunological and non-peptide receptor ligand binding techniques and to ascertain the activation of intracellular signal transduction in glomerular epithelial cells in response to angiotensin II. Confluent monolayer cultures of glomerular epithelial cells were incubated with angiotensin II, with or without losartan and/or PD-123,319 in the medium. Membrane vesicle preparations were obtained by homogenization of washed cells followed by centrifugation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of membrane proteins followed by multiscreen immunoblotting was used to determine the presence of angiotensin II receptor type 1 (AT1) or type 2 (AT2). Angiotensin II-mediated signal transduction in glomerular epithelial cells was studied by measuring the levels of cAMP, using radioimmunoassay. Results obtained in these experiments showed the presence of both AT1 and AT2 receptor types in glomerular epithelial cells. Angiotensin II was found to cause an accumulation of cAMP in glomerular epithelial cells, which could be prevented only by simultaneous use of losartan and PD-123,319, antagonists for AT1 and AT2, respectively. The presence of both AT1 and AT2 receptors and an increase in cAMP indicate that glomerular epithelial cells respond to angiotensin II in a manner distinct from that of mesangial cells or proximal tubular epithelial cells. Our results suggest that glomerular epithelial

  18. Angiotensin II receptor type 1 blockade decreases CTGF/CCN2-mediated damage and fibrosis in normal and dystrophic skeletal muscles

    PubMed Central

    Cabello-Verrugio, Claudio; Morales, María Gabriela; Cabrera, Daniel; Vio, Carlos P; Brandan, Enrique

    2012-01-01

    Abstract Connective tissue growth factor (CTGF/CCN-2) is mainly involved in the induction of extracellular matrix (ECM) proteins. The levels of CTGF correlate with the degree and severity of fibrosis in many tissues, including dystrophic skeletal muscle. The CTGF overexpression in tibialis anterior skeletal muscle using an adenoviral vector reproduced many of the features observed in dystrophic muscles including muscle damage and regeneration, fibrotic response and decrease in the skeletal muscle strength. The renin–angiotensin system is involved in the genesis and progression of fibrotic diseases through its main fibrotic components angiotensin-II and its transducer receptor AT-1. The use of AT-1 receptor blockers (ARB) has been shown to decrease fibrosis. In this paper, we show the effect of AT-1 receptor blockade on CTGF-dependent biological activity in skeletal muscle cells as well as the response to CTGF overexpression in normal skeletal muscle. Our results show that in myoblasts ARB decreased CTGF-mediated increase of ECM protein levels, extracellular signal regulated kinases 1/2 (ERK-1/2) phosphorylation and stress fibres formation. In tibialis anterior muscle overexpressing CTGF using an adenovirus, ARB treatment decreased CTGF-mediated increase of ECM molecules, α-SMA and ERK-1/2 phosphorylation levels. Quite remarkable, ARB was able to prevent the loss of contractile force of tibialis anterior muscles overexpressing CTGF. Finally, we show that ARB decreased the levels of fibrotic proteins, CTGF and ERK-1/2 phosphorylation augmented in a dystrophic skeletal muscle from mdx mice. We propose that ARB is a novel pharmacological tool that can be used to decrease the fibrosis induced by CTGF in skeletal muscle associated with muscular dystrophies. PMID:21645240

  19. HMG-CoA reductase inhibitors decrease angiotensin II-induced vascular fibrosis: role of RhoA/ROCK and MAPK pathways.

    PubMed

    Rupérez, Mónica; Rodrigues-Díez, Raquel; Blanco-Colio, Luis Miguel; Sánchez-López, Elsa; Rodríguez-Vita, Juan; Esteban, Vanesa; Carvajal, Gisselle; Plaza, Juan José; Egido, Jesús; Ruiz-Ortega, Marta

    2007-08-01

    3-Hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) present beneficial effects in cardiovascular diseases. Angiotensin II (Ang II) contributes to cardiovascular damage through the production of profibrotic factors, such as connective tissue growth factor (CTGF). Our aim was to investigate whether HMG-CoA reductase inhibitors could modulate Ang II responses, evaluating CTGF expression and the mechanisms underlying this process. In cultured vascular smooth muscle cells (VSMCs) atorvastatin and simvastatin inhibited Ang II-induced CTGF production. The inhibitory effect of statins on CTGF upregulation was reversed by mevalonate and geranylgeranylpyrophosphate, suggesting that RhoA inhibition could be involved in this process. In VSMCs, statins inhibited Ang II-induced Rho membrane localization and activation. In these cells Ang II regulated CTGF via RhoA/Rho kinase activation, as shown by inhibition of Rho with C3 exoenzyme, RhoA dominant-negative overexpression, and Rho kinase inhibition. Furthermore, activation of p38MAPK and JNK, and redox process were also involved in Ang II-mediated CTGF upregulation, and were downregulated by statins. In rats infused with Ang II (100 ng/kg per minute) for 2 weeks, treatment with atorvastatin (5 mg/kg per day) diminished aortic CTGF and Rho activation without blood pressure modification. Rho kinase inhibition decreased CTGF upregulation in rat aorta, mimicking statin effect. CTGF is a vascular fibrosis mediator. Statins diminished extracellular matrix (ECM) overexpression caused by Ang II in vivo and in vitro. In summary, HMG-CoA reductase inhibitors inhibit several intracellular signaling systems activated by Ang II (RhoA/Rho kinase and MAPK pathways and redox process) involved in the regulation of CTGF. Our results may explain, at least in part, some beneficial effects of statins in cardiovascular diseases.

  20. Upregulation of ERK1/2-eNOS via AT2 Receptors Decreases the Contractile Response to Angiotensin II in Resistance Mesenteric Arteries from Obese Rats

    PubMed Central

    Hagihara, Graziela N.; Lobato, Nubia S.; Filgueira, Fernando P.; Akamine, Eliana H.; Aragão, Danielle S.; Casarini, Dulce E.; Carvalho, Maria Helena C.; Fortes, Zuleica B.

    2014-01-01

    It has been clearly established that mitogen-activated protein kinases (MAPKS) are important mediators of angiotensin II (Ang II) signaling via AT1 receptors in the vasculature. However, evidence for a role of these kinases in changes of Ang II-induced vasoconstriction in obesity is still lacking. Here we sought to determine whether vascular MAPKs are differentially activated by Ang II in obese animals. The role of AT2 receptors was also evaluated. Male monosodium glutamate-induced obese (obese) and non-obese Wistar rats (control) were used. The circulating concentrations of Ang I and Ang II, determined by HPLC, were increased in obese rats. Ang II-induced isometric contraction was decreased in endothelium-intact resistance mesenteric arteries from obese compared with control rats and exhibited a retarded AT1 receptor antagonist response. Blocking of AT2 receptors and inhibition of either endothelial nitric oxide synthase (eNOS) or extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) restored Ang II-induced contraction in obese rats. Western blot analysis revealed increased protein expression of AT2 receptors in arteries from obese rats. Basal and Ang II-induced ERK1/2 phosphorylation was also increased in obese rats. Blockade of either AT1 or AT2 receptors corrected the increased ERK1/2 phosphorylation in arteries from obese rats to levels observed in control preparations. Phosphorylation of eNOS was increased in obese rats. Incubation with the ERK1/2 inhibitor before Ang II stimulation did not affect eNOS phosphorylation in control rats; however, it corrected the increased phosphorylation of eNOS in obese rats. These results clearly demonstrate that enhanced AT2 receptor and ERK1/2-induced, NO-mediated vasodilation reduces Ang II-induced contraction in an endothelium-dependent manner in obese rats. PMID:25170617

  1. Mechanisms of angiotensin II natriuresis and antinatriuresis.

    PubMed

    Olsen, M E; Hall, J E; Montani, J P; Guyton, A C; Langford, H G; Cornell, J E

    1985-08-01

    The aim of this study was to determine the role of changes in renal arterial pressure (RAP), renal hemodynamics, and tubular reabsorption in mediating the natriuretic and antinatriuretic actions of angiotensin II (ANG II). In seven anesthetized dogs, endogenous ANG II formation was blocked with captopril, and ANG II was infused intravenously at rates of 5-1,215 ng X kg-1 X min-1 while RAP was either servo-controlled at the preinfusion level or permitted to increase. When RAP was servo-controlled, ANG II infusion at all rates from 5-1,215 ng X kg-1 X min-1 decreased urinary sodium excretion (UNaV) and fractional sodium excretion (FENa) while increasing fractional reabsorption of lithium (FRLi) (an index of proximal tubular fractional sodium reabsorption) and causing no change in calculated distal tubule fractional sodium reabsorption (FRDNa). When RAP was permitted to increase, ANG II infusion rates up to 45 ng X kg-1. min-1 also decreased UNaV and FENa while increasing FRLi and causing no change in FRDNa. However, at 135 ng X kg-1 X min-1 and above, UNaV and FENa increased while FRLi and FRDNa decreased when RAP was allowed to rise, even though renal blood flow and filtration fraction were not substantially different from the values observed when RAP was servo-controlled. Filtered sodium load was slightly higher when RAP was permitted to increase during ANG II infusion compared with when RAP was servo-controlled, although the differences were not statistically significant. Thus, even very large doses of ANG II cause antinatriuresis when RAP is prevented from increasing.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Unexpected binding of an octapeptide to the angiotensin II receptor

    SciTech Connect

    Soffer, R.L.; Bandyopadhyay, S.; Rosenberg, E.; Hoeprich, P.; Teitelbaum, A.; Brunck, T.; Colby, C.B.; Gloff, C.

    1987-12-01

    An octapeptide, TBI-22 (Lys-Gly-Val-Tyr-Ile, His-Ala-Leu), inhibited binding of angiotensin II by a solubilized angiotensin receptor partially purified from rabbit liver. This inhibition appears to result from competition for binding to the same receptor. Radioiodinated TBI-22, like angiotensin II, bound to the solubilized receptor with an affinity such that the binding was inhibited 50% by unlabeled TBI-22 or angiotensin II at nanomolar concentrations. The binding reaction, like that for angiotensin II, required p-chloromercuriphenylsulfonic acid and was reversed in the presence of dithiothreitol. TBI-22 and angiotensin II share the sequence Val-Tyr-Ile-His; this tetrapeptide alone, however, did not inhibit binding of angiotensin II. Replacement of the tyrosine residue by aspartic acid in TBI-22 greatly reduced the ability of the peptide to compete with angiotensin II for binding, suggesting an important contribution of this residue to the configuration required for recognition by the receptor.

  3. Control of glomerular filtration rate by circulating angiotensin II.

    PubMed

    Hall, J E; Coleman, T G; Guyton, A C; Kastner, P R; Granger, J P

    1981-09-01

    Previous studies from our laboratory have provided evidence that the renin-angiotensin system plays an important role in controlling glomerular filtration rate (GFR) through an efferent arteriolar vasoconstrictor mechanism; however, the relative importance of circulating versus intrarenally formed angiotensin II (ANG II) in this control has not been determined. In the present study, the role of circulating ANG II in regulating GFR during reduced renal artery pressure (RAP) was examined in sodium-depleted dogs. After 90 min of infusion of the angiotensin-converting enzyme inhibitor SQ 14225, which presumably inhibited formation of both circulating and intrarenal ANG II, reduction of RAP to 81 +/- 2 mmHg resulted in marked decreases in GFR, filtration fraction (FF), and calculated efferent arteriolar resistance (RE), whereas renal blood flow (RBF) was maintained approximately 40% above initial control levels determined before SQ 14225 infusion. Replacement of circulating ANG II during SQ 14225 infusion, by intravenous infusion of ANG II at rates that decreased RBF to control levels, increased GFR, FF, and RE to levels not significantly different from control while RAP was maintained constant by aortic constriction. These observations suggest that circulating ANG II plays an important role in regulating RE and GFR during reductions in RAP. The importance of intrarenally formed ANG II in controlling GFR remains to be determined.

  4. Use of Enterally Delivered Angiotensin II Type Ia Receptor Antagonists to Reduce the Severity of Colitis

    PubMed Central

    Okawada, Manabu; Koga, Hiroyuki; Larsen, Scott D.; Showalter, Hollis D.; Turbiak, Anjanette J.; Jin, Xiaohong; Lucas, Peter C.; Lipka, Elke; Hillfinger, John; Kim, Jae Seung

    2011-01-01

    Background Renin-angiotensin system blockade reduces inflammation in several organ systems. Having found a fourfold increase in angiotensin II type Ia receptor expression in a dextran sodium sulfate colitis model, we targeted blockade with angiotensin II type Ia receptor antagonists to prevent colitis development. Because hypotension is a major complication of angiotensin II type Ia receptor antagonists use, we hypothesized that use of angiotensin II type Ia receptor antagonists compounds which lack cell membrane permeability, and thus enteric absorption, would allow for direct enteral delivery at far higher concentrations than would be tolerated systemically, yet retain efficacy. Methods Based on the structure of the angiotensin II type Ia receptor antagonist losartan, deschloro-losartan was synthesized, which has extremely poor cell membrane permeability. Angiotensin II type Ia receptor antagonist efficacy was evaluated by determining the ability to block NF-κB activation in vitro. Dextran sodium sulfate colitis was induced in mice and angiotensin II type Ia receptor antagonist efficacy delivered transanally was assessed. Results In vitro, deschloro-losartan demonstrated near equal angiotensin II type Ia receptor blockade compared to losartan as well as another angiotensin II type Ia receptor antagonist, candesartan. In the dextran sodium sulfate model, each compound significantly improved clinical and histologic scores and epithelial cell apoptosis. Abundance of TNF-α, IL-1β, and IL6 mRNA were significantly decreased with each compound. In vitro and in vivo intestinal drug absorption, as well as measures of blood pressure and mucosal and colonic blood flow, showed significantly lower uptake of deschloro-losartan compared to losartan and candesartan. Conclusions This study demonstrated efficacy of high-dose angiotensin II type Ia receptor antagonists in this colitis model. We postulate that a specially designed angiotensin II type Ia receptor antagonist with

  5. Angiotensin II receptors in the gonads

    SciTech Connect

    Aguilera, G.; Millan, M.A.; Harwood, J.P.

    1989-05-01

    The presence of components of the renin-angiotensin system in ovaries and testes suggests that angiotensin II (AII) is involved in gonadal function, and thus we sought to characterize receptors for AII in rat and primate gonads. In the testes, autoradiographic studies showed receptors in the interstitium in all species. In rat interstitial cells fractionated by Percoll gradient, AII receptors coincided with hCG receptors indicating that AII receptors are located on the Leydig cells. In Leydig cells and membranes from rat and rhesus monkey prepuberal testes, AII receptors were specific for AII analogues and of high affinity (Kd=nM). During development, AII receptor content in rat testes decreases with age parallel to a fall in the ratio of interstitial to tubular tissue. In the ovary, the distribution of AII receptors was dependent on the stage of development, being high in the germinal epithelium and stromal tissue between five and 15 days, and becoming localized in secondary follicles in 20-and 40-day-old rats. No binding was found in primordial or primary follicles. In rhesus monkey ovary, AII receptors were higher in stromal tissue and lower in granulosa and luteal cells of the follicles. Characterization of the binding in rat and monkey ovarian membranes showed a single class of sites with a Kd in the nmol/L range and specificity similar to that of the adrenal glomerulosa and testicular AII receptors. Receptors for AII were also present in membrane fractions from PMSG/hCG primed rat ovaries. Infusion of AII (25 ng/min) or captopril (1.4 micrograms/min) during the PMSG/hCG induction period had no effect on ovarian weight or AII receptor concentration in the ovaries.

  6. Oxidative DNA Damage in Kidneys and Heart of Hypertensive Mice Is Prevented by Blocking Angiotensin II and Aldosterone Receptors

    PubMed Central

    Brand, Susanne; Amann, Kerstin; Mandel, Philipp; Zimnol, Anna; Schupp, Nicole

    2014-01-01

    Introduction Recently, we could show that angiotensin II, the reactive peptide of the blood pressure-regulating renin-angiotensin-aldosterone-system, causes the formation of reactive oxygen species and DNA damage in kidneys and hearts of hypertensive mice. To further investigate on the one hand the mechanism of DNA damage caused by angiotensin II, and on the other hand possible intervention strategies against end-organ damage, the effects of substances interfering with the renin-angiotensin-aldosterone-system on angiotensin II-induced genomic damage were studied. Methods In C57BL/6-mice, hypertension was induced by infusion of 600 ng/kg • min angiotensin II. The animals were additionally treated with the angiotensin II type 1 receptor blocker candesartan, the mineralocorticoid receptor blocker eplerenone and the antioxidant tempol. DNA damage and the activation of transcription factors were studied by immunohistochemistry and protein expression analysis. Results Administration of angiotensin II led to a significant increase of blood pressure, decreased only by candesartan. In kidneys and hearts of angiotensin II-treated animals, significant oxidative stress could be detected (1.5-fold over control). The redox-sensitive transcription factors Nrf2 and NF-κB were activated in the kidney by angiotensin II-treatment (4- and 3-fold over control, respectively) and reduced by all interventions. In kidneys and hearts an increase of DNA damage (3- and 2-fold over control, respectively) and of DNA repair (3-fold over control) was found. These effects were ameliorated by all interventions in both organs. Consistently, candesartan and tempol were more effective than eplerenone. Conclusion Angiotensin II-induced DNA damage is caused by angiotensin II type 1 receptor-mediated formation of oxidative stress in vivo. The angiotensin II-mediated physiological increase of aldosterone adds to the DNA-damaging effects. Blocking angiotensin II and mineralocorticoid receptors therefore

  7. Angiotensin II-regulated transcription regulatory genes in adrenal steroidogenesis.

    PubMed

    Romero, Damian G; Gomez-Sanchez, Elise P; Gomez-Sanchez, Celso E

    2010-11-29

    Transcription regulatory genes are crucial modulators of cell physiology and metabolism whose intracellular levels are tightly controlled in response to extracellular stimuli. We previously reported a set of 29 transcription regulatory genes modulated by angiotensin II in H295R human adrenocortical cells and their roles in regulating the expression of the last and unique enzymes of the glucocorticoid and mineralocorticoid biosynthetic pathways, 11β-hydroxylase and aldosterone synthase, respectively, using gene expression reporter assays. To study the effect of this set of transcription regulatory genes on adrenal steroidogenesis, H295R cells were transfected by high-efficiency nucleofection and aldosterone and cortisol were measured in cell culture supernatants under basal and angiotensin II-stimulated conditions. BCL11B, BHLHB2, CITED2, ELL2, HMGA1, MAFF, NFIL3, PER1, SERTAD1, and VDR significantly stimulated aldosterone secretion, while EGR1, FOSB, and ZFP295 decreased aldosterone secretion. BTG2, HMGA1, MITF, NR4A1, and ZFP295 significantly increased cortisol secretion, while BCL11B, NFIL3, PER1, and SIX2 decreased cortisol secretion. We also report the effect of some of these regulators on the expression of endogenous aldosterone synthase and 11β-hydroxylase under basal and angiotensin II-stimulated conditions. In summary, this study reports for the first time the effects of a set of angiotensin II-modulated transcription regulatory genes on aldosterone and cortisol secretion and the expression levels of the last and unique enzymes of the mineralocorticoid and glucocorticoid biosynthetic pathways. Abnormal regulation of mineralocorticoid or glucocorticoid secretion is involved in several pathophysiological conditions. These transcription regulatory genes may be involved in adrenal steroidogenesis pathologies; thus they merit additional study as potential candidates for therapeutic intervention.

  8. Angiotensin-II mediates ACE2 Internalization and Degradation through an Angiotensin-II type I receptor-dependent mechanism

    PubMed Central

    Lazartigues, Eric; Filipeanu, Catalin M.

    2014-01-01

    Angiotensin Converting Enzyme type 2 (ACE2) is a pivotal component of the renin-angiotensin system, promoting the conversion of Angiotensin (Ang)-II to Ang-(1-7). We previously reported that decreased ACE2 expression and activity contribute to the development of Ang-II-mediated hypertension in mice. The present study aimed to investigate the mechanisms involved in ACE2 down-regulation during neurogenic hypertension. In ACE2-transfected Neuro-2A cells, Ang-II treatment resulted in a significant attenuation of ACE2 enzymatic activity. Examination of the subcellular localization of ACE2 revealed that Ang-II treatment leads to ACE2 internalization and degradation into lysosomes. These effects were prevented by both the Ang-II type 1 receptor (AT1R) blocker losartan and the lysosomal inhibitor leupeptin. In contrast, in HEK293T cells, which lack endogenous AT1R, Ang-II failed to promote ACE2 internalization. Moreover, this effect could be induced after AT1R transfection. Further, co-immunoprecipitation experiments demonstrated that AT1R and ACE2 form complexes and these interactions were decreased by Ang-II treatment, which also enhanced ACE2 ubiquitination. In contrast, ACE2 activity was not changed by transfection of AT2 or Mas receptors. In vivo, Ang-II-mediated hypertension was blunted by chronic infusion of leupeptin in wildtype C57Bl/6, but not in ACE2 knockout mice. Overall, this is the first demonstration that elevated Ang-II levels reduce ACE2 expression and activity by stimulation of lysosomal degradation through an AT1R-dependent mechanism. PMID:25225202

  9. Angiotensin II, hypertension, and angiotensin II receptor antagonism: Roles in the behavioural and brain pathology of a mouse model of Alzheimer's disease.

    PubMed

    Wiesmann, Maximilian; Roelofs, Monica; van der Lugt, Robert; Heerschap, Arend; Kiliaan, Amanda J; Claassen, Jurgen Ahr

    2016-01-01

    Elevated angiotensin II causes hypertension and contributes to Alzheimer's disease by affecting cerebral blood flow. Angiotensin II receptor blockers may provide candidates to reduce (vascular) risk factors for Alzheimer's disease. We studied effects of two months of angiotensin II-induced hypertension on systolic blood pressure, and treatment with the angiotensin II receptor blockers, eprosartan mesylate, after one month of induced hypertension in wild-type C57bl/6j and AβPPswe/PS1ΔE9 (AβPP/PS1/Alzheimer's disease) mice. AβPP/PS1 showed higher systolic blood pressure than wild-type. Subsequent eprosartan mesylate treatment restored this elevated systolic blood pressure in all mice. Functional connectivity was decreased in angiotensin II-infused Alzheimer's disease and wild-type mice, and only 12 months of Alzheimer's disease mice showed impaired cerebral blood flow. Only angiotensin II-infused Alzheimer's disease mice exhibited decreased spatial learning in the Morris water maze. Altogether, angiotensin II-induced hypertension not only exacerbated Alzheimer's disease-like pathological changes such as impairment of cerebral blood flow, functional connectivity, and cognition only in Alzheimer's disease model mice, but it also induced decreased functional connectivity in wild-type mice. However, we could not detect hypertension-induced overexpression of Aβ nor increased neuroinflammation. Our findings suggest a link between midlife hypertension, decreased cerebral hemodynamics and connectivity in an Alzheimer's disease mouse model. Eprosartan mesylate treatment restored and beneficially affected cerebral blood flow and connectivity. This model could be used to investigate prevention/treatment strategies in early Alzheimer's disease.

  10. Gender differences in response to acute and chronic angiotensin II infusion: a translational approach

    PubMed Central

    Toering, Tsjitske J; van der Graaf, Anne Marijn; Visser, Folkert W; Buikema, Hendrik; Navis, Gerjan; Faas, Marijke M; Lely, A Titia

    2015-01-01

    Women with renal disease progress at a slower rate to end stage renal disease than men. As angiotensin II has both hemodynamic and direct renal effects, we hypothesized that the female protection may result from gender differences in responses to angiotensin II. Therefore, we studied gender differences in response to angiotensin II, during acute (human) and chronic (rats) angiotensin II administration. In young healthy men (n = 18) and women (n = 18) we studied the responses of renal hemodynamics (125I-iothalamate and 131I-Hippuran) and blood pressure to graded angiotensin II infusion (0.3, 1.0, and 3.0 ng/kg/min for 1 h). Men had increased responses of diastolic blood pressure (P = 0.01), mean arterial pressure (P = 0.05), and a more pronounced decrease in effective renal plasma flow (P = 0.009) than women. We measured the changes in proteinuria and blood pressure in response to chronic administration (200 ng/kg/min for 3 weeks) of angiotensin II in rats. Male rats had an increased response of proteinuria compared with females (GEE analysis, P = 0.001). Male, but not female, angiotensin II-treated rats had increased numbers of renal interstitial macrophages compared to sham-treated rats (P < 0.001). In conclusion, gender differences are present in the response to acute and chronic infusion of angiotensin II. Difference in angiotensin II sensitivity could play a role in gender differences in progression of renal disease. PMID:26149279

  11. Identification of angiotensin II receptor subtypes

    SciTech Connect

    Chiu, A.T.; Herblin, W.F.; McCall, D.E.; Ardecky, R.J.; Carini, D.J.; Duncia, J.V.; Pease, L.J.; Wong, P.C.; Wexler, R.R.; Johnson, A.L.; )

    1989-11-30

    We have demonstrated the existence of two distinct subtypes of the angiotensin II receptor in the rat adrenal gland using radioligand binding and tissue section autoradiography. The identification of the subtypes was made possible by the discovery of two structurally dissimilar, nonpeptide compounds, DuP 753 and EXP655, that show reciprocal selectivity for the two subtypes. In the rat adrenal cortex, DuP 753 inhibited 80% of the total AII binding with an IC50 value on the sensitive sites of 2 x 10(-8) M, while EXP655 displaced only 20%. In the rat adrenal medulla, EXP655 gave 90% inhibition of AII binding with an IC50 value of 3.0 x 10(-8) M, while DuP 753 was essentially inactive. The combination of the two compounds completely inhibited AII binding in both tissues.

  12. [Angiotensin II receptor antagonists: different or equivalent?].

    PubMed

    Mounier-Vehier, C; Devos, P

    ARA-II: Angiotensin II receptor antagonists (ARA-II) belong to a recent class of antihypertensive drugs whose mechanism of action is similar to converting enzyme inhibitors (CEI). ARA-II are particularly interesting due to the excellent clinical and biological tolerance, similar to placebo, and their antihypertensive efficacy, comparable with classical drug classes. PUBLISHED TRIALS: A meta-analysis, published by Conlin in the American Journal of Hypertension, suggests that ARA-II, specifically losartan, valsartan, irbesartan and candesartan, have an equipotent blood pressure lowering effect. The careful lecture of this meta-analysis however discloses a faulty methodology from which no valid conclusion can be drawn. Since this early publication, several other comparative studies have been published. These multicentric, randomized double-blind studies enrolled a sufficient number of patients and demonstrated a clinical difference between certain ARA-II at usual dosages. CLINICAL PRACTICE: These studies do have an impact on everyday practice. For the practitioner, the goal is to obtain and then maintain a long-term and optimal reduction in the blood pressure level (reduction or prevention of target-organ disorders and cardiovascular complications of high blood pressure). This reduction in the cardiovascular risk will also depend directly on tolerance and compliance to the antihypertensive treatment. This element must also be considered in assessing treatment efficacy, independent of the blood pressure lowering effect. The results of several other studies will be published in 2001-2003. These large-scale studies on ARA-II related morbidity and mortality will be most useful in determining the role of these drugs in different therapeutic strategies compared with other drug classes.

  13. Cyclooxygenase-2 Inhibition Limits Angiotensin II-Induced DNA Oxidation and Protein Nitration in Humans

    PubMed Central

    Pialoux, Vincent; Poulin, Marc J.; Hemmelgarn, Brenda R.; Muruve, Daniel A.; Chirico, Erica N.; Faes, Camille; Sola, Darlene Y.; Ahmed, Sofia B.

    2017-01-01

    Compared to other cyclooxygenase-2 inhibitors, celecoxib is associated with a lower cardiovascular risk, though the mechanism remains unclear. Angiotensin II is an important mediator of oxidative stress in the pathophysiology of vascular disease. Cyclooxygenase-2 may modify the effects of angiotensin II though this has never been studied in humans. The purpose of the study was to test the effects of selective cyclooxygenase-2 inhibition on plasma measures of oxidative stress, the vasoconstrictor endothelin-1, and nitric oxide metabolites, both at baseline and in respose to Angiotensin II challenge in healthy humans. Measures of 8-hydroxydeoxyguanosine, advanced oxidation protein products, nitrotyrosine, endothelin-1, and nitric oxide metabolites were assessed from plasma samples drawn at baseline and in response to graded angiotensin II infusion (3 ng/kg/min × 30 min, 6 ng/kg/min × 30 min) before and after 14 days of cyclooxygenase-2 inhibition in 14 healthy subjects (eight male, six female) in high salt balance, a state of maximal renin angiotensin system suppression. Angiotensin II infusion significantly increased plasma oxidative stress compared to baseline (8-hydroxydeoxyguanosine; +17%; advanced oxidation protein products; +16%), nitrotyrosine (+76%). Furthermore, levels of endothelin-1 levels were significantly increased (+115%) and nitric oxide metabolites were significantly decreased (−20%). Cycloxygenase-2 inhibition significantly limited the increase in 8-hydroxydeoxyguanosine, nitrotyrosine and the decrease in nitric oxide metabolites induced by angiotensin II infusion, though no changes in advanced oxidation protein products and endothelin-1 concentrations were observed. Cyclooxygenase-2 inhibition with celecoxib partially limited the angiotensin II-mediated increases in markers of oxidative stress in humans, offering a potential physiological pathway for the improved cardiovascular risk profile of this drug. PMID:28344559

  14. ACE2: Angiotensin II/Angiotensin-(1-7) balance in cardiorenal injury

    PubMed Central

    Varagic, Jasmina; Ahmad, Sarfaraz; Nagata, Sayaka; Ferrario, Carlos M.

    2014-01-01

    Our current recognition of the renin-angiotensin system is more convoluted than originally thought due to the discovery of multiple novel enzymes, peptides, and receptors inherent to this interactive biochemical cascade. Over the last decade angiotensin converting enzyme 2 (ACE2) has emerged as a key player in the pathophysiology of hypertension and cardiovascular and renal disease due to its pivotal role in metabolizing vasoconstrictive/hypertrophic/proliferative angiotensin II into favorable angiotensin-(1-7). This review addresses a considerable advancement in research on the role of tissue ACE2 in development and progression of hypertension and cardiorenal injury. We also summarize the results from recent clinical and experimental studies suggesting that serum or urine soluble ACE2 may serve as a novel biomarker or independent risk factor relevant for diagnosis and prognosis of cardiorenal disease. Recent proceedings on novel therapeutic approaches to enhance ACE2/angiotensin-(1-7) axis are also reviewed. PMID:24510672

  15. Decreased Androgen Levels and Improved Menstrual Pattern after Angiotensin II Receptor Antagonist Telmisartan Treatment in Four Hypertensive Patients with Polycystic Ovary Syndrome: Case Series

    PubMed Central

    Jensterle, Mojca; Janez, Andrej; Vrtovec, Bojan; Meden-Vrtovec, Helena; Pfeifer, Marija; Prezelj, Janez; Kocjan, Tomaz

    2007-01-01

    We describe 4 consecutive hypertensive women with polycystic ovary syndrome, classified according to the National Institute of Child Health and Human Development (NICHD) criteria, treated with telmisartan 40 mg/d for six months. Blood pressure, menstrual pattern, body mass index (BMI), homeostasis model assessment of insulin resistance, testosterone, dehydroepiandrosterone sulfate (DHEAS), and androstenedione were recorded and measured before and after telmisartan treatment. Obese hypertensive polycystic ovary syndrome patients had a decrease in systolic blood pressure. Marked drop-off in serum androgen concentrations was observed in all four patients. Three patients improved their menstrual cyclicity. The improvements were independent of changes in weight. The reduction of androgen concentrations and improvement in menstrual pattern was achieved despite a non-significant change of fasting insulin levels in patients, who were not considered severely insulin resistant at baseline. These findings may provide a new basis for a proper choice of the antihypertensive drug in hypertensive women with polycystic ovary syndrome. PMID:18074422

  16. Decreased androgen levels and improved menstrual pattern after angiotensin II receptor antagonist telmisartan treatment in four hypertensive patients with polycystic ovary syndrome: case series.

    PubMed

    Jensterle, Mojca; Janez, Andrej; Vrtovec, Bojan; Meden-Vrtovec, Helena; Pfeifer, Marija; Prezelj, Janez; Kocjan, Tomaz

    2007-12-01

    We describe 4 consecutive hypertensive women with polycystic ovary syndrome, classified according to the National Institute of Child Health and Human Development (NICHD) criteria, treated with telmisartan 40 mg/d for six months. Blood pressure, menstrual pattern, body mass index (BMI), homeostasis model assessment of insulin resistance, testosterone, dehydroepiandrosterone sulfate (DHEAS), and androstenedione were recorded and measured before and after telmisartan treatment. Obese hypertensive polycystic ovary syndrome patients had a decrease in systolic blood pressure. Marked drop-off in serum androgen concentrations was observed in all four patients. Three patients improved their menstrual cyclicity. The improvements were independent of changes in weight. The reduction of androgen concentrations and improvement in menstrual pattern was achieved despite a non-significant change of fasting insulin levels in patients, who were not considered severely insulin resistant at baseline. These findings may provide a new basis for a proper choice of the antihypertensive drug in hypertensive women with polycystic ovary syndrome.

  17. Angiotensin II stimulates sympathetic neurotransmission to adipose tissue

    PubMed Central

    King, Victoria L; English, Victoria L; Bharadwaj, Kalyani; Cassis, Lisa A

    2013-01-01

    Angiotensin II (AngII) facilitates sympathetic neurotransmission by regulating norepinephrine (NE) synthesis, release, and uptake. These effects of AngII contribute to cardiovascular control. Previous studies in our laboratory demonstrated that chronic AngII infusion decreased body weight of rats. We hypothesized that AngII facilitates sympathetic neurotransmission to adipose tissue and may thereby decrease body weight. The effect of chronic AngII infusion on the NE uptake transporter and NE turnover was examined in metabolic (interscapular brown adipose tissue, ISBAT; epididymal fat, EF) and cardiovascular tissues (left ventricle, LV; kidney) of rats. To examine the uptake transporter saturation isotherms were performed using [3H]nisoxetine (NIS). At doses that lowered body weight, AngII significantly increased ISBAT [3H]NIS binding density. To quantify NE turnover, alpha-methyl-para-tyrosine (AMPT) was injected in saline-infused, AngII-infused, or saline-infused rats that were pair-fed to food intake of AngII-infused rats. AngII significantly increased the rate of NE decline in all tissues compared to saline. The rate of NE decline in EF was increased to a similar extent by AngII and by pair feeding. In rats administered AngII and propranolol, reductions in food and water intake and body weight were eliminated. These data support the hypothesis that AngII facilitates sympathetic neurotransmission to adipose tissue. Increased sympathetic neurotransmission to adipose tissue following AngII exposure is suggested to contribute to reductions in body weight. PMID:24224084

  18. DIOL Triterpenes Block Profibrotic Effects of Angiotensin II and Protect from Cardiac Hypertrophy

    PubMed Central

    Jurado-López, Raquel; Martínez-Martínez, Ernesto; Gómez-Hurtado, Nieves; Delgado, Carmen; Visitación Bartolomé, Maria; San Román, José Alberto; Cordova, Claudia; Lahera, Vicente; Nieto, Maria Luisa; Cachofeiro, Victoria

    2012-01-01

    Background The natural triterpenes, erythrodiol and uvaol, exert anti-inflammatory, vasorelaxing and anti-proliferative effects. Angiotensin II is a well-known profibrotic and proliferative agent that participates in the cardiac remodeling associated with different pathological situations through the stimulation and proliferation of cardiac fibroblasts. Therefore, the aim of the study was to investigate the preventive effects of the natural triterpenes erythrodiol and uvaol on the proliferation and collagen production induced by angiotensin II in cardiac myofibroblasts. Their actions on cardiac hypertrophy triggered by angiotensin II were also studied. Methodology/Principal Findings The effect of erythrodiol and uvaol on angiotensin II-induced proliferation was evaluated in cardiac myofibroblasts from adult rats in the presence or the absence of the inhibitors of PPAR-γ, GW9662 or JNK, SP600125. The effect on collagen levels induced by angiotensin II was evaluated in cardiac myofibroblasts and mouse heart. The presence of low doses of both triterpenes reduced the proliferation of cardiac myofibroblasts induced by angiotensin II. Pretreatment with GW9662 reversed the effect elicited by both triterpenes while SP600125 did not modify it. Both triterpenes at high doses produced an increase in annexing-V binding in the presence or absence of angiotensin II, which was reduced by either SP600125 or GW9662. Erythrodiol and uvaol decreased collagen I and galectin 3 levels induced by angiotensin II in cardiac myofribroblasts. Finally, cardiac hypertrophy, ventricular remodeling, fibrosis, and increases in myocyte area and brain natriuretic peptide levels observed in angiotensin II-infused mice were reduced in triterpene-treated animals. Conclusions/Significance Erythrodiol and uvaol reduce cardiac hypertrophy and left ventricle remodeling induced by angiotensin II in mice by diminishing fibrosis and myocyte area. They also modulate growth and survival of cardiac

  19. Angiotensin II binding to cultured bovine adrenal chromaffin cells: identification of angiotensin II receptors

    SciTech Connect

    Boyd, V.L.; Printz, M.P.

    1986-03-05

    Physiological experiments have provided evidence that angiotensin II stimulates catecholamine secretion from the adrenal gland. Their laboratory and others have now shown by receptor autoradiography the presence of angiotensin II receptors (AIIR) in bovine and rat adrenal medulla. In order to extend these studies they have undertaken to define AIIR on cultured bovine adrenal chromaffin cells. Cells were isolated using the method of Levitt including cell enrichment with Percoll gradient centrifugation. Primary cultures of bovine adrenal medullary cells were maintained in DME/F12 medium containing 10% FCS. Cells were characterized by immunocytochemistry for Met- and Leu-enkephalin, PNMT, DBH and Chromagranin A. Cultured cells bind with high affinity and specificity (/sup 125/I)-ANG II yielding a K/sub D/ of 0.74 nM and B/sub max/ of 24,350 sites/cell. After Percoll treatment values of .77 nm and 34,500 sites/cell are obtained. K/sub D/ values are in close agreement with that obtained in adrenal slices by Healy. Competition studies identify a rank order of binding by this receptor similar to that of other tissues. They conclude that cultured chromaffin cells provide a suitable model system for the investigation and characterization of the ANG II receptor and for cellular studies of its functional significance.

  20. Effect of chronic intracerebroventricular angiotensin II infusion on vasopressin release in rats

    NASA Technical Reports Server (NTRS)

    Sterling, G. H.; Chee, O.; Riggs, R. V.; Keil, L. C.

    1980-01-01

    The effects of the chronic infusion of angiotensin II into the lateral cerebral ventricle on the release of arginine vasopressin in rats are investigated. Rats were subjected to a continuous infusion of angiotensin at a rate of 1 microgram/h for five days, during which they were offered water, isotonic saline or hypertonic saline ad libitum or 40 ml water/day, and fluid intake, changes in body weight, plasma sodium ion concentrations and plasma and pituitary arginine vasopressin levels were measured. Angiotensin II is found to increase the fluid intake of rats given isotonic saline and decrease plasma sodium ion levels with no changes in plasma or pituitary arginine vasopressin in those given water or isotonic saline. However, in rats given hypertonic saline, plasma sodium concentrations remained at control levels while plasma vasopressin increased, and in water-restricted rats the effects of angiotensin II were intermediate. Results thus demonstrate that angiotensin II-stimulated arginine vasopressin release is reduced under conditions in which plasma sodium ion concentration becomes dilute, compatible with a central role of angiotensin in the regulation of salt and water balance.

  1. Origin of the angiotensin II secreted by cells.

    PubMed

    Ganong, W F

    1994-03-01

    Circulating angiotensin II is unique in that it is formed in the blood by the interaction of circulating proteins. There are in addition many local renin-angiotensin systems in tissues in which angiotensin II is apparently secreted by various types of cells. This brief review considers the possible pathways for synthesis of locally produced angiotensin II in the brain, the anterior pituitary, the testes, the ovaries, the adrenal cortex, the kidneys, the heart, blood vessel walls, and brown and white fat. Synthesis by cells in culture is also reviewed. The possibility that certain cells contain a complete intracellular renin-angiotensin system is not ruled out, but there are problems with this hypothesis. Proteases other than renin may be involved, and there may be different pathways in different tissues. However, it appears that at least in some tissues, angiotensinogen is produced in one population of cells and transported in a paracrine fashion to other renin-containing cells, where it serves as the substrate for production of angiotensin II.

  2. Angiotensin II directly impairs adipogenic differentiation of human preadipose cells.

    PubMed

    Palominos, Marisol M; Dünner, Natalia H; Wabitsch, Martin; Rojas, Cecilia V

    2015-10-01

    Angiotensin II reduces adipogenic differentiation of preadipose cells present in the stroma-vascular fraction of human adipose tissue, which also includes several cell types. Because of the ability of non-adipose lineage cells in the stroma-vascular fraction to respond to angiotensin II, it is not possible to unequivocally ascribe the anti-adipogenic response to a direct effect of this hormone on preadipose cells. Therefore, we used the human Simpson-Golabi-Behmel syndrome (SGBS) preadipocyte cell strain to investigate the consequences of angiotensin II treatment on adipogenic differentiation under serum-free conditions, by assessing expression of typical adipocyte markers perilipin and fatty acid-binding protein 4 (FABP4), at the transcript and protein level. Reverse transcription-polymerase chain reaction showed that perilipin and FABP4 transcripts were, respectively, reduced to 0.33 ± 0.07 (P < 0.05) and 0.41 ± 0.19-fold (P < 0.05) in SGBS cells induced to adipogenic differentiation in the presence of angiotensin II. Western Blot analysis corroborated reduction of the corresponding proteins to 0.23 ± 0.21 (P < 0.01) and 0.46 ± 0.30-fold (P < 0.01) the respective controls without angiotensin II. Angiotensin II also impaired morphological changes associated with early adipogenesis. Hence, we demonstrated that angiotensin II is able to directly reduce adipogenic differentiation of SGBS preadipose cells.

  3. Mechanism of adrenal angiotensin II receptor changes after nephrectomy in rats.

    PubMed Central

    Douglas, J G

    1981-01-01

    At 48 h after bilateral nephrectomy in rats there is a two- to threefold increase in the number of adrenal angiotensin II receptors and a decrease in Kd of smooth muscle angiotensin II receptors. These changes have been attributed to the absence of circulating angiotensin II. Serum K+, which increases after nephrectomy may be an important and overlooked modulator. Therefore, the present experiments were designed to assess the role of K+ as a regulator of angiotensin II receptors after nephrectomy. Serum K+ was controlled with Na polystyrene sulfonate (Kayexalate), a resin designed to exchange Na+ for K+ in the gastrointestinal tract. Acutely nephrectomized rats were divided into two groups: experimental animals received Kayexalate resin every 12 h for four doses, and controls received Kayexalate exchanged with KCl in vitro before gavage. There was a significant positive correlation serum K+ and aldosterone (r = 0.78, P less than 0.001). Kayexalate maintained a normal serum K+ of 5.9 +/- 0.2 meq/liter (n = 27), aldosterone 25 +/- 3 ng/dl (n = 27) and adrenal receptor concentration of 934 +/- 156 fmol/mg protein (n = 4). Control animals had significantly higher serum K+ of 10.5 +/- 0.4 meq/liter (n = 23), aldosterone 435 +/- 32 (n = 23), and adrenal receptors of 2726 +/- 235 fmol/mg protein (n = 4). There was a linear relationship between serum K+ and number of adrenal receptors (r = 0.87). No such relationship was present in uterine smooth muscle. Therefore, these studies demonstrate that K+ modulates the number of adrenal but not smooth muscle angiotensin II receptors after nephrectomy. This is the first evidence that potassium modulates angiotensin II receptors independently of changes in angiotensin II blood levels. PMID:6259213

  4. Central interactions of aldosterone and angiotensin II in aldosterone- and angiotensin II-induced hypertension.

    PubMed

    Xue, Baojian; Beltz, Terry G; Yu, Yang; Guo, Fang; Gomez-Sanchez, Celso E; Hay, Meredith; Johnson, Alan Kim

    2011-02-01

    Many studies have implicated both angiotensin II (ANG II) and aldosterone (Aldo) in the pathogenesis of hypertension, the progression of renal injury, and cardiac remodeling after myocardial infarction. In several cases, ANG II and Aldo have been shown to have synergistic interactions in the periphery. In the present studies, we tested the hypothesis that ANG II and Aldo interact centrally in Aldo- and ANG II-induced hypertension in male rats. In rats with blood pressure (BP) and heart rate (HR) measured by DSI telemetry, intracerebroventricular (icv) infusions of the mineralocorticoid receptor (MR) antagonists spironolactone and RU28318 or the angiotensin type 1 receptor (AT1R) antagonist irbesartan significantly inhibited Aldo-induced hypertension. In ANG II-induced hypertension, icv infusion of RU28318 significantly reduced the increase in BP. Moreover, icv infusions of the reactive oxygen species (ROS) scavenger tempol or the NADPH oxidase inhibitor apocynin attenuated Aldo-induced hypertension. To confirm these effects of pharmacological antagonists, icv injections of either recombinant adeno-associated virus carrying siRNA silencers of AT1aR (AT1aR-siRNA) or MR (MR-siRNA) significantly attenuated the development of Aldo-induced hypertension. The immunohistochemical and Western blot analyses of AT1aR-siRNA- or MR-siRNA-injected rats showed a marked reduction in the expression of AT1R or MR in the paraventricular nucleus compared with scrambled siRNA rats. When animals from all studies underwent ganglionic blockade with hexamethonium, there was a smaller reduction in the fall of BP in animals receiving icv AT1R or MR antagonists. These results suggest that ANG II and Aldo interact in the brain in a mutually cooperative manner such that the functional integrity of both brain AT1R and MR are necessary for hypertension to be induced by either systemic ANG II or Aldo. The pressor effects produced by systemic ANG II or Aldo involve increased central ROS and

  5. Inhibition of prolyl hydroxylase domain-containing protein downregulates vascular angiotensin II type 1 receptor.

    PubMed

    Matsuura, Hirohide; Ichiki, Toshihiro; Ikeda, Jiro; Takeda, Kotaro; Miyazaki, Ryohei; Hashimoto, Toru; Narabayashi, Eriko; Kitamoto, Shiro; Tokunou, Tomotake; Sunagawa, Kenji

    2011-09-01

    Inhibition of prolyl hydroxylase domain-containing protein (PHD) by hypoxia stabilizes hypoxia-inducible factor 1 and increases the expression of target genes, such as vascular endothelial growth factor. Although the systemic renin-angiotensin system is activated by hypoxia, the role of PHD in the regulation of the renin-angiotensin system remains unknown. We examined the effect of PHD inhibition on the expression of angiotensin II type 1 receptor (AT(1)R). Hypoxia, cobalt chloride, and dimethyloxalylglycine, all known to inhibit PHD, reduced AT(1)R expression in vascular smooth muscle cells. Knockdown of PHD2, a major isoform of PHDs, by RNA interference also reduced AT(1)R expression. Cobalt chloride diminished angiotensin II-induced extracellular signal-regulated kinase phosphorylation. Cobalt chloride decreased AT(1)R mRNA through transcriptional and posttranscriptional mechanisms. Oral administration of cobalt chloride (14 mg/kg per day) to C57BL/6J mice receiving angiotensin II infusion (490 ng/kg per minute) for 4 weeks significantly attenuated perivascular fibrosis of the coronary arteries without affecting blood pressure level. These data suggest that PHD inhibition may be beneficial for the treatment of cardiovascular diseases by inhibiting renin-angiotensin system via AT(1)R downregulation.

  6. Angiotensin II-induced angiotensin II type I receptor lysosomal degradation studied by fluorescence lifetime imaging microscopy

    NASA Astrophysics Data System (ADS)

    Li, Hewang; Yu, Peiying; Felder, Robin A.; Periasamy, Ammasi; Jose, Pedro A.

    2009-02-01

    Upon activation, the angiotensin (Ang) II type 1 receptor (AT1Rs) rapidly undergoes endocytosis. After a series of intracellular processes, the internalized AT1Rs recycle back to the plasma membrane or are trafficked to proteasomes or lysosomes for degradation. We recently reported that AT1Rs degrades in proteasomes upon stimulation of the D5 dopamine receptor (D5R) in human renal proximal tubule and HEK-293 cells. This is in contrast to the degradation of AT1R in lysosomes upon binding Ang II. However, the dynamic regulation of the AT1Rs in lysosomes is not well understood. Here we investigated the AT1Rs lysosomal degradation using FRET-FLIM in HEK 293 cells heterologously expressing the human AT1R tagged with EGFP as the donor fluorophore. Compared to its basal state, the lifetime of AT1Rs decreased after a 5-minute treatment with Ang II treatment and colocalized with Rab5 but not Rab7 and LAMP1. With longer Ang II treatment (30 min), the AT1Rs lifetime decreased and co-localized with Rab5, as well as Rab7 and LAMP1. The FLIM data are corroborated with morphological and biochemical co-immunoprecipitation studies. These data demonstrate that Ang II induces the internalization of AT1Rs into early sorting endosomes prior to trafficking to late endosomes and subsequent degradation in lysosomes.

  7. Chronic blockade of angiotensin II formation during sodium deprivation.

    PubMed

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

    1979-12-01

    The present study was designed to investigate the mechanisms by which the renin-angiotensin system (RAS) regulates arterial pressure (AP) and renal function during chronic sodium deprivation. Intravenous infusion of the converting enzyme inhibitor SQ 14225 (14 microgram.kg-1.mm-1) for 8 days in 12 sodium-deficient dogs caused a marked decrease in AP from 90 +/- 1 to 67 +/- 2 mmHg and a reduction in glomerular filtration rate (GFR), filtration fraction (FF), and plasma aldosterone concentration (PAC). Despite the fall in AP and GFR, urinary Na excretion and effective renal plasma flow (ERPF) increased above control levels. In four dogs, infusion of aldosterone (200 micrograms/day) for 8 days during continuous SQ 14225 infusion restored PAC to levels above control, but did not significantly change AP or renal function from the values observed during SQ 14225 infusion alone. However, infusion of angiotensin II (AII) (10 or 20 ng.kg-1.min-1) for 5--8 days during continuous SQ 14225 infusion almost completely restored AP and renal function to control levels. These data indicate that the RAS plays a major role in regulating AP, renal hemodynamics, and Na excretion during Na deprivation, probably through the direct effects of AII rather than through changes in PAC.

  8. Metabolomics in angiotensin II-induced cardiac hypertrophy.

    PubMed

    Mervaala, Eero; Biala, Agnieszka; Merasto, Saara; Lempiäinen, Juha; Mattila, Ismo; Martonen, Essi; Eriksson, Ove; Louhelainen, Marjut; Finckenberg, Piet; Kaheinen, Petri; Muller, Dominik N; Luft, Friedrich C; Lapatto, Risto; Oresic, Matej

    2010-02-01

    Angiotensin II (Ang II) induces mitochondrial dysfunction. We tested whether Ang II alters the "metabolomic" profile. We harvested hearts from 8-week-old double transgenic rats harboring human renin and angiotensinogen genes (dTGRs) and controls (Sprague-Dawley), all with or without Ang II type 1 receptor (valsartan) blockade. We used gas chromatography coupled with time-of-flight mass spectrometry to detect 247 intermediary metabolites. We used a partial least-squares discriminate analysis and identified 112 metabolites that differed significantly after corrections (false discovery rate q <0.05). We found great differences in the use of fatty acids as an energy source, namely, decreased levels of octanoic, oleic, and linoleic acids in dTGR (all P<0.01). The increase in cardiac hypoxanthine levels in dTGRs suggested an increase in purine degradation, whereas other changes supported an increased ketogenic amino acid tyrosine level, causing energy production failure. The metabolomic profile of valsartan-treated dTGRs more closely resembled Sprague-Dawley rats than untreated dTGRs. Mitochondrial respiratory chain activity of cytochrome C oxidase was decreased in dTGRs, whereas complex I and complex II were unaltered. Mitochondria from dTGR hearts showed morphological alterations suggesting increased mitochondrial fusion. Cardiac expression of the redox-sensitive and the cardioprotective metabolic sensor sirtuin 1 was increased in dTGRs. Interestingly, valsartan changed the level of 33 metabolites and induced mitochondrial biogenesis in Sprague-Dawley rats. Thus, distinct patterns of cardiac substrate use in Ang II-induced cardiac hypertrophy are associated with mitochondrial dysfunction. The finding underscores the importance of Ang II in the regulation of mitochondrial biogenesis and cardiac metabolomics, even in healthy hearts.

  9. Angiotensin II potentiates α-adrenergic vasoconstriction in the elderly.

    PubMed

    Barrett-O'Keefe, Zachary; Witman, Melissa A H; McDaniel, John; Fjeldstad, Anette S; Trinity, Joel D; Ives, Stephen J; Conklin, Jamie D; Reese, Van; Runnels, Sean; Morgan, David E; Sander, Mikael; Richardson, Russell S; Wray, D Walter

    2013-03-01

    Aging is characterized by increased sympatho-excitation, expressed through both the α-adrenergic and RAAS (renin-angiotensin-aldosterone) pathways. Although the independent contribution of these two pathways to elevated vasoconstriction with age may be substantial, significant cross-talk exists that could produce potentiating effects. To examine this interaction, 14 subjects (n=8 young, n=6 old) underwent brachial artery catheterization for administration of AngII (angiotensin II; 0.8-25.6 ng/dl per min), NE [noradrenaline (norepinephrine); 2.5-80 ng/dl per min] and AngII with concomitant α-adrenergic antagonism [PHEN (phentolamine); 10 μg/dl per min]. Ultrasound Doppler was utilized to determine blood flow, and therefore vasoconstriction, in both infused and contralateral (control) limbs. Arterial blood pressure was measured directly, and sympathetic nervous system activity was assessed via microneurography and plasma NE analysis. AngII sensitivity was significantly greater in the old, indicated by both greater maximal vasoconstriction (-59±4% in old against -48±3% in young) and a decreased EC50 (half-maximal effective concentration) (1.4±0.2 ng/dl per min in old against 2.6±0.7 μg/dl per min in young), whereas the maximal NE-mediated vasoconstriction was similar between these groups (-58±9% in old and -62±5% in young). AngII also increased venous NE in the old group, but was unchanged in the young group. In the presence of α-adrenergic blockade (PHEN), maximal AngII-mediated vasoconstriction in the old was restored to that of the young (-43±8% in old and -39±6% in young). These findings indicate that, with healthy aging, the increased AngII-mediated vasoconstriction may be attributed, in part, to potentiation of the α-adrenergic pathway, and suggest that cross-talk between the RAAS and adrenergic systems may be an important consideration in therapeutic strategies targeting these two pathways.

  10. CD38 promotes angiotensin II-induced cardiac hypertrophy.

    PubMed

    Guan, Xiao-Hui; Hong, Xuan; Zhao, Ning; Liu, Xiao-Hong; Xiao, Yun-Fei; Chen, Ting-Tao; Deng, Li-Bin; Wang, Xiao-Lei; Wang, Jian-Bin; Ji, Guang-Ju; Fu, Mingui; Deng, Ke-Yu; Xin, Hong-Bo

    2017-03-12

    Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and regulated by various signalling pathways. Recently, we observed that mouse embryonic fibroblasts from CD38 knockout mice were significantly resistant to oxidative stress such as H2 O2 -induced injury and hypoxia/reoxygenation-induced injury. In addition, we also found that CD38 knockout mice protected heart from ischaemia reperfusion injury through activating SIRT1/FOXOs-mediated antioxidative stress pathway. However, the role of CD38 in cardiac hypertrophy is not explored. Here, we investigated the roles and mechanisms of CD38 in angiotensin II (Ang-II)-induced cardiac hypertrophy. Following 14 days of Ang-II infusion with osmotic mini-pumps, a comparable hypertension was generated in both of CD38 knockout and wild-type mice. However, the cardiac hypertrophy and fibrosis were much more severe in wild-type mice compared with CD38 knockout mice. Consistently, RNAi-induced knockdown of CD38 decreased the gene expressions of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) and reactive oxygen species generation in Ang-II-stimulated H9c2 cells. In addition, the expression of SIRT3 was elevated in CD38 knockdown H9c2 cells, in which SIRT3 may further activate the FOXO3 antioxidant pathway. The intracellular Ca(2+) release induced by Ang-II markedly decreased in CD38 knockdown H9c2 cells, which might be associated with the decrease of nuclear translocation of NFATc4 and inhibition of ERK/AKT phosphorylation. We concluded that CD38 plays an essential role in cardiac hypertrophy probably via inhibition of SIRT3 expression and activation of Ca(2+) -NFAT signalling pathway. Thus, CD38 may be a novel target for treating cardiac hypertrophy.

  11. p47(phox) is required for afferent arteriolar contractile responses to angiotensin II and perfusion pressure in mice.

    PubMed

    Lai, En Yin; Solis, Glenn; Luo, Zaiming; Carlstrom, Mattias; Sandberg, Kathryn; Holland, Steven; Wellstein, Anton; Welch, William J; Wilcox, Christopher S

    2012-02-01

    Myogenic and angiotensin contractions of afferent arterioles generate reactive oxygen species. Resistance vessels express neutrophil oxidase-2 and -4. Angiotensin II activates p47(phox)/neutrophil oxidase-2, whereas it downregulates NOX-4. Therefore, we tested the hypothesis that p47(phox) enhances afferent arteriolar angiotensin contractions. Angiotensin II infusion in p47(phox) +/+ but not -/- mice increased renal cortical NADPH oxidase activity (7±1-12±1 [P<0.01] versus 5±1-7±1 10(3) · RLU · min(-1) · μg protein(-1) [P value not significant]), mean arterial pressure (77±2-91±2 [P<0.005] versus 74±2-77±1 mm Hg [P value not significant]), and renal vascular resistance (7.5±0.4-10.1±0.7 [P<0.01] versus 7.9±0.4-8.3±0.4 mm Hg/mL · min(-1) · gram kidney weight(-1) [P value not significant]). Afferent arterioles from p47(phox) -/- mice had a lesser myogenic response (3.1±0.4 versus 1.4±0.2 dynes · cm(-1) · mm Hg(-1); P<0.02) and a lesser (P<0.05) contraction to 10(-6) M angiotensin II (diameter change +/+: 9.3±0.2-3.4±0.6 μm versus -/-: 9.9±0.6-7.5±0.4 μm). Angiotensin and increased perfusion pressure generated significantly (P<0.05) more reactive oxygen species in p47(phox) +/+ than -/- arterioles. Angiotensin II infusion increased the maximum responsiveness of afferent arterioles from p47(phox) +/+ mice to 10(-6) M angiotensin II yet decreased the response in p47(phox) -/- mice. The angiotensin infusion increased the sensitivity to angiotensin II only in p47(phox) +/+ mice. We conclude that p47(phox) is required to enhance renal NADPH oxidase activity and basal afferent arteriolar myogenic and angiotensin II contractions and to switch afferent arteriolar tachyphylaxis to sensitization to angiotensin during a prolonged angiotensin infusion. These effects likely contribute to hypertension and renal vasoconstriction during infusion of angiotensin II.

  12. 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.

  13. 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

  14. Signaling of angiotensin II-induced vascular protein synthesis in conduit and resistance arteries in vivo

    PubMed Central

    Daigle, Christine; Martens, Fabrice MAC; Girardot, Daphné; Dao, Huy Hao; Touyz, Rhian M; Moreau, Pierre

    2004-01-01

    Background From in vitro studies, it has become clear that several signaling cascades are involved in angiotensin II-induced cellular hypertrophy. The aim of the present study was to determine some of the signaling pathways mediating angiotensin II (Ang II)-induced protein synthesis in vivo in large and small arteries. Methods Newly synthesized proteins were labeled during 4 hours with tritiated leucine in conscious control animals, or animals infused for 24 hours with angiotensin II (400 ng/kg/min). Hemodynamic parameters were measure simultaneously. Pharmacological agents affecting signaling cascades were injected 5 hours before the end of Ang II infusion. Results Angiotensin II nearly doubled the protein synthesis rate in the aorta and small mesenteric arteries, without affecting arterial pressure. The AT1 receptor antagonist Irbesartan antagonized the actions of Ang II. The Ang II-induced protein synthesis was associated with increased extracellular signal-regulated kinases (ERK)1/2 phosphorylation in aortic, but not in mesenteric vessels. Systemic administration of PD98059, an inhibitor of the ERK-1/2 pathway, produced a significant reduction of protein synthesis rate in the aorta, and only a modest decrease in mesenteric arteries. Rapamycin, which influences protein synthesis by alternative signaling, had a significant effect in both vessel types. Rapamycin and PD98059 did not alter basal protein synthesis and had minimal effects on arterial pressure. Conclusion ERK1/2 and rapamycin-sensitive pathways are involved in pressure-independent angiotensin II-induced vascular protein synthesis in vivo. However, their relative contribution may vary depending on the nature of the artery under investigation. PMID:15134586

  15. RGS4 inhibits angiotensin II signaling and macrophage localization during renal reperfusion injury independent of vasospasm

    PubMed Central

    Pang, Paul; Jin, Xiaohua; Proctor, Brandon M.; Farley, Michelle; Roy, Nilay; Chin, Matthew S.; von Andrian, Ulrich H.; Vollmann, Elisabeth; Perro, Mario; Hoffman, Ryan J.; Chung, Joseph; Chauhan, Nikita; Mistri, Murti; Muslin, Anthony J.; Bonventre, Joseph V.; Siedlecki, Andrew M.

    2014-01-01

    Vascular inflammation is a major contributor to the severity of acute kidney injury. In the context of vasospasm-independent reperfusion injury we studied the potential anti-inflammatory role of the Gα-related RGS protein, RGS4. Transgenic RGS4 mice were resistant to 25 minute injury, although post-ischemic renal arteriolar diameter was equal to the wild type early after injury. A 10 minute unilateral injury was performed to study reperfusion without vasospasm. Eighteen hours after injury blood flow was decreased in the inner cortex of wild type mice with preservation of tubular architecture. Angiotensin II levels in the kidneys of wild type and transgenic mice were elevated in a sub-vasoconstrictive range 12 and 18 hours after injury. Angiotensin II stimulated pre-glomerular vascular smooth muscle cells (VSMC) to secrete the macrophage chemoattractant, RANTES; a process decreased by angiotensin II R2 (AT2) inhibition. However, RANTES increased when RGS4 expression was suppressed implicating Gα protein activation in an AT2-RGS4-dependent pathway. RGS4 function, specific to VSMC, was tested in a conditional VSMC-specific RGS4 knockout showing high macrophage density by T2 MRI compared to transgenic and non-transgenic mice after the 10 minute injury. Arteriolar diameter of this knockout was unchanged at successive time points after injury. Thus, RGS4 expression, specific to renal VSMC, inhibits angiotensin II-mediated cytokine signaling and macrophage recruitment during reperfusion, distinct from vasomotor regulation. PMID:25469849

  16. Intrarenal role of angiotensin II in controlling sodium excretion during dehydration in dogs.

    PubMed

    Trippodo, N C; Hall, J E; Lohmeier, T E; Guyton, A C

    1977-05-01

    1. The intrarenal role of angiotensin II in controlling sodium excretion was examined in anaesthetized, dehydrated dogs by infusing the angiotensin II antagonist Sar1-Ile8-angiotensin II directly into the renal artery. Comparisons were made with dehydrated dogs receiving only sodium chloride solution intrarenally. 2. Intrarenal angiotensin II blockade resulted in significant increases in urinary sodium excretion and urine flow rate. 3. The results indicate that during the high-renin state of dehydration endogenous angiotensin II has intrarenal effects which lead to salt and water retention.

  17. Angiotensin II induces differential insulin action in rat skeletal muscle.

    PubMed

    Surapongchai, Juthamard; Prasannarong, Mujalin; Bupha-Intr, Tepmanas; Saengsirisuwan, Vitoon

    2017-03-01

    Angiotensin II (ANGII) is reportedly involved in the development of skeletal muscle insulin resistance. The present investigation evaluated the effects of two ANGII doses on the phenotypic characteristics of insulin resistance syndrome and insulin action and signaling in rat skeletal muscle. Male Sprague-Dawley rats were infused with either saline (SHAM) or ANGII at a commonly used pressor dose (100 ng/kg/min; ANGII-100) or a higher pressor dose (500 ng/kg/min; ANGII-500) via osmotic minipumps for 14 days. We demonstrated that ANGII-100-infused rats exhibited the phenotypic features of non-obese insulin resistance syndrome, including hypertension, impaired glucose tolerance and insulin resistance of glucose uptake in the soleus muscle, whereas ANGII-500-treated rats exhibited diabetes-like symptoms, such as post-prandial hyperglycemia, impaired insulin secretion and hypertriglyceridemia. At the cellular level, insulin-stimulated glucose uptake in the soleus muscle of the ANGII-100 group was 33% lower (P < 0.05) than that in the SHAM group and was associated with increased insulin-stimulated IRS-1 Ser(307) and decreased Akt Ser(473) and AS160 Thr(642) phosphorylation and GLUT-4 expression. However, ANGII-500 infusion did not induce skeletal muscle insulin resistance or impair insulin signaling elements as initially anticipated. Moreover, we found that insulin-stimulated glucose uptake in the ANGII-500 group was accompanied by the enhanced expression of ACE2 and MasR proteins, which are the key elements in the non-classical pathway of the renin-angiotensin system. Collectively, this study demonstrates for the first time that chronic infusion with these two pressor doses of ANGII induced differential metabolic responses at both the systemic and skeletal muscle levels.

  18. Clinical Profile of Eprosartan: A Different Angiotensin II Receptor Blocker

    PubMed Central

    Blankestijn, P. J; Rupp, H

    2008-01-01

    Rationale. The goal of antihypertensive treatment is to reduce risk of cardiovascular morbidity and mortality. Apart from blood pressure lowering per se, also reducing the activities of the renin-angiotensin system and sympathetic nervous system appears to be important. Angiotensin II receptor blocker drugs (ARBs) have provided a useful class of anti-hypertensive drugs. Eprosartan is a relatively new ARB which is chemically distinct (non-biphenyl, non-tetrazole) from all other ARBs (biphenyl tetrazoles). An analysis has been made on available experimental and clinical data on eprosartan which not only is an effective and well tolerated antihypertensive agent, but also lowers the activities of the renin-angiotensin system and sympathetic nervous system. Experimental and pharmacokinetic studies on eprosartan have shown differences with the other ARBs. The distinct properties of this non-biphenyl, non-tetrazole ARB might be relevant in the effort to reduce cardiovascular risk, also beyond its blood pressure lowering capacity. PMID:18855637

  19. Captopril intake decreases body weight gain via angiotensin-(1-7).

    PubMed

    Oh, Young-Bin; Kim, Jong Hun; Park, Byung Mun; Park, Byung Hyun; Kim, Suhn Hee

    2012-09-01

    Angiotensin-(1-7) [Ang-(1-7)] plays a beneficial role in cardiovascular physiology by providing a counterbalance to the function of angiotensin II (Ang II). Although Ang II has been shown to be an adipokine secreted by adipocyte and affect lipid metabolism, the role of Ang-(1-7) in adipose tissue remains to be clarified. The aim of the present study was to investigate whether Ang-(1-7) affects lipid metabolism in adipose tissue. Ang-(1-7) increased glycerol release from primary adipocytes in a dose-dependent manner. A lipolytic effect of Ang-(1-7) was attenuated by pretreatment with A-779, a Mas receptor blocker and with an inhibitor of phosphoinositol 3-kinase (PI3K), or eNOS. However, losartan and PD123319 did not cause any change in Ang-(1-7)-induced lipolysis. Ang-(1-7)-induced lipolysis had an addictive effect with isoproterenol. In normal rats, chronic intake of captopril for 4 wks decreased body weight gain and the amount of adipose tissue and increased plasma Ang-(1-7) level. These effects were attenuated by administration of A-779. The levels of Mas receptor and phosphorylation of hormone-sensitive lipase (p-HSL) were significantly increased by treatment with captopril and these captopril-mediated effects were attenuated by the administration of A-779. There was no difference in diameter of adipocytes among sham, captopril- and captopril+A-779-treated groups. The similar effects of captopril on body weight, expression of Mas receptor, and p-HSL were observed in Ang-(1-7)-treated rats. These results suggest that captopril intake decreased body weight gain partly through Ang-(1-7)/Mas receptor/PI3K pathway.

  20. Reciprocal roles of angiotensin II and Angiotensin II Receptors Blockade (ARB) in regulating Cbfa1/RANKL via cAMP signaling pathway: possible mechanism for hypertension-related osteoporosis and antagonistic effect of ARB on hypertension-related osteoporosis.

    PubMed

    Guan, Xiao-Xu; Zhou, Yi; Li, Ji-Yao

    2011-01-01

    Hypertension is a risk factor for osteoporosis. Animal and epidemiological studies demonstrate that high blood pressure is associated with increased calcium loss, elevated parathyroid hormone, and increased calcium movement from bone. However, the mechanism responsible for hypertension-related osteoporosis remains elusive. Recent epidemiological studies indicate the benefits of Angiotensin II Receptors Blockade (ARB) on decreasing fracture risks. Since receptors for angiotensin II, the targets of ARB, are expressed in both osteoblasts and osteoclasts, we postulated that angiotensin II plays an important role in hypertension-related osteoporosis. Cbfa1 and RANKL, the important factors for maintaining bone homeostasis and key mediators in controlling osteoblast and osteoclast differentiation, are both regulated by cAMP-dependent signaling. Angiotensin II along with factors such as LDL, HDL, NO and homocysteine that are commonly altered both in hypertension and osteoporosis, can down-regulate the expression of Cbfa1 but up-regulate RANKL expression via the cAMP signaling pathway. We thus hypothesized that, by altering the ratio of Cbfa1/RANKL expression via the cAMP-dependent pathway, angiotensin II differently regulates osteoblast and osteoclast differentiation leading to enhanced bone resorption and reduced bone formation. Since ARB can antagonize the adverse effect of angiotensin II on bone by lowering cAMP levels and modifying other downstream targets, including LDL, HDL, NO and Cbfa1/RANKL, we propose the hypothesis that the antagonistic effects of ARB may also be exerted via cAMP signaling pathway.

  1. Central cardiovascular actions of angiotensin II in trout.

    PubMed

    Le Mével, Jean-Claude; Lancien, Frédéric; Mimassi, Nagi

    2008-05-15

    In mammals, a large body of evidence supports the existence of a brain renin-angiotensin system (RAS) acting independently or synergistically with the endocrine RAS to maintain diverse physiological functions, notably cardiovascular homeostasis. The RAS is of ancient origin and although most components of the RAS are present within the brain of teleost fishes, little is known regarding the central physiological actions of the RAS in these vertebrates. The present review encompasses the most relevant functional data for a role of the brain RAS in cardiovascular regulations in our experimental animal model, the unanesthetized trout Oncorhynchus mykiss. This paper mainly focuses on the central effect of angiotensin II (ANG II) on heart rate, blood pressure, heart rate variability and cardiac baroreflex, after intracerebroventricular injection or local microinjection of the peptide within the dorsal vagal motor nucleus. The probable implications of the parasympathetic nervous system in ANG II-evoked changes in the cardiac responses are also discussed.

  2. Role of α1D -adrenoceptors in vascular wall hypertrophy during angiotensin II-induced hypertension.

    PubMed

    Gallardo-Ortíz, I A; Rodríguez-Hernández, S N; López-Guerrero, J J; Del Valle-Mondragón, L; López-Sánchez, P; Touyz, R M; Villalobos-Molina, R

    2015-09-01

    The in vivo effect of continuous angiotensin II (Ang II) infusion on arterial blood pressure, vascular hypertrophy and α1 -adrenoceptors (α1 -ARs) expression was explored. Alzet(®) minipumps filled with Ang II (200 ng kg(-1)  min(-1) ) were subcutaneously implanted in male Wistar rats (3 months-old). Groups of rats were also treated with losartan, an AT1 R antagonist, or with BMY 7378, a selective α1D -AR antagonist. Blood pressure was measured by tail-cuff; after 2 or 4 weeks of treatment, vessels were isolated for functional and structural analyses. Angiotensin II increased systolic blood pressure. Phenylephrine-induced contraction in aorta was greater (40% higher) in Ang II-treated rats than in the controls, and similar effect occurred with KCl 80 mm. Responses in tail arteries were not significantly different among the different groups. Angiotensin II decreased α1D -ARs without modifying the other α1 -ARs and induced an increase in media thickness (hypertrophy) in aorta, while no structural change occurred in tail artery. Losartan prevented and reversed hypertension and hypertrophy, while BMY 7378 prevented and reversed the aorta's hypertrophic response, without preventing or reversing hypertension. Findings indicate that Ang II-induced aortic hypertrophic response involves Ang II-AT1 Rs and α1D -ARs. Angiotensin II-induced α1D -AR-mediated vascular remodeling occurs independently of hypertension. Findings identify a α1D -AR-mediated process whereby Ang II influences aortic hypertrophy independently of blood pressure elevation.

  3. 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.

  4. Metabolic switch and hypertrophy of cardiomyocytes following treatment with angiotensin II are prevented by AMP-activated protein kinase.

    PubMed

    Stuck, Bettina Johanna; Lenski, Matthias; Böhm, Michael; Laufs, Ulrich

    2008-11-21

    Angiotensin II induces cardiomyocyte hypertrophy, but its consequences on cardiomyocyte metabolism and energy supply are not completely understood. Here we investigate the effect of angiotensin II on glucose and fatty acid utilization and the modifying role of AMP-activated protein kinase (AMPK), a key regulator of metabolism and proliferation. Treatment of H9C2 cardiomyocytes with angiotensin II (Ang II, 1 microm, 4 h) increased [(3)H]leucine incorporation, up-regulated the mRNA expression of the hypertrophy marker genes MLC, ANF, BNP, and beta-MHC, and decreased the phosphorylation of the negative mTOR-regulator tuberin (TSC-2). Rat neonatal cardiomyocytes showed similar results. Western blot analysis revealed a time- and concentration-dependent down-regulation of AMPK-phosphorylation in the presence of angiotensin II, whereas the protein expression of the catalytic alpha-subunit remained unchanged. This was paralleled by membrane translocation of glucose-transporter type 4 (GLUT4), increased uptake of [(3)H]glucose and transient down-regulation of phosphorylation of acetyl-CoA carboxylase (ACC), whereas fatty acid uptake remained unchanged. Similarly, short-term transaortic constriction in mice resulted in down-regulation of P-AMPK and P-ACC but up-regulation of GLUT4 membrane translocation in the heart. Preincubation of cardiomyocytes with the AMPK stimulator 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR; 1 mM, 4 h) completely prevented the angiotensin II-induced cardiomyocytes hypertrophy. In addition, AICAR reversed the metabolic effects of angiotensin II: GLUT4 translocation was reduced, but ACC phosphorylation and TSC phosphorylation were elevated. In summary, angiotensin II-induced hypertrophy of cardiomyocytes is accompanied by decreased activation of AMPK, increased glucose uptake, and decreased mTOR inhibition. Stimulation with the AMPK activator AICAR reverses these metabolic changes, increases fatty acid utilization, and inhibits

  5. Angiotensin-(1-7) regulates Angiotensin II-induced VCAM-1 expression on vascular endothelial cells

    SciTech Connect

    Zhang, Feng; Ren, Jingyi; Chan, Kenneth; Chen, Hong

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer We for the first time found that Ang-(1-7) inhibits Ang II-induced VCAM-1 expression. Black-Right-Pointing-Pointer The inhibitory effect of Ang-(1-7) on VCAM-1 is mediated by MAS receptor. Black-Right-Pointing-Pointer The effect of Ang-(1-7) is due to the suppression of NF-kappaB translocation. -- Abstract: Angiotensin II (Ang II) and Angiotensin-(1-7) (Ang-(1-7)) are key effector peptides in the renin-angiotensin system. Increased circulatory Ang II level is associated with the development of hypertension and atherosclerosis, whereas Ang-(1-7) is a counter-regulatory mediator of Ang II which appears to be protective against cardiovascular disease. However, whether Ang-(1-7) regulates the action of Ang II on vascular endothelial cells (EC) remains unclear. We investigated the effects of Ang II and Ang-(1-7) in the context of atherogenesis, specifically endothelial cell VCAM-1 expression that is implicated in early plaque formation. The results show that Ang II increased VCAM-1 mRNA expression and protein displayed on EC surface, while Ang-(1-7) alone exerted no effects. However, Ang-(1-7) significantly suppressed Ang II-induced VCAM-1 expression. Ang-(1-7) also inhibited the Ang II-induced VCAM-1 promoter activity driven by transcription factor NF-KappaB. Furthermore, immunofluorescence assay and ELISA showed that Ang II facilitated the nuclear translocation of NF-kappaB in ECs, and this was attenuated by the presence of Ang-(1-7). The inhibitory effects of Ang-(1-7) on Ang II-induced VCAM-1 promoter activity and NF-kappaB nuclear translocation were all reversed by the competitive antagonist of Ang-(1-7) at the Mas receptor. Our results suggest that Ang-(1-7) mediates its affects on ECs through the Mas receptor, and negatively regulates Ang II-induced VCAM-1 expression by attenuating nuclear translocation of NF-kappaB.

  6. Angiotensin II type I receptor (AT1R) is an independent prognosticator of esophageal squamous cell carcinoma and promotes cells proliferation via mTOR activation

    PubMed Central

    Li, Shau-Hsuan; Lu, Hung-I; Chang, Alice Y.W.; Huang, Wan-Ting; Lin, Wei-Che; Lee, Ching-Chang; Tien, Wan-Yu; Lan, Ya-Chun; Tsai, Hsin-Ting; Chen, Chang-Han

    2016-01-01

    Background The aim of this study was to investigate the effects of the angiotensin II/ angiotensin II type I receptor (AT1R) and angiotensin II type II receptor (AT2R) signaling pathway in esophageal squamous cell carcinoma (ESCC). Methods Immunohistochemistry was performed to evaluate the expression levels of AT1R and AT2R in tissues from 152 surgically resected ESCC patients, and those expression levels were then correlated with treatment outcomes. The angiotensin II/AT1R/AT2R signaling pathway and its biological effects in the context of ESCC were investigated in vitro and in vivo. Results In human samples, AT1R overexpression was univariately associated with inferior overall survival and remained multivariately independent (hazard ratio=1.812). In vitro, angiotensin II stimulated the growth of ESCC cells in a dose-dependent manner. Treatment with irbesartan or AT1R-RNAi knockdown but not treatment with PD123319 significantly decreased the level of angiotensin II-induced ESCC cell proliferation. Angiotensin II also caused mTOR activation in a dose-dependent manner, and everolimus or mTOR-RNAi knockdown significantly suppressed the level of angiotensin II-induced ESCC cell proliferation. Furthermore, AT1R-RNAi knockdown suppressed the activation of mTOR. Clinically, AT1R expression was also correlated with phosphorylated mTOR expression. In a xenograft model, local angiotensin II injection enhanced tumor growth, and this effect could be decreased by treatment with irbesartan or everolimus. In a 4-NQO-induced-ESCC murine model, irbesartan significantly decreased the incidence of esophageal tumor. Conclusions These findings suggest that AT1R overexpression is an independent adverse prognosticator for patients with ESCC and that angiotensin II/AT1R signaling stimulates ESCC growth, in part through mTOR activation. PMID:27564102

  7. Local actions of angiotensin II: quantitative in vitro autoradiographic localization of angiotensin II receptor binding and angiotensin converting enzyme in target tissues

    SciTech Connect

    Chai, S.Y.; Allen, A.M.; Adam, W.R.; Mendelsohn, F.A.

    1986-01-01

    In order to gain insight into the local actions of angiotensin II (ANG II) we have determined the distribution of a component of the effector system for the peptide, the ANG II receptor, and that of an enzyme-catalysing ANG II formation, angiotensin converting enzyme (ACE), by in vitro autoradiography in several target tissues. The superagonist ANG II analog, /sup 125/I(Sar1)ANG II, or the antagonist analog, /sup 125/I(Sar1,Ile8)ANG II, were used as specific radioligands for ANG II receptors. A derivative of the specific ACE inhibitor, lysinopril, called /sup 125/I-351A, was used to label ACE in tissues. In the adrenal, a high density of ANG II receptors occurs in the glomerulosa zone of the cortex and in the medulla. ACE is also localized in these two zones, indicating that local production of ANG II may occur close to its sites of action in the zona glomerulosa and adrenal medulla. In the kidney, a high density of ANG II receptors is associated with glomeruli in the cortex and also with vasa recta bundles in the inner stripe of the outer medulla. ACE is found in very high concentration in deep proximal convoluted tubules of the cortex, while much lower concentrations of the enzyme occur in the vascular endothelium throughout the kidney. In the central nervous system three classes of relationships between ANG II receptors and ACE are observed: In the circumventricular organs, including the subfornical organ and organum vasculosum of the lamina terminalis, a high concentration of both components occurs. Since these structures have a deficient blood-brain barrier, local conversion of circulating angiotensin I (ANG I) to ANG II may contribute to the action of ANG II at these sites.

  8. 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

  9. Adhesion ability of angiotensin II with model membranes.

    PubMed

    Preu, Julia; Tiefenauer, Louis; Gutberlet, Thomas

    2017-02-01

    The octa-peptide angiotensin II (Ang II, (H2NAspArgValTyrIleHisProPheCOOH)) is one of the key player on blood pressure regulation in mammals. Predominantly binding to the Angiotensin type 1 and 2 receptors, the hormone is one of several peptide ligands binding to G protein coupled receptors (GPCR). The active hormone derives from a high molecular weight precursor sequentially cleaved by the proteases renin and the angiotensin converting enzyme (ACE). The chemical nature of the amino acid sequence has an impact on the behavior in the proximity of membranes, demonstrated using different membrane model systems and biophysical methods. Applying electrochemical impedance spectroscopy and small angle X-ray scattering a detailed view on the adhesion of the peptide with model membrane surfaces was performed. The role of specific amino acids involved in the interaction with the phospholipid head group were investigated and, studying a truncated version of Ang II, Ang (1-7), the key role of the C-terminal phenylalanine was proven. Truncation of the C-terminal amino acid abolishes the binding of the peptide to the membrane surface. A shift in pH, altering the protonation state of the central histidine residue impairs the adhesion of Ang II.

  10. Auto-inhibitory regulation of angiotensin II functionality in hamster aorta during the early phases of dyslipidemia.

    PubMed

    Pereira, Priscila Cristina; Pernomian, Larissa; Côco, Hariane; Gomes, Mayara Santos; Franco, João José; Marchi, Kátia Colombo; Hipólito, Ulisses Vilela; Uyemura, Sergio Akira; Tirapelli, Carlos Renato; de Oliveira, Ana Maria

    2016-06-15

    Emerging data point the crosstalk between dyslipidemia and renin-angiotensin system (RAS). Advanced dyslipidemia is described to induce RAS activation in the vasculature. However, the interplay between early dyslipidemia and the RAS remains unexplored. Knowing that hamsters and humans have a similar lipid profile, we investigated the effects of early and advanced dyslipidemia on angiotensin II-induced contraction. Cumulative concentration-response curves for angiotensin II (1.0pmol/l to 1.0µmol/l) were obtained in the hamster thoracic aorta. We also investigated the modulatory action of NAD(P)H oxidase on angiotensin II-induced contraction using ML171 (Nox-1 inhibitor, 0.5µmol/l) and VAS2870 (Nox-4 inhibitor, 5µmol/l). Early dyslipidemia was detected in hamsters treated with a cholesterol-rich diet for 15 days. Early dyslipidemia decreased the contraction induced by angiotensin II and the concentration of Nox-4-derived hydrogen peroxide. Advanced dyslipidemia, observed in hamsters treated with cholesterol-rich diet for 30 days, restored the contractile response induced by angiotensin II by compensatory mechanism that involves Nox-4-mediated oxidative stress. The hyporresponsiveness to angiotensin II may be an auto-inhibitory regulation of the angiotensinergic function during early dyslipidemia in an attempt to reduce the effects of the upregulation of the vascular RAS during the advanced stages of atherogenesis. The recovery of vascular angiotensin II functionality during the advanced phases of dyslipidemia is the result of the upregulation of redox-pro-inflammatory pathway that might be most likely involved in atherogenesis progression rather than in the recovery of vascular function. Taken together, our findings show the early phase of dyslipidemia may be the most favorable moment for effective atheroprotective therapeutic interventions.

  11. Comparative effects of contraction and angiotensin II on growth of adult feline cardiocytes in primary culture

    NASA Technical Reports Server (NTRS)

    Wada, H.; Zile, M. R.; Ivester, C. T.; Cooper, G. 4th; McDermott, P. J.

    1996-01-01

    The purposes of this study were 1) to determine whether angiotensin II causes growth of adult feline cardiocytes in long-term culture, 2) to compare the growth effects of angiotensin II with those resulting from electrically stimulated contraction, and 3) to determine whether the anabolic effects of contraction are exerted via the angiotensin type 1 receptor. Adult feline cardiocytes were cultured on laminin-coated trays in a serum-free medium. Cardiocytes were either electrically stimulated to contract (1 Hz, 5-ms pulse duration, alternating polarity) or were nonstimulated and quiescent. Quiescent cells were studied as controls and after treatment with angiotensin II (10(-8) M), losartan (10(-6) M; an angiotensin type 1-receptor antagonist), or angiotensin II plus losartan. Contracting cells were studied in the presence and absence of angiotensin II or losartan. In quiescent cardiocytes, angiotensin II treatment on day 7 significantly increased protein synthesis rates by 22% and protein content per cell by 17%. The effects of angiotensin II were completely blocked by losartan. Electrically stimulated contraction on days 4 and 7 in culture significantly increased protein synthesis rate by 18 and 38% and protein content per cell by 19 and 46%, respectively. Angiotensin II treatment did not further increase protein synthesis rate or protein content in contracting cardiocytes. Furthermore, losartan did not block the anabolic effects of contraction on protein synthesis rates or protein content. In conclusion, angiotensin II can exert a modest anabolic effect on adult feline cardiocytes in culture. In contracting feline cardiocytes, angiotensin II has no effect on growth. Growth caused by electrically stimulated contraction occurs more rapidly and is greater in magnitude than that caused by angiotensin II. Growth of contracting adult feline cardiocytes is not dependent on activation of the angiotensin receptor.

  12. Myometrial angiotensin II receptor subtypes change during ovine pregnancy.

    PubMed Central

    Cox, B E; Ipson, M A; Shaul, P W; Kamm, K E; Rosenfeld, C R

    1993-01-01

    Although regulation of angiotensin II receptor (AT) binding in vascular and uterine smooth muscle is similar in nonpregnant animals, studies suggest it may differ during pregnancy. We, therefore, examined binding characteristics of myometrial AT receptors in nulliparous (n = 7), pregnant (n = 24, 110-139 d of gestation), and postpartum (n = 21, 5 to > or = 130 d) sheep and compared this to vascular receptor binding. We also determined if changes in myometrial binding reflect alterations in receptor subtype. By using plasma membrane preparations from myometrium and medial layer of abdominal aorta, we determined receptor density and affinity employing radioligand binding; myometrial AT receptor subtypes were assessed by inhibiting [125I]-ANG II binding with subtype-specific antagonists. Compared to nulliparous ewes, myometrial AT receptor density fell approximately 90% during pregnancy (1,486 +/- 167 vs. 130 +/- 16 fmol/mg protein) and returned to nulliparous values > or = 4 wk postpartum; vascular binding was unchanged. Nulliparous myometrium expressed predominantly AT2 receptors (AT1/AT2 congruent to 15%/85%), whereas AT1 receptors predominated during pregnancy (AT1/AT2 congruent to 80%/20%). By 5 d postpartum AT1/AT2 congruent to 40%/60%, and > 4 wk postpartum AT2 receptors again predominated (AT1/AT2 congruent to 15%/85%). In studies of ANG II-induced force generation, myometrium from pregnant ewes (n = 10) demonstrated dose-dependent increases in force (P < 0.001), which were inhibited with an AT1 receptor antagonist. Postpartum myometrial responses were less at doses > or = 10(-9) M (P < 0.05) and unaffected by AT2 receptor antagonists. Vascular and myometrial AT receptor binding are differentially regulated during ovine pregnancy, the latter primarily reflecting decreases in AT2 receptor expression. This is the first description of reversible changes in AT receptor subtype in adult mammals. PMID:8227339

  13. Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia

    PubMed Central

    Burke, Suzanne D.; Zsengellér, Zsuzsanna K.; Khankin, Eliyahu V.; Lo, Agnes S.; Rajakumar, Augustine; DuPont, Jennifer J.; McCurley, Amy; Moss, Mary E.; Zhang, Dongsheng; Clark, Christopher D.; Seely, Ellen W.; Kang, Peter M.; Stillman, Isaac E.; Jaffe, Iris Z.

    2016-01-01

    Preeclampsia is a hypertensive disorder of pregnancy in which patients develop profound sensitivity to vasopressors, such as angiotensin II, and is associated with substantial morbidity for the mother and fetus. Enhanced vasoconstrictor sensitivity and elevations in soluble fms-like tyrosine kinase 1 (sFLT1), a circulating antiangiogenic protein, precede clinical signs and symptoms of preeclampsia. Here, we report that overexpression of sFlt1 in pregnant mice induced angiotensin II sensitivity and hypertension by impairing endothelial nitric oxide synthase (eNOS) phosphorylation and promoting oxidative stress in the vasculature. Administration of the NOS inhibitor l-NAME to pregnant mice recapitulated the angiotensin sensitivity and oxidative stress observed with sFlt1 overexpression. Sildenafil, an FDA-approved phosphodiesterase 5 inhibitor that enhances NO signaling, reversed sFlt1-induced hypertension and angiotensin II sensitivity in the preeclampsia mouse model. Sildenafil treatment also improved uterine blood flow, decreased uterine vascular resistance, and improved fetal weights in comparison with untreated sFlt1-expressing mice. Finally, sFLT1 protein expression inversely correlated with reductions in eNOS phosphorylation in placental tissue of human preeclampsia patients. These data support the concept that endothelial dysfunction due to high circulating sFLT1 may be the primary event leading to enhanced vasoconstrictor sensitivity that is characteristic of preeclampsia and suggest that targeting sFLT1-induced pathways may be an avenue for treating preeclampsia and improving fetal outcomes. PMID:27270170

  14. Angiotensin-(1-7) blocks the angiotensin II-stimulated superoxide production.

    PubMed

    Polizio, Ariel Héctor; Gironacci, Mariela Mercedes; Tomaro, Maria Luján; Peña, Clara

    2007-07-01

    Angiotensin (Ang)-(1-7), a bioactive compound of the renin-angiotensin system, exerts effects leading to blood pressure reduction which counterbalance Ang II pressor actions. The present study was conducted to examine Ang-(1-7) and Ang II effects on superoxide anion production in rat aorta using the lucigenin chemiluminescence method. Ang II dose-dependently increased superoxide anion formation when compared to control levels; a maximal increase (2.5-fold) was observed with 1 x 10(-10)M peptide concentration. The Ang II-stimulated superoxide formation was blocked by 1 x 10(-10)M losartan, the specific AT(1) receptor antagonist, but not by 1 x 10(-10)M PD 123319, the AT(2) receptor antagonist, suggesting that the increased superoxide levels caused by Ang II are mediated through AT(1) receptors activation. The Ang II-stimulated superoxide production was not modified by 2 x 10(-8)M allopurinol or 1 x 10(-7)M indomethacin, but was completely abolished by NAD(P)H oxidase inhibitors: 1 x 10(-8)M diphenylene iodonium, or 2 x 10(-8)M apocynin, demonstrating that NAD(P)H oxidase participates in such response. In contrast to Ang II, Ang-(1-7) concentrations ranging 1 x 10(-12) to 1 x 10(-6)M did not modify superoxide anion levels, but prevented the Ang II-enhanced superoxide production. In conclusion, we demonstrated that Ang-(1-7) blocks the pro-oxidant effects of Ang II, thus reducing the superoxide anion production and delaying the hypertension development.

  15. Angiotensin II type 2 receptors and nitric oxide sustain oxygenation in the clipped kidney of early Goldblatt hypertensive rats.

    PubMed

    Palm, Fredrik; Connors, Stephanie G; Mendonca, Margarida; Welch, William J; Wilcox, Christopher S

    2008-02-01

    Angiotensin-converting enzyme inhibitors (ACEIs) decrease the glomerular filtration rate and renal blood flow in the clipped kidneys of early 2-kidney, 1-clip Goldblatt hypertensive rats, but the consequences for oxygenation are unclear. We investigated the hypothesis that angiotensin II type 1 or angiotensin II type 2 receptors or NO synthase mediate renal oxygenation responses to ACEI. Three weeks after left renal artery clipping, kidney function, oxygen (O(2)) use, renal blood flow, renal cortical blood flow, and renal cortical oxygen tension (Po(2)) were measured after acute administration of an ACEI (enalaprilat) and after acute administration of ACEI following acute administration of an angiotensin II type 1 or angiotensin II type 2 receptor blocker (candesartan or PD-123,319) or an NO synthase blocker (N(G)-nitro-L-arginine methyl ester with control of renal perfusion pressure) and compared with mechanical reduction in renal perfusion pressure to the levels after ACEI. The basal renal cortical Po(2) of clipped kidneys was significantly lower than contralateral kidneys (35+/-1 versus 51+/-1 mm Hg; n=40 each). ACEI lowered renal venous Po(2), cortical Po(2), renal blood flow, glomerular filtration rate, and cortical blood flow and increased the renal vascular resistance in the clipped kidney, whereas mechanical reduction in renal perfusion pressure was ineffective. PD-123,319 and N(G)-nitro-L-arginine methyl ester, but not candesartan, reduced the Po(2) of clipped kidneys and blocked the fall in Po(2) with acute ACEI administration. In conclusion, oxygen availability in the clipped kidney is maintained by angiotensin II generation, angiotensin II type 2 receptors, and NO synthase. This discloses a novel mechanism whereby angiotensin can prevent hypoxia in a kidney challenged with a reduced perfusion pressure.

  16. Long-term regulation of arterial pressure, glomerular filtration and renal sodium reabsorption by angiotensin II in dogs.

    PubMed

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

    1980-12-01

    1. This study was designed to quantify the role of angiotensin II in determining the chronic relationships between arterial pressure, renal haemodynamics and sodium excretion. 2. In six control dogs sodium balance was achieved during chronic increases in sodium intake from 5 to 495 mmol/day with small increases in arterial pressure (7mmHg), moderate increases in glomerular filtration rate (19%) and decreases in filtration fraction. Similar increases in sodium intake in dogs whose circulating levels of angiotensin II were fixed, due to a constant intravenous infusion of 4.85 pmol of angiotensin II min-1 kg-1, caused large increases in arterial pressure (42%), glomerular filtration rate (31%), filtration fraction and calculated renal sodium reabsorption above control. In six dogs whose angiotensin II formation was blocked by SQ 14 225, sodium balance at intakes of 5-80 mmol/day occurred at reduced arterial pressure, glomerular filtration rate, filtration fraction and sodium reabsorption although plasma aldosterone concentration was not substantially different from that in control dogs. At sodium intakes above 240 mmoL/day arterial pressure was not altered by SQ 14 225. 3. These data indicate that during chronic variations in sodium intake angiotensin II plays a major role, independently of changes in plasma aldosterone concentration, in allowing sodium balance without large fluctuations in glomerular filtration rate or arterial pressure. The mechanism whereby angiotensin II conserves sodium chronically is through increased sodium reabsorption, since steady-state sodium reabsorption was increased by angiotensin II and decreased by SQ 14 225.

  17. Photoreleasable ligands to study intracrine angiotensin II signalling

    PubMed Central

    Tadevosyan, Artavazd; Létourneau, Myriam; Folch, Benjamin; Doucet, Nicolas; Villeneuve, Louis R; Mamarbachi, Aida M; Pétrin, Darlaine; Hébert, Terence E; Fournier, Alain; Chatenet, David; Allen, Bruce G; Nattel, Stanley

    2015-01-01

    Several lines of evidence suggest that intracellular angiotensin II (Ang-II) contributes to the regulation of cardiac contractility, renal salt reabsorption, vascular tone and metabolism; however, work on intracrine Ang-II signalling has been limited to indirect approaches because of a lack of selective intracellularly-acting probes. Here, we aimed to synthesize and characterize cell-permeant Ang-II analogues that are inactive without uncaging, but release active Ang-II upon exposure to a flash of UV-light, and act as novel tools for use in the study of intracrine Ang-II physiology. We prepared three novel caged Ang-II analogues, [Tyr(DMNB)4]Ang-II, Ang-II-ODMNB and [Tyr(DMNB)4]Ang-II-ODMNB, based upon the incorporation of the photolabile moiety 4,5-dimethoxy-2-nitrobenzyl (DMNB). Compared to Ang-II, the caged Ang-II analogues showed 2–3 orders of magnitude reduced affinity toward both angiotensin type-1 (AT1R) and type-2 (AT2R) receptors in competition binding assays, and greatly-reduced potency in contraction assays of rat thoracic aorta. After receiving UV-irradiation, all three caged Ang-II analogues released Ang-II and potently induced the contraction of rat thoracic aorta. [Tyr(DMNB)4]Ang-II showed the most rapid photolysis upon UV-irradiation and was the focus of subsequent characterization. Whereas Ang-II and photolysed [Tyr(DMNB)4]Ang-II increased ERK1/2 phosphorylation (via AT1R) and cGMP production (AT2R), caged [Tyr(DMNB)4]Ang-II did not. Cellular uptake of [Tyr(DMNB)4]Ang-II was 4-fold greater than that of Ang-II and significantly greater than uptake driven by the positive-control HIV TAT(48–60) peptide. Intracellular photolysis of [Tyr(DMNB)4]Ang-II induced an increase in nucleoplasmic Ca2+ ([Ca2+]n), and initiated 18S rRNA and nuclear factor kappa B mRNA synthesis in adult cardiac cells. We conclude that caged Ang-II analogues represent powerful new tools for use in the selective study of intracrine signalling via Ang-II. PMID:25433071

  18. Angiotensin I conversion to angiotensin II stimulates cortical collecting duct sodium transport.

    PubMed

    Komlosi, Peter; Fuson, Amanda L; Fintha, Attila; Peti-Peterdi, János; Rosivall, Laszlo; Warnock, David G; Bell, Phillip Darwin

    2003-08-01

    Angiotensin (Ang) II directly stimulates epithelial sodium channel activity in the rabbit cortical collecting duct. Because Ang I and converting enzyme analogues might be present in the distal nephron, this raises the possibility of intraluminal generation of Ang II. Conversion of Ang I to Ang II was monitored by Ang II-dependent changes in intracellular sodium concentration as a reflection of sodium transport across the apical membrane. This involved imaging-based fluorescence microscopy with sodium-binding benzofuran isophthalate in isolated, perfused, cortical collecting-duct segments from rabbit kidney. Principal and intercalated cells were differentiated by rhodamine-conjugated peanut lectin. Control principal cell intracellular sodium concentration, during perfusion with 25 mmol/L NaCl and zero sodium in the bath plus monensin (10(-5) mol/L) averaged 5.8+/-0.14 mmol/L (n=156). The increase in intracellular sodium concentration, when luminal NaCl was increased from 25 to 150 mmol/L, was elevated by 3.5-fold in the presence of intraluminal Ang I (10(-6) mol/L). Also, the effects of Ang I on sodium transport were not significantly different from the effects of Ang II (10(-9) mol/L). Ang I was used in micromolar concentrations to ensure that there was sufficient substrate available for conversion to Ang II. Inhibition of the angiotensin-converting enzyme with captopril reduced the stimulatory effect of Ang I. These results suggest that intraluminal conversion of Ang I to Ang II can occur in the cortical collecting duct, resulting in enhanced apical sodium entry.

  19. Angiotensin II protects cultured midbrain dopaminergic neurons against rotenone-induced cell death.

    PubMed

    Grammatopoulos, Tom N; Ahmadi, Ferogh; Jones, Susan M; Fariss, Marc W; Weyhenmeyer, James A; Zawada, W Michael

    2005-05-31

    In this study, we demonstrate that angiotensin II (Ang II) protects dopamine (DA) neurons from rotenone toxicity in vitro. Primary ventral mesencephalic (VM) cultures from E15 rats were grown for 5 days and then cultured in the presence of the mitochondrial complex I inhibitor, rotenone. Acute exposure (20 h) to 20 nM rotenone reduced the number of tyrosine hydroxylase-positive (TH+) neurons by 50 +/- 6% when compared to untreated cultures. Pre-treatment of VM cultures with 100 nM Ang II decreased TH+ neuronal loss to 25 +/- 10% at the 20-nM rotenone concentration. Ang II in the presence of the angiotensin type 1 receptor (AT1R) antagonist, losartan, was even more effective in protecting DA neurons showing a loss of only 13 +/- 4% at 20 nM rotenone. Conversely, the AT2R antagonist, PD123319, abolished the protective effects of Ang II. Furthermore, both the NMDA receptor antagonist, MK801, and the antioxidant, alpha-tocopheryl succinate (vitamin E analogue), prevented rotenone-induced toxicity. Here, we show that acute exposure of VM cultures to the pesticide rotenone leads to dopaminergic neuronal cell death and that angiotensin acting through the AT2 receptor protects dopamine neurons from rotenone toxicity.

  20. Angiotensin II Increased Neuronal Stem Cell Proliferation: Role of AT2R

    PubMed Central

    Chao, Jie; Yang, Lu; Buch, Shilpa; Gao, Lie

    2013-01-01

    Angiotensin II (Ang II), known a potent vasoactive substance in the renin-angiotensin system in the brain, plays a critical role in systemic blood pressure control. However, increasing evidence indicated that the physiological role of Ang II go beyond its vasoactive effect. In the present study, we demonstrated that Ang II type-1 receptor (AT1R) and type-2 receptor (AT2R) were expressed in primary rat hippocampal neuronal stem cells (NSCs). Treatment of rat hippocampal NSCs with Ang II increased cell proliferation. Pretreatment of NSCs with specific AT2R, but not AT1R, antagonist significantly suppressed Ang II-induced cell proliferation. Furthermore, Ang II stimulated ERK and Akt phosphorylation in NSCs. Pretreatment of MEK inhibitor, but not PI3K inhibitor, inhibited Ang II-induced ERK phosphorylation as well as cell proliferation. In addition, stimulation of NSCs with Ang II decreased expression of KV 1.2/KV 3.1 channels and blocked K+ currents which lie downstream of ERK activation. Taken together, these findings underpin the role of AT2R as a novel target that regulates cell proliferation mediated by Ang II with implications for therapeutic intervention for regulation of neurogenesis. PMID:23691054

  1. The effect of sublingual captopril versus intravenous enalaprilat on angiotensin II plasma levels.

    PubMed

    van Onzenoort, Hein A; Bussink, Michiel; Menheere, Paul P; van Mook, Walther N; van der Kuy, Paul-Hugo M

    2006-06-01

    A 44-year-old woman, with a history of familial adenomatous polyposis, complicated by carcinoma of the colon, for which a proctocolectomy had been performed, now presented with metastasis located in the pancreas. Treatment consisted of chemotherapy followed by a partial pancreaticoduodenectomy. Due to ischemia, resection of the small intestines was performed the same day. After admission, a transesophageal echocardiography showed an ejection fraction of 40%. Because enteral administration of drugs was impossible, intravenous enalaprilat 2 mg once a day for 1 day followed by sublingual captopril 25 mg twice a day were started. Blood samples were taken before and after administration. After 1 day of sublingual captopril treatment the angiotensin II level decreased with more than 50%, comparable to the decrease seen after intravenous administration of enalaprilat. Sublingual captopril has been used in the treatment of hypertensive crisis and heart failure. Although frequently reported, no study has investigated the effect on angiotensin II levels after sublingual administration in heart failure patients. This case-report demonstrated that sublingual administration of 25 mg captopril twice a day yielded a considerable decrease in angiotensin II plasma levels which was comparable to the effect seen after an intravenous administration of 2 mg enalaprilat.

  2. Osthole Alleviates Bleomycin-Induced Pulmonary Fibrosis via Modulating Angiotensin-Converting Enzyme 2/Angiotensin-(1-7) Axis and Decreasing Inflammation Responses in Rats.

    PubMed

    Hao, Yuewen; Liu, Yan

    2016-01-01

    Studies have shown that angiotensin-converting enzyme 2 (ACE2) plays modulating roles in lung pathophysiology, including pulmonary fibrosis (PF) and acute lung injury. Pulmonary fibrosis is a common complication in these interstitial lung diseases, and PF always has a poor prognosis and short survival. To date, there are few promising methods for treating PF, and they are invariably accompanied by severe side effects. Recent studies have showed that the traditional Chinese herbal extract, osthole, had beneficial effects on lipopolysaccharide (LPS) induced acute lung injury (ALI) via an ACE2 pathway. Here we further investigated the protective effects of osthole on bleomycin induced pulmonary fibrosis and attempted to determine the underlying mechanism. PF mode rats were induced by bleomycin (BLM) and then subsequently administered osthole. Histopathological analyses were employed to identify PF changes. The results showed that BLM resulted in severe PF and diffuse lung inflammation, together with significant elevation of inflammatory factors and a marked increase in expression of angiotensin II (ANG II) and transforming growth factor-beta 1 (TGF-β1). ACE2 and angiotensin-(1-7) [ANG-(1-7)] were both greatly reduced after BLM administration. Meanwhile, osthole treatment attenuated BLM induced PF and inflammation, decreased the expression of these inflammatory mediators, ANG II, and TGF-β1, and reversed ACE2 and ANG-(1-7) production in rat lungs. We conclude that osthole may exert beneficial effects on BLM induced PF in rats, perhaps via modulating the ACE2/ANG-(1-7) axis and inhibiting lung inflammation pathways.

  3. Neurorestoration after traumatic brain injury through angiotensin II receptor blockage.

    PubMed

    Villapol, Sonia; Balarezo, María G; Affram, Kwame; Saavedra, Juan M; Symes, Aviva J

    2015-11-01

    See Moon (doi:10.1093/awv239) for a scientific commentary on this article.Traumatic brain injury frequently leads to long-term cognitive problems and physical disability yet remains without effective therapeutics. Traumatic brain injury results in neuronal injury and death, acute and prolonged inflammation and decreased blood flow. Drugs that block angiotensin II type 1 receptors (AT1R, encoded by AGTR1) (ARBs or sartans) are strongly neuroprotective, neurorestorative and anti-inflammatory. To test whether these drugs may be effective in treating traumatic brain injury, we selected two sartans, candesartan and telmisartan, of proven therapeutic efficacy in animal models of brain inflammation, neurodegenerative disorders and stroke. Using a validated mouse model of controlled cortical impact injury, we determined effective doses for candesartan and telmisartan, their therapeutic window, mechanisms of action and effect on cognition and motor performance. Both candesartan and telmisartan ameliorated controlled cortical impact-induced injury with a therapeutic window up to 6 h at doses that did not affect blood pressure. Both drugs decreased lesion volume, neuronal injury and apoptosis, astrogliosis, microglial activation, pro-inflammatory signalling, and protected cerebral blood flow, when determined 1 to 3 days post-injury. Controlled cortical impact-induced cognitive impairment was ameliorated 30 days after injury only by candesartan. The neurorestorative effects of candesartan and telmisartan were reduced by concomitant administration of the peroxisome proliferator-activated receptor gamma (PPARγ, encoded by PPARG) antagonist T0070907, showing the importance of PPARγ activation for the neurorestorative effect of these sartans. AT1R knockout mice were less vulnerable to controlled cortical impact-induced injury suggesting that the sartan's blockade of the AT1R also contributes to their efficacy. This study strongly suggests that sartans with dual AT1R blocking and

  4. Neurorestoration after traumatic brain injury through angiotensin II receptor blockage

    PubMed Central

    Balarezo, María G.; Affram, Kwame; Saavedra, Juan M.; Symes, Aviva J.

    2015-01-01

    See Moon (doi:10.1093/awv239) for a scientific commentary on this article. Traumatic brain injury frequently leads to long-term cognitive problems and physical disability yet remains without effective therapeutics. Traumatic brain injury results in neuronal injury and death, acute and prolonged inflammation and decreased blood flow. Drugs that block angiotensin II type 1 receptors (AT1R, encoded by AGTR1) (ARBs or sartans) are strongly neuroprotective, neurorestorative and anti-inflammatory. To test whether these drugs may be effective in treating traumatic brain injury, we selected two sartans, candesartan and telmisartan, of proven therapeutic efficacy in animal models of brain inflammation, neurodegenerative disorders and stroke. Using a validated mouse model of controlled cortical impact injury, we determined effective doses for candesartan and telmisartan, their therapeutic window, mechanisms of action and effect on cognition and motor performance. Both candesartan and telmisartan ameliorated controlled cortical impact-induced injury with a therapeutic window up to 6 h at doses that did not affect blood pressure. Both drugs decreased lesion volume, neuronal injury and apoptosis, astrogliosis, microglial activation, pro-inflammatory signalling, and protected cerebral blood flow, when determined 1 to 3 days post-injury. Controlled cortical impact-induced cognitive impairment was ameliorated 30 days after injury only by candesartan. The neurorestorative effects of candesartan and telmisartan were reduced by concomitant administration of the peroxisome proliferator-activated receptor gamma (PPARγ, encoded by PPARG) antagonist T0070907, showing the importance of PPARγ activation for the neurorestorative effect of these sartans. AT1R knockout mice were less vulnerable to controlled cortical impact-induced injury suggesting that the sartan’s blockade of the AT1R also contributes to their efficacy. This study strongly suggests that sartans with dual AT1R blocking

  5. Rosuvastatin prevents angiotensin II-induced vascular changes by inhibition of NAD(P)H oxidase and COX-1

    PubMed Central

    Colucci, Rocchina; Fornai, Matteo; Duranti, Emiliano; Antonioli, Luca; Rugani, Ilaria; Aydinoglu, Fatma; Ippolito, Chiara; Segnani, Cristina; Bernardini, Nunzia; Taddei, Stefano; Blandizzi, Corrado; Virdis, Agostino

    2013-01-01

    Background and Purpose NAD(P)H oxidase and COX-1 participate in vascular damage induced by angiotensin II. We investigated the effect of rosuvastatin on endothelial dysfunction, vascular remodelling, changes in extracellular matrix components and mechanical properties of small mesenteric arteries from angiotensin II-infused rats. Experimental Approach Male rats received angiotensin II (120 ng·kg−1·min−1, subcutaneously) for 14 days with or without rosuvastatin (10 mg·kg−1·day−1, oral gavage) or vehicle. Vascular functions and morphological parameters were assessed by pressurized myography. Key Results In angiotensin II-infused rats, ACh-induced relaxation was attenuated compared with controls, less sensitive to L-NAME, enhanced by SC-560 (COX-1 inhibitor) or SQ-29548 (prostanoid TP receptor antagonist), and normalized by the antioxidant ascorbic acid or NAD(P)H oxidase inhibitors. After rosuvastatin, relaxations to ACh were normalized, fully sensitive to L-NAME, and no longer affected by SC-560, SQ-29548 or NAD(P)H oxidase inhibitors. Angiotensin II enhanced intravascular superoxide generation, eutrophic remodelling, collagen and fibronectin depositions, and decreased elastin content, resulting in increased vessel stiffness. All these changes were prevented by rosuvastatin. Angiotensin II increased phosphorylation of NAD(P)H oxidase subunit p47phox and its binding to subunit p67phox, effects inhibited by rosuvastatin. Rosuvastatin down-regulated vascular Nox4/NAD(P)H isoform and COX-1 expression, attenuated the vascular release of 6-keto-PGF1α, and enhanced copper/zinc-superoxide dismutase expression. Conclusion and Implications Rosuvastatin prevents angiotensin II-induced alterations in resistance arteries in terms of function, structure, mechanics and composition. These effects depend on restoration of NO availability, prevention of NAD(P)H oxidase-derived oxidant excess, reversal of COX-1 induction and its prostanoid production, and stimulation of

  6. Postjunctional regulation by angiotensin II of alpha 1-adrenoceptor-mediated pressor responses in the rat.

    PubMed

    Marano, G; Argiolas, L

    1994-08-11

    The effects of angiotensin II on the vasopressor responses to the selective alpha 1-adrenoceptor agonist, phenylephrine, in intact and sympathectomized rats were investigated. Infusion of angiotensin II at subpressor doses significantly enhanced the pressor effects of phenylephrine in intact rats. We also found that in the chemically sympathectomized rat, where prejunctional sympathetic function is impaired, the effects of angiotensin II infusion on the pressor effects of phenylephrine were similar to those obtained in intact rats. Furthermore, pretreatment with valsartan ((S)-N-valeryl-N-([2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl)-val ine), a new selective angiotensin AT1 receptor antagonist, antagonized the effects of angiotensin II on phenylephrine-mediated pressor responses, whereas the administration of the selective angiotensin AT2 receptor antagonist, PD 123319 (1-[[4-(dimethylamino)-3-methylphenyl]-methyl]-5-(diphenylacetyl)- 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]-pyridine-6-carboxylic acid, ditriflouroacetate, monohydrate), injected in bolus doses of 100 micrograms/kg, did not antagonize the enhancing effect of angiotensin II. Collectively, these data suggest that angiotensin II modulates the response to phenylephrine primarily at a postjunctional level through the activation of angiotensin AT1 receptors and that the suggested prejunctional facilitation mediated by angiotensin receptors is quantitatively much less important in the intact animal.

  7. 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

  8. The Cooperative Effect of Local Angiotensin-II in Liver with Adriamycin Hepatotoxicity on Mitochondria

    PubMed Central

    Taskin, Eylem; Guven, Celal; Sahin, Leyla; Dursun, Nurcan

    2016-01-01

    Background Adriamycin (ADR) is a drug used clinically for anticancer treatment; however, it causes adverse effects in the liver. The mechanism by which these adverse effects occur remains unclear, impeding efforts to enhance the therapeutic effects of ADR. Its hepatotoxicity might be related to increasing reactive oxygen species (ROS) and mitochondrial dysfunction. The interaction between ADR and the local renin-angiotensin system (RAS) in the liver is unclear. ADR might activate the RAS. Angiotensin-II (Ang-II) leads to ROS production and mitochondrial dysfunction. In the present study we investigated whether ADR’s hepatotoxicity interacts with local RAS in causing oxidative stress resulting from mitochondrial dysfunction in the rat liver. Material/Methods Rats were divided into 5 groups: control, ADR, co-treated ADR with captopril, co-treated ADR with Aliskiren, and co-treated ADR with both captopril and Aliskiren. Mitochondria and cytosol were separated from the liver, then biochemical measurements were made from them. Mitochondrial membrane potential (MMP) and ATP levels were evaluated. Results ADR remarkably decreased MMP and ATP in liver mitochondria (p<0.05). Co-administration with ADR and Aliskiren and captopril improved the dissipation of MMP (p<0.05). The decreased ATP level was restored by treatment with inhibitors of ACE and renin. Conclusions Angiotensin-II may contribute to hepatotoxicity of in the ADR via mitochondrial oxidative production, resulting in the attenuation of MMP and ATP production. PMID:27019222

  9. Angiotensin II-related hypertension and eye diseases

    PubMed Central

    Marin Garcia, Pablo Jesus; Marin-Castaño, Maria Encarna

    2014-01-01

    Systemic vascular disease, especially hypertension, has been suspected as a risk factor for some eye diseases including, diabetic retinopathy and age-related macular degeneration. Hypertension can contribute to chronic diseases by hemodynamic injury and/or cellular actions induced by hypertension-related hormones or growth factors. Among the most important is Angiotensin II (Ang II), which controls blood pressure and induces different cellular functions that may be dependent or independent of its effect on blood pressure. Importantly, as is true for heart, kidney and other organs, the renin-angiotensin system (RAS) is present in the eye. So, even in the absence of hypertension, local production of Ang II could be involved in eye diseases. The goal of this manuscript is to review the most relevant scientific evidence supporting the role of the RAS activation, in the development of age-related macular degeneration and diabetic retinopathy, and highlight the importance of Ang II in the etiology of these diseases. PMID:25276298

  10. Inhibition of Angiotensin Converting Enzyme, Angiotensin II Receptor Blocking, and Blood Pressure Lowering Bioactivity across Plant Families.

    PubMed

    Patten, Glen S; Abeywardena, Mahinda Y; Bennett, Louise E

    2016-01-01

    Hypertension is a major risk factor for coronary heart disease, kidney disease, and stroke. Interest in medicinal or nutraceutical plant bioactives to reduce hypertension has increased dramatically. The main biological regulation of mammalian blood pressure is via the renin-angiotensin-aldosterone system. The key enzyme is angiotensin converting enzyme (ACE) that converts angiotensin I into the powerful vasoconstrictor, angiotensin II. Angiotensin II binds to its receptors (AT1) on smooth muscle cells of the arteriole vasculature causing vasoconstriction and elevation of blood pressure. This review focuses on the in vitro and in vivo reports of plant-derived extracts that inhibit ACE activity, block angiotensin II receptor binding and demonstrate hypotensive activity in animal or human studies. We describe 74 families of plants that exhibited significant ACE inhibitory activity and 16 plant families with potential AT1 receptor blocking activity, according to in vitro studies. From 43 plant families including some of those with in vitro bioactivity, the extracts from 73 plant species lowered blood pressure in various normotensive or hypertensive in vivo models by the oral route. Of these, 19 species from 15 families lowered human BP when administered orally. Some of the active plant extracts, isolated bioactives and BP-lowering mechanisms are discussed.

  11. RGS4 inhibits angiotensin II signaling and macrophage localization during renal reperfusion injury independent of vasospasm.

    PubMed

    Pang, Paul; Jin, Xiaohua; Proctor, Brandon M; Farley, Michelle; Roy, Nilay; Chin, Matthew S; von Andrian, Ulrich H; Vollmann, Elisabeth; Perro, Mario; Hoffman, Ryan J; Chung, Joseph; Chauhan, Nikita; Mistri, Murti; Muslin, Anthony J; Bonventre, Joseph V; Siedlecki, Andrew M

    2015-04-01

    Vascular inflammation is a major contributor to the severity of acute kidney injury. In the context of vasospasm-independent reperfusion injury we studied the potential anti-inflammatory role of the Gα-related RGS protein, RGS4. Transgenic RGS4 mice were resistant to 25 min injury, although post-ischemic renal arteriolar diameter was equal to the wild type early after injury. A 10 min unilateral injury was performed to study reperfusion without vasospasm. Eighteen hours after injury, blood flow was decreased in the inner cortex of wild-type mice with preservation of tubular architecture. Angiotensin II levels in the kidneys of wild-type and transgenic mice were elevated in a sub-vasoconstrictive range 12 and 18 h after injury. Angiotensin II stimulated pre-glomerular vascular smooth muscle cells (VSMCs) to secrete the macrophage chemoattractant RANTES, a process decreased by angiotensin II R2 (AT2) inhibition. However, RANTES increased when RGS4 expression was suppressed implicating Gα protein activation in an AT2-RGS4-dependent pathway. RGS4 function, specific to VSMC, was tested in a conditional VSMC-specific RGS4 knockout showing high macrophage density by T2 MRI compared with transgenic and non-transgenic mice after the 10 min injury. Arteriolar diameter of this knockout was unchanged at successive time points after injury. Thus, RGS4 expression, specific to renal VSMC, inhibits angiotensin II-mediated cytokine signaling and macrophage recruitment during reperfusion, distinct from vasomotor regulation.

  12. Angiotensin II Signaling in Human Preadipose Cells: Participation of ERK1,2-Dependent Modulation of Akt

    PubMed Central

    Dünner, Natalia; Quezada, Carolina; Berndt, F. Andrés; Cánovas, José; Rojas, Cecilia V.

    2013-01-01

    The renin-angiotensin system expressed in adipose tissue has been implicated in the modulation of adipocyte formation, glucose metabolism, triglyceride accumulation, lipolysis, and the onset of the adverse metabolic consequences of obesity. As we investigated angiotensin II signal transduction mechanisms in human preadipose cells, an interplay of extracellular-signal-regulated kinases 1 and 2 (ERK1,2) and Akt/PKB became evident. Angiotensin II caused attenuation of phosphorylated Akt (p-Akt), at serine 473; the p-Akt/Akt ratio decreased to 0.5±0.2-fold the control value without angiotensin II (p<0.001). Here we report that the reduction of phosphorylated Akt associates with ERK1,2 activities. In the absence of angiotensin II, inhibition of ERK1,2 activation with U0126 or PD98059 resulted in a 2.1±0.5 (p<0.001) and 1.4±0.2-fold (p<0.05) increase in the p-Akt/Akt ratio, respectively. In addition, partial knockdown of ERK1 protein expression by the short hairpin RNA technique also raised phosphorylated Akt in these cells (the p-Akt/Akt ratio was 1.5±0.1-fold the corresponding control; p<0.05). Furthermore, inhibition of ERK1,2 activation with U0126 prevented the reduction of p-Akt/Akt by angiotensin II. An analogous effect was found on the phosphorylation status of Akt downstream effectors, the forkhead box (Fox) proteins O1 and O4. Altogether, these results indicate that angiotensin II signaling in human preadipose cells involves an ERK1,2-dependent attenuation of Akt activity, whose impact on the biological functions under its regulation is not fully understood. PMID:24098385

  13. Increased colonic mucosal angiotensin I and II concentrations in Crohn's colitis.

    PubMed

    Jaszewski, R; Tolia, V; Ehrinpreis, M N; Bodzin, J H; Peleman, R R; Korlipara, R; Weinstock, J V

    1990-06-01

    To define a potential role for the angiotensin system in Crohn's colitis, the colonic mucosal levels of angiotensin I and II were measured in endoscopic biopsy samples from patients with active Crohn's colitis (n = 20), ulcerative colitis (n = 13), other forms of colitis (n = 3), and normal controls (n = 17). Colonic mucosal levels of angiotensin I and II were greater in patients with Crohn's colitis than in normal subjects (p less than 0.001 and p less than 0.001, respectively). Mucosal levels of angiotensin I and II were also higher in Crohn's colitis than in ulcerative colitis (p less than 0.001 and p less than 0.001, respectively), and levels of angiotensin II were higher in Crohn's than in other forms of colitis (p = 0.014). Mucosal levels of angiotensin I and II correlated well with the degree of macroscopic inflammation in Crohn's colitis (r = 0.86, p less than 0.001 and r = 0.68, p less than 0.001, respectively). Mucosal levels of angiotensin I correlated fairly well with the Crohn's Disease Activity Index (r = 0.46, p less than 0.05) while angiotensin II levels correlated poorly. These studies suggest that angiotensin I and II may have a role in the inflammation associated with Crohn's colitis.

  14. Norepinephrine metabolism in neuronal cultures is increased by angiotensin II

    SciTech Connect

    Sumners, C.; Shalit, S.L.; Kalberg, C.J.; Raizada, M.K.

    1987-06-01

    In this study the authors have examined the actions of angiotensin II (ANG II) on catecholamine metabolism in neuronal brain cell cultures prepared from the hypothalamus and brain stem. Neuronal cultures prepared from the brains of 1-day-old Sprague-Dawley rats exhibit specific neuronal uptake mechanisms for both norepinephrine (NE) and dopamine (DA), and also monoamine oxidase (MAO) and catechol O-methyltransferase (COMT) activity. Separate neuronal uptake sites for NE and DA were identified by using specific neuronal uptake inhibitors for each amine. In previous studies, they determined that ANG II (10 nM-1 ..mu..M) stimulates increased neuronal (/sup 3/H)NE uptake by acting as specific receptors. They have confirmed these results here and in addition have shown that ANG II has not significant effects on neuronal (/sup 3/H)DA uptake. These results suggest that the actions of ANG II are restricted to the NE transporter in neuronal cultures. It is possible that ANG II stimulates the intraneuronal metabolism of at least part of the NE that is taken up, because the peptide stimulates MAO activity, an effect mediated by specific ANG II receptors. ANG II had no effect on COMT activity in neuronal cultures. Therefore, the use of neuronal cultures of hypothalamus and brain stem they have determined that ANG II can specifically alter NE metabolism in these areas, while apparently not altering DA metabolism.

  15. 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.

  16. Angiotensin II receptor antagonists and heart failure: angiotensin-converting-enzyme inhibitors remain the first-line option.

    PubMed

    2005-10-01

    (1) Some angiotensin-converting-enzyme inhibitors (ACE inhibitors) reduce mortality in patients with heart failure (captopril, enalapril, ramipril and trandolapril), and in patients with recent myocardial infarction and heart failure or marked left ventricular dysfunction (captopril, ramipril and trandolapril). (2) Angiotensin II receptor antagonists, otherwise known as angiotensin receptor blockers, have haemodynamic effects similar to ACE inhibitors, but differ in their mechanism of action and certain adverse effects. (3) Five clinical trials have evaluated angiotensin II receptor antagonists (candesartan, losartan and valsartan) in terms of their effect on mortality and on the risk of clinical deterioration in patients with symptomatic heart failure, but without severe renal failure, hyperkalemia or hypotension. In these trials, candesartan and valsartan were used at much higher doses than those recommended for the treatment of arterial hypertension. (4) In patients with heart failure who were not taking an angiotensin II receptor antagonist or an ACE inhibitor at enrollment, no significant difference was found between losartan and captopril in terms of mortality or the risk of clinical deterioration. (5) In patients with heart failure who had stopped taking an ACE inhibitor because of adverse effects, candesartan had no effect on mortality as compared with placebo, but it did reduce the risk of clinical deterioration (3 fewer hospitalisations per year per 100 patients). However, candesartan was associated with adverse effects such as renal failure and hyperkalemia, especially in patients who had experienced these same adverse effects while taking an ACE inhibitor. (6) In patients with heart failure who were already taking an ACE inhibitor, adjunctive candesartan or valsartan treatment did not influence mortality in comparison to the addition of a placebo. Adding candesartan or valsartan reduced the risk of hospitalisation (between 1 and 3 fewer hospitalisations

  17. Renal hemodynamic responses to increased renal venous pressure: role of angiotensin II.

    PubMed

    Kastner, P R; Hall, J E; Guyton, A C

    1982-09-01

    Studies were performed to quantitate the effects of progressive increases in renal venous pressure (RVP) on renin secretion (RS) and renal hemodynamics. RVP was raised in 10 mmHg increments to 50 mmHg. Renin secretion rate increased modestly as RVP was increased to 30 mmHg and then increased sharply after RVP exceeded 30 mmHg. Glomerular filtration rate (GFR), renal blood flow (RBF), and filtration fraction (FF) did not change significantly when RVP was elevated to 50 mmHg. GFR and RBF were also measured after the renin-angiotension system (RAS) was blocked with the angiotensin converting enzyme inhibitor (CEI) SQ 14225. After a 60-min CEI infusion, RBF was elevated (32%), GFR was unchanged, FF was decreased, and total renal resistance (TRR) was decreased. As RVP was increased to 50 mmHg, GFR and FF decreased to 36.3 and 40.0% of control, respectively, RBF returned to a value not significantly different from control, and TRR decreased to 44.8% of control. The data indicate that the RAS plays an important role in preventing reductions in GFR during increased RVP because blockade of angiotensin II (ANG II) formation by the CEI results in marked decreases in GFR at high RVPs. The decreases in GFR after ANG II blockade and RVP elevation were not due to lack of renal vasodilation, since TRR was maintained below while RBF was maintained either above or at the pre-CEI levels.

  18. Localized accumulation of angiotensin II and production of angiotensin-(1-7) in rat luteal cells and effects on steroidogenesis.

    PubMed

    Pepperell, John R; Nemeth, Gabor; Yamada, Yuji; Naftolin, Frederick; Merino, Maricruz

    2006-08-01

    These studies aim to investigate subcellular distribution of angiotensin II (ANG II) in rat luteal cells, identify other bioactive angiotensin peptides, and investigate a role for angiotensin peptides in luteal steroidogenesis. Confocal microscopy showed ANG II distributed within the cytoplasm and nuclei of luteal cells. HPLC analysis showed peaks that eluted with the same retention times as ANG-(1-7), ANG II, and ANG III. Their relative concentrations were ANG II >or= ANG-(1-7) > ANG III, and accumulation was modulated by quinapril, an inhibitor of angiotensin-converting enzyme (ACE), Z-proprolinal (ZPP), an inhibitor of prolyl endopeptidase (PEP), and parachloromercurylsulfonic acid (PCMS), an inhibitor of sulfhydryl protease. Phenylmethylsulfonyl fluoride (PMSF), a serine protease inhibitor, did not affect peptide accumulation. Quinapril, ZPP, PCMS, and PMSF, as well as losartan and PD-123319, the angiotensin receptor type 1 (AT1) and type 2 (AT2) receptor antagonists, were used in progesterone production studies. ZPP significantly reduced luteinizing hormone (LH)-dependent progesterone production (P < 0.05). Quinapril plus ZPP had a greater inhibitory effect on LH-stimulated progesterone than either inhibitor alone, but this was not reversed by exogenous ANG II or ANG-(1-7). Both PCMS and PMSF acutely blocked LH-stimulated progesterone, and PCMS blocked LH-sensitive cAMP accumulation. Losartan inhibited progesterone production in permeabilized but not intact luteal cells and was reversed by ANG II. PD-123319 had no significant effect on luteal progesterone production in either intact or permeabilized cells. These data suggest that steroidogenesis may be modulated by angiotensin peptides that act in part through intracellular AT1 receptors.

  19. MiR-30-regulated autophagy mediates angiotensin II-induced myocardial hypertrophy.

    PubMed

    Pan, Wei; Zhong, Yun; Cheng, Chuanfang; Liu, Benrong; Wang, Li; Li, Aiqun; Xiong, Longgen; Liu, Shiming

    2013-01-01

    Dysregulated autophagy may lead to the development of disease. Role of autophagy and the diagnostic potential of microRNAs that regulate the autophagy in cardiac hypertrophy have not been evaluated. A rat model of cardiac hypertrophy was established using transverse abdominal aortic constriction (operation group). Cardiomyocyte autophagy was enhanced in rats from the operation group, compared with those in the sham operation group. Moreover, the operation group showed up-regulation of beclin-1 (an autophagy-related gene), and down-regulation of miR-30 in cardiac tissue. The effects of inhibition and over-expression of the beclin-1 gene on the expression of hypertrophy-related genes and on autophagy were assessed. Angiotensin II-induced myocardial hypertrophy was found to be mediated by over-expression of the beclin-1 gene. A dual luciferase reporter assay confirmed that beclin-1 was a target gene of miR-30a. miR-30a induced alterations in beclin-1 gene expression and autophagy in cardiomyocytes. Treatment of cardiomyocytes with miR-30a mimic attenuated the Angiotensin II-induced up-regulation of hypertrophy-related genes and decreased in the cardiomyocyte surface area. Conversely, treatment with miR-30a inhibitor enhanced the up-regulation of hypertrophy-related genes and increased the surface area of cardiomyocytes induced by Angiotensin II. In addition, circulating miR-30 was elevated in patients with left ventricular hypertrophy, and circulating miR-30 was positively associated with left ventricular wall thickness. Collectively, these above-mentioned results suggest that Angiotensin II induces down-regulation of miR-30 in cardiomyocytes, which in turn promotes myocardial hypertrophy through excessive autophagy. Circulating miR-30 may be an important marker for the diagnosis of left ventricular hypertrophy.

  20. MiR-30-Regulated Autophagy Mediates Angiotensin II-Induced Myocardial Hypertrophy

    PubMed Central

    Pan, Wei; Zhong, Yun; Cheng, Chuanfang; Liu, Benrong; Wang, Li; Li, Aiqun; Xiong, Longgen; Liu, Shiming

    2013-01-01

    Dysregulated autophagy may lead to the development of disease. Role of autophagy and the diagnostic potential of microRNAs that regulate the autophagy in cardiac hypertrophy have not been evaluated. A rat model of cardiac hypertrophy was established using transverse abdominal aortic constriction (operation group). Cardiomyocyte autophagy was enhanced in rats from the operation group, compared with those in the sham operation group. Moreover, the operation group showed up-regulation of beclin-1 (an autophagy-related gene), and down-regulation of miR-30 in cardiac tissue. The effects of inhibition and over-expression of the beclin-1 gene on the expression of hypertrophy-related genes and on autophagy were assessed. Angiotensin II-induced myocardial hypertrophy was found to be mediated by over-expression of the beclin-1 gene. A dual luciferase reporter assay confirmed that beclin-1 was a target gene of miR-30a. miR-30a induced alterations in beclin-1 gene expression and autophagy in cardiomyocytes. Treatment of cardiomyocytes with miR-30a mimic attenuated the Angiotensin II-induced up-regulation of hypertrophy-related genes and decreased in the cardiomyocyte surface area. Conversely, treatment with miR-30a inhibitor enhanced the up-regulation of hypertrophy-related genes and increased the surface area of cardiomyocytes induced by Angiotensin II. In addition, circulating miR-30 was elevated in patients with left ventricular hypertrophy, and circulating miR-30 was positively associated with left ventricular wall thickness. Collectively, these above-mentioned results suggest that Angiotensin II induces down-regulation of miR-30 in cardiomyocytes, which in turn promotes myocardial hypertrophy through excessive autophagy. Circulating miR-30 may be an important marker for the diagnosis of left ventricular hypertrophy. PMID:23326547

  1. Dietary sodium deprivation evokes activation of brain regional neurons and down-regulation of angiotensin II type 1 receptor and angiotensin-convertion enzyme mRNA expression.

    PubMed

    Lu, B; Yang, X J; Chen, K; Yang, D J; Yan, J Q

    2009-12-15

    Previous studies have indicated that the renin-angiotensin-aldosterone system (RAAS) is implicated in the induction of sodium appetite in rats and that different dietary sodium intakes influence the mRNA expression of central and peripheral RAAS components. To determine whether dietary sodium deprivation activates regional brain neurons related to sodium appetite, and changes their gene expression of RAAS components of rats, the present study examined the c-Fos expression after chronic exposure to low sodium diet, and determined the relationship between plasma and brain angiotensin I (ANG I), angiotensin II (ANG II) and aldosterone (ALD) levels and the sodium ingestive behavior variations, as well as the effects of prolonged dietary sodium deprivation on ANG II type 1 (AT1) and ANG II type 2 (AT2) receptors and angiotensin-convertion enzyme (ACE) mRNA levels in the involved brain regions using the method of real-time polymerase chain reaction (PCR). Results showed that the Fos immunoreactivity (Fos-ir) expression in forebrain areas such as subfornical organ (SFO), paraventricular hypothalamic nuclei (PVN), supraoptic nucleus (SON) and organum vasculosum laminae terminalis (OVLT) all increased significantly and that the levels of ANG I, ANG II and ALD also increased in plasma and forebrain in rats fed with low sodium diet. In contrast, AT1, ACE mRNA in PVN, SON and OVLT decreased significantly in dietary sodium depleted rats, while AT2 mRNA expression did not change in the examined areas. These results suggest that many brain areas are activated by increased levels of plasma and/or brain ANG II and ALD, which underlies the elevated preference for hypertonic salt solution after prolonged exposure to low sodium diet, and that the regional AT1 and ACE mRNA are down-regulated after dietary sodium deprivation, which may be mediated by increased ANG II in plasma and/or brain tissue.

  2. 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.

  3. Hypotensive effect of angiotensin II after AT1-receptor blockade with losartan.

    PubMed

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

    2000-03-01

    Recent data suggest that hypotensive effect of losartan may not be attributed solely to AT1-receptor blockade, but also to excessive AT2 or other receptors stimulation by elevated angiotensin II and its derivative peptides. Therefore in the present study we examined the effect of angiotensin II on mean blood pressure after AT -receptor blockade with losartan. Male Wistar rats were anaesthetised and received injection of either losartan (30 mg/kg, 1 ml/kg, i.v.) or saline (the same volume and route) followed by bolus injection of angiotensin II (100, 300 or 1,000 ng/kg; 1 ml/kg, i.v.) or 1-hour infusion of angiotensin II (200 ng/kg/min; 2.5 ml/kg/h, i.v.). Control animals received saline instead. Angiotensin II, given either as the injection or the infusion, caused an evident increase in mean blood pressure (p ranged from 0.05 to 0.001 depending on the experimental group). Losartan caused a rapid drop in mean blood pressure and blunted the hypertensive effect of angiotensin II (p < 0.01). Moreover, in the losartan-pretreated animals the hypotensive phase was enhanced by the infusion, but not single injection of angiotensin II, which was most evident from the 30 th minute of observation (p < 0.05 vs control). In conclusion, hypotensive effect of losartan may be amplified by simultaneous increase in angiotensin II level, the situation observed during chronic AT1-receptor blockade.

  4. Purification of an angiotensin II binding protein by using antibodies to a peptide encoded by angiotensin II complementary RNA

    SciTech Connect

    Elton, T.S.; Dion, L.D.; Bost, K.L.; Oparil, S.; Blalock, J.E.

    1988-04-01

    The authors have generated a monospecific antibody to a synthetic peptide encoded by an RNA complementary to the mRNA for angiotensin II (AII) and determined whether this antibody recognizes the AII receptor. They demonstrate that the antibody competes specifically with /sup 125/I-labeled AII for the same binding site on rat adrenal membranes. Furthermore, they show this antibody inhibits the secretion of aldosterone from cultured rat adrenal cells, suggesting that the antibody recognizes the biologically relevant AII receptor. Finally, they demonstrate that antibody to the complementary peptide can be used to immunoaffinity-purify a protein of M/sub r/ 66,000 that specifically binds radiolabeled AII.

  5. The angiotensin-(1-7)/Mas axis reduces myonuclear apoptosis during recovery from angiotensin II-induced skeletal muscle atrophy in mice.

    PubMed

    Meneses, Carla; Morales, María Gabriela; Abrigo, Johanna; Simon, Felipe; Brandan, Enrique; Cabello-Verrugio, Claudio

    2015-09-01

    Angiotensin-(1-7) [Ang (1-7)] is a peptide belonging to the non-classical renin-angiotensin system (RAS). Ang (1-7), through its receptor Mas, has an opposite action to angiotensin II (Ang II), the typical peptide of the classical RAS axis. Ang II produces skeletal muscle atrophy, a pathological condition characterised by the loss of strength and muscle mass. A feature of muscle atrophy is the decrease of the myofibrillar proteins produced by the activation of the ubiquitin-proteasome pathway (UPP), evidenced by the increase in the expression of two muscle-specific ubiquitin ligases: atrogin-1 and MuRF-1. In addition, it has been described that Ang II also induces myonuclear apoptosis during muscle atrophy. We assessed the effects of Ang (1-7) and Mas participation on myonuclear apoptosis during skeletal muscle atrophy induced by Ang II. Our results show that Ang (1-7), through Mas, prevents the effects induced by Ang II in the diaphragm muscles and decreases several events associated with apoptosis in the diaphragm (increased apoptotic nuclei, increased expression of caspase-8 and caspase-9, increased caspase-3 activity and increased Bax/Bcl-2 ratio). Concomitantly, Ang (1-7) also attenuates the decrease in fibre diameter and muscle strength, and prevents the increase in atrogin-1 and MuRF-1 during the muscle wasting induced by Ang II. Interestingly, these effects of Ang (1-7) are dependent on the Mas receptor. Thus, we demonstrated for the first time that Ang (1-7) prevents myonuclear apoptosis during the recovery of skeletal muscle atrophy induced by Ang II.

  6. Age determines the magnitudes of angiotensin II-induced contractions, mRNA, and protein expression of angiotensin type 1 receptors in rat carotid arteries.

    PubMed

    Vamos, Zoltan; Cseplo, Peter; Ivic, Ivan; Matics, Robert; Hamar, Janos; Koller, Akos

    2014-05-01

    In this study, we hypothesized that aging alters angiotensin II (Ang II)-induced vasomotor responses and expression of vascular mRNA and protein angiotensin type 1 receptor (AT1R). Thus, carotid arteries were isolated from the following age groups of rats: 8 days, 2-9 months, 12-20 months, and 20-30 months, and their vasomotor responses were measured in a myograph after repeated administrations of Ang II. Vascular relative AT1R mRNA level was determined by quantitative reverse-transcriptase polymerase chain reaction and the AT1R protein density was measured by Western blot. Contractions to the first administration of Ang II increased from 8 days to 6 months and then they decreased to 30 months. In general, second administration of Ang II elicited reduced contractions, but they also increased from 8 days until 2 months and then they decreased to 30 months. Similarly the AT1R mRNA level increased from 8 days to 12 months and then decreased to 30 months. Similarly the AT1R protein density increased from 8 days until 16 months and then they decreased to 30 months. The pattern of these changes correlated with functional vasomotor data. We conclude that aging (newborn to senescence) has substantial effects on Ang II-induced vasomotor responses and AT1R signaling suggesting the importance of genetic programs.

  7. Ets-1 upregulation mediates angiotensin II-related cardiac fibrosis.

    PubMed

    Hao, Guanghua; Han, Zhenhua; Meng, Zhe; Wei, Jin; Gao, Dengfeng; Zhang, Hong; Wang, Nanping

    2015-01-01

    Ets-1, the prototypical member of the family of Ets transcription factors, has been shown to participate in tissue fibrotic remodeling. However, its role in cardiac fibrosis has not been established. The aim of this study was to investigate the role of Ets-1 in profibrotic actions of angiotensin II (Ang II) in cardiac fibroblasts (CFs) and in the in vivo heart. In growth-arrested CFs, Ang II induced Ets-1 expression in a time- and concentration-dependent manner. Pretreatment with Ang II type 1 receptor blocker losartan, protein kinase C inhibitor bisindolylmaleimide I, extracellular signal-regulated kinase (ERK) inhibitor PD98059, or c-Jun NH(2)-terminal kinase (JNK) inhibitor SP600125 partly inhibited this induction accompanied with impaired cell proliferation and production of plasminogen activator inhibitor-1 (PAI-1) and connective tissue growth factor (CTGF) protein, the two downstream targets of Ets-1. Knockdown of Ets-1 by siRNA significantly inhibited the inductive effects of Ang II on cell proliferation and expression of CTGF and PAI-1. Moreover, the levels of Ets-1, PAI-1 and CTGF protein were simultaneously upregulated in left ventricle of Ang II-infused rats in parallel with an increase in the activation of ERK and JNK. Our data suggest that Ets-1 may mediate Ang II-induced cardiac fibrotic effects.

  8. Salt preference elicited by chronic intracerebroventricular angiotensin II.

    PubMed

    Izumi, H; Nakamura, I

    1994-10-01

    1. Much more water was consumed than either 0.9% or 2.7% saline in response to various dipsogenic stimuli in untreated normal replete rats when they had free access to water, 0.9% and 2.7% saline. On the other hand, the rats drank more 0.9% saline than water and 2.7% saline when each solution is the sole drinking fluid offered. 2. A marked increase in preference for 0.9% saline was observed during the chronic i.c.v. injection of angiotensin II at a dose of 25 ng/hr for 7 consecutive days in the three bottle choice test. After the cessation of angiotensin II infusion, most rats (45 out of 50 rats) returned to drink much more water than 0.9% and 2.7% saline, similar to the drinking pattern of the 0.9% saline-treated control rats. However, some rats (5 out of 50 rats) still preferred 0.9% saline and this persisted for up to 3 months although these rats did not show a hypertensive state and an increase of plasma renin activity.

  9. Identification and characterization of an angiotensin II receptor on cultured bovine adrenal chromaffin cells

    SciTech Connect

    Boyd, V.L.

    1987-01-01

    The presence of an angiotensin II receptor on cultured bovine adrenal chromaffin cells was demonstrated by radioligand binding. A single class of finding sites with a K/sub D/ of 0.7 nM was characterized. The use of radioligands also allows the localization of receptors by autoradiography. Autoradiography demonstrated that approximately 50% of the isolated cells bound angiotensin II. It was of interest to see if angiotensin II bound to a cell that possessed a certain phenotype. In order to evaluate this possibility a technique was developed that combined autoradiography and immunocytochemistry. Results indicated that angiotensin II binding sites were not localized preferentially to either norepinephrine or epinephrine cells. Binding of angiotensin II was associated with the release of intracellular catecholamine stores. Cells were pre-loaded with /sup 3/H-norepinephrine and secretion was monitored by following radioactivity released into the supernatant. Alternatively, release of endogenous catecholamines was determined by fluorometric assay.

  10. Quantitative autoradiography of angiotensin II receptors in brain and kidney: focus on cardiovascular implications

    SciTech Connect

    Gehlert, D.R.; Speth, R.C.; Wamsley, J.K.

    1985-01-01

    Quantitative techniques of receptor autoradiography have been applied to localize (/sup 125/I)-angiotensin II binding sites in brain and kidney. High densities of autoradiographic grains, indicating the presence of angiotensin II receptors, have been localized to several rat brain nuclei including the dorsal motor nucleus of the vagus, nucleus of the solitary tract, anterior pituitary, locus coeruleus and several hypothalamic nuclei. Cat thoracic spinal cord exhibited a high density of sites over the intermedio-lateral cell column. In sections of rat kidney, angiotensin II receptors were detected in the glomerulus, vasa recta and ureter. The cardiovascular implications of these results are apparent and relate angiotensin II to hypertensive mechanisms. Thus, angiotensin II represents an endocoid which is involved in control of blood pressure through its effects on peripheral organs as well as the central nervous system.

  11. Low-Salt Diet and Circadian Dysfunction Synergize to Induce Angiotensin II-Dependent Hypertension in Mice.

    PubMed

    Pati, Paramita; Fulton, David J R; Bagi, Zsolt; Chen, Feng; Wang, Yusi; Kitchens, Julia; Cassis, Lisa A; Stepp, David W; Rudic, R Daniel

    2016-03-01

    Blood pressure exhibits a robust circadian rhythm in health. In hypertension, sleep apnea, and even shift work, this balanced rhythm is perturbed via elevations in night-time blood pressure, inflicting silent damage to the vasculature and body organs. Herein, we examined the influence of circadian dysfunction during experimental hypertension in mice. Using radiotelemetry to measure ambulatory blood pressure and activity, the effects of angiotensin II administration were studied in wild-type (WT) and period isoform knockout (KO) mice (Per2-KO, Per2, 3-KO, and Per1, 2, 3-KO/Per triple KO [TKO] mice). On a normal diet, administration of angiotensin II caused nondipping blood pressure and exacerbated vascular hypertrophy in the Period isoform KO mice relative to WT mice. To study the endogenous effects of angiotensin II stimulation, we then administered a low-salt diet to the mice, which does stimulate endogenous angiotensin II in addition to lowering blood pressure. A low-salt diet decreased blood pressure in wild-type mice. In contrast, Period isoform KO mice lost their circadian rhythm in blood pressure on a low-salt diet, because of an increase in resting blood pressure, which was restorable to rhythmicity by the angiotensin receptor blocker losartan. Chronic administration of low salt caused vascular hypertrophy in Period isoform KO mice, which also exhibited increased renin levels and altered angiotensin 1 receptor expression. These data suggest that circadian clock genes may act to inhibit or control renin/angiotensin signaling. Moreover, circadian disorders such as sleep apnea and shift work may alter the homeostatic responses to sodium restriction to potentially influence nocturnal hypertension.

  12. Angiotensin II regulates growth of the developing papillas ex vivo

    PubMed Central

    Song, Renfang; Preston, Graeme; Khalili, Ali; El-Dahr, Samir S.

    2012-01-01

    We tested the hypothesis that lack of angiotensin (ANG) II production in angiotensinogen (AGT)-deficient mice or pharmacologic antagonism of ANG II AT1 receptor (AT1R) impairs growth of the developing papillas ex vivo, thus contributing to the hypoplastic renal medulla phenotype observed in AGT- or AT1R-null mice. Papillas were dissected from Hoxb7GFP+ or AGT+/+, +/−, −/− mouse metanephroi on postnatal day P3 and grown in three-dimentional collagen matrix gels in the presence of media (control), ANG II (10−5 M), or the specific AT1R antagonist candesartan (10−6 M) for 24 h. Percent reduction in papillary length was attenuated in AGT+/+ and in AGT+/− compared with AGT−/− (−18.4 ± 1.3 vs. −32.2 ± 1.6%, P < 0.05, −22.8 ± 1.3 vs. −32.2 ± 1.6%, P < 0.05, respectively). ANG II blunted the decrease in papilla length observed in respective media-treated controls in Hoxb7GFP+ (−1.5 ± 0.3 vs. −10.0 ± 1.4%, P < 0.05) or AGT+/+, +/−, and −/− papillas (−12.8 ± 0.7 vs. −18.4 ± 1.3%, P < 0.05, −16.8 ± 1.1 vs. −23 ± 1.2%, P < 0.05; −26.2 ± 1.6 vs. −32.2 ± 1.6%, P < 0.05, respectively). In contrast, percent decrease in the length of Hoxb7GFP+ papillas in the presence of the AT1R antagonist candesartan was higher compared with control (−24.3 ± 2.1 vs. −10.5 ± 1.8%, P < 0.05). The number of proliferating phospho-histone H3 (pH3)-positive collecting duct cells was lower, whereas the number of caspase 3-positive cells undergoing apoptosis was higher in candesartan- vs. media-treated papillas (pH3: 12 ± 1.4 vs. 21 ± 2.1, P < 0.01; caspase 3: 3.8 ± 0.5 vs. 1.7 ± 0.2, P < 0.01). Using quantitative RT-PCR, we demonstrate that AT1R signaling regulates the expression of genes implicated in morphogenesis of the renal medulla. We conclude that AT1R prevents shrinkage of the developing papillas observed ex vivo via control of Wnt7b, FGF7, β-catenin, calcineurin B1, and α3 integrin gene expression, collecting duct cell

  13. Angiotensin II Induced Cardiac Dysfunction on a Chip

    PubMed Central

    Horton, Renita E.; Yadid, Moran; McCain, Megan L.; Sheehy, Sean P.; Pasqualini, Francesco S.; Park, Sung-Jin; Cho, Alexander; Campbell, Patrick; Parker, Kevin Kit

    2016-01-01

    In vitro disease models offer the ability to study specific systemic features in isolation to better understand underlying mechanisms that lead to dysfunction. Here, we present a cardiac dysfunction model using angiotensin II (ANG II) to elicit pathological responses in a heart-on-a-chip platform that recapitulates native laminar cardiac tissue structure. Our platform, composed of arrays of muscular thin films (MTF), allows for functional comparisons of healthy and diseased tissues by tracking film deflections resulting from contracting tissues. To test our model, we measured gene expression profiles, morphological remodeling, calcium transients, and contractile stress generation in response to ANG II exposure and compared against previous experimental and clinical results. We found that ANG II induced pathological gene expression profiles including over-expression of natriuretic peptide B, Rho GTPase 1, and T-type calcium channels. ANG II exposure also increased proarrhythmic early after depolarization events and significantly reduced peak systolic stresses. Although ANG II has been shown to induce structural remodeling, we control tissue architecture via microcontact printing, and show pathological genetic profiles and functional impairment precede significant morphological changes. We assert that our in vitro model is a useful tool for evaluating tissue health and can serve as a platform for studying disease mechanisms and identifying novel therapeutics. PMID:26808388

  14. Enhancement by exogenous and locally generated angiotensin II of purinergic neurotransmission via angiotensin type 1 receptor in the guinea-pig isolated mesenteric artery

    PubMed Central

    Onaka, Uran; Fujii, Koji; Abe, Isao; Fujishima, Masatoshi

    1997-01-01

    Angiotensin II is known to enhance sympathetic neurotransmission in the vasculature by increasing the release of noradrenaline, but little is known about the effect on the co-released transmitter, adenosine 5′-triphosphate (ATP). In the present study we have examined the effect of angiotensin II on the excitatory junction potential (e.j.p.) elicited by repetitive field stimulation in the guinea-pig isolated mesenteric artery, to establish the angiotensin II receptor subtype involved in modulating the release of ATP and the role of the endothelium in converting angiotensin I to angiotensin II. Suramin (300 μM), a P2 purinoceptor antagonist, abolished both the e.j.ps and depolarizing response to α,β-methylene-ATP, a stable analogue of ATP, without affecting the resting membrane potential and noradrenaline-induced depolarization. Angiotensin II (0.1 μM) affected neither the resting membrane potential nor the amplitude of the first e.j.p., but increased the amplitudes of the subsequent e.j.ps. This enhancing effect of angiotensin II was abolished by CV-11974 (0.1 μM), an angiotensin II type 1 (AT1) receptor antagonist, but unaffected by PD 123319 (1 μM), an angiotensin II type 2 (AT2) receptor antagonist, or CGP 42112A (1 μM), AT2 receptor ligand. Angiotensin I (0.1 μM) exerted a similar effect on e.j.ps to that of angiotensin II. CV-11974 (0.1 μM) or temocaprilat (10 μM), an angiotensin converting enzyme (ACE) inhibitor, abolished the effect of angiotensin I. Removal of the endothelium did not alter the action of angiotensin I. The results of the present study indicate that the release of ATP from sympathetic nerves innervating the guinea-pig isolated mesenteric artery, as determined from the magnitude of the e.j.p., can be enhanced by angiotensin II via activation of prejunctional AT1 receptors. Qualitatively similar effects were observed with angiotensin I, which appears to be converted into angiotensin II by a subendothelial process

  15. Mechanism of Hepatocyte Growth Factor Inhibition of Angiotensin II-induced Apoptosis in Primary Lung Cells

    DTIC Science & Technology

    2010-02-19

    her unwavering support, insights, patience…and of course, her zucchini chocolate cake! Gina, thank you for helping me grow as a scientist. You are...has 36 Renin Angiotensinogen Angiotensin I Angiotensin Converting Enzyme Liver Kidney Lung Angiotensin II Brain Vasopressin Water retention...The AT2 receptor is highly expressed in the fetal tissue, including skeletal system, brain , fetal aorta, adrenal medulla, heart, kidney, and lung but

  16. Angiotensin II Enhances Connecting Tubule Glomerular Feedback (CTGF)

    PubMed Central

    Ren, YiLin; D’Ambrosio, Martin A.; Garvin, Jeffrey L.; Carretero, Oscar A.

    2011-01-01

    Increasing Na delivery to epithelial Na channels (ENaC) in the connecting tubule (CNT) causes dilation of the afferent arteriole (Af-Art), a process we call CNT glomerular feedback (CTGF). Angiotensin II (Ang II) stimulates ENaC in the collecting duct via AT1 receptors. We hypothesized that Ang II in the CNT lumen enhances CTGF by activation of AT1 receptors, protein kinase C (PKC) and ENaC. Rabbit Af-Arts and their adherent CNT were microperfused and preconstricted with norepinephrine. Each experiment involved generating two consecutive concentration-response curves by increasing NaCl in the CNT lumen. During the control period, the maximum dilation of the Af-Art was 7.9 ± 0.4 μm, and the concentration of NaCl in the CNT needed to achieve half maximal response (EC50) was 34.7 ± 5.2 mmol/L. After adding Ang II (10−9 mol/L) to the CNT lumen, the maximal response was 9.5 ± 0.7 μm and the EC50 was 11.6 ± 1.3 mmol/L (P=0.01 vs. control). Losartan, an AT1 antagonist (10−6 mol/L) blocked the stimulatory effect of Ang II, PD123319, an AT2 antagonist (10−6 mol/L) did not. The PKC inhibitor staurosporine (10−8 mol/L) added to the CNT inhibited the stimulatory effect of Ang II. The ENaC inhibitor benzamil (10−6 mol/L) prevented both CTGF and its stimulation by Ang II. We concluded that Ang II in the CNT lumen enhances CTGF via activation of AT1, and that this effect requires activation of PKC and ENaC. Potentiation of CTGF by Ang II could help preserve glomerular filtration rate in the presence of renal vasoconstriction. PMID:20696981

  17. Angiotensin II activates endothelial constitutive nitric oxide synthase via AT1 receptors.

    PubMed

    Saito, S; Hirata, Y; Emori, T; Imai, T; Marumo, F

    1996-09-01

    To determine whether angiotensin (ANG) II, a vasoconstrictor hormone, activates constitutive nitric oxide synthase (cNOS) in endothelial cells (ECs), we investigated the cellular mechanism by which ANG II induces nitric oxide (NO) formation in cultured bovine ECs. ANG II rapidly (within 1 min) and dose-dependently (10(-9)-10(-6) M) increased nitrate/nitrite (NOx) production. This effect of ANG II was abolished by a NOS inhibitor, NG-monomethyl-L-arginine. An ANG II type 1 (AT1) receptor antagonist (DuP 753), but not an ANG II type 2 (AT2) receptor antagonist (PD 123177), dose-dependently inhibited ANG II-induced NOx production. A Ca(2+)-channel blocker (barnidipine) failed to affect ANG II-induced NOx production, whereas an intracellular Ca2+ chelator (BAPTA) and a calmodulin inhibitor (W-7) abolished NOx production induced by ANG II. A protein kinase C (PKC) inhibitor (H-7) and down-regulation of endogenous PKC after pretreatment with phorbol ester decreased NOx production stimulated by ANG II. ANG II transiently stimulated inositol 1,4,5-trisphosphate (IP3) formation, and increased cytosolic free Ca2+ concentrations; these effects were blocked by DuP 753. Our data demonstrate that ANG II stimulates NO release by activation of Ca2+/calmodulin-dependent cNOS via AT1 receptors in bovine ECs.

  18. Intracrine action of angiotensin II in the intact ventricle of the failing heart: angiotensin II changes cardiac excitability from within

    PubMed Central

    2013-01-01

    The influence of intracellular injection of angiotensin II (Ang II) on electrical properties of single right ventricular fibers from the failing heart of cardiomyopathic hamsters (TO2) was investigated in the intact ventricle of 8-month-old animals. Intracellular injection was performed using pressure pulses (40–70 psi) for short periods of time (20 ms) while recoding the action potential simultaneously from the same fiber. The results indicated that intracellular Ang II caused a hyperpolarization of 7.7 mV ± 4.3 mV (n = 39) (4 animals) (P < 0.05) followed by a small fall in membrane potential. The action potential duration was significantly increased at 50% and at 90% repolarization, and the refractoriness was significantly enhanced. The effect of intracellular Ang II on action potential duration was related to the inhibition of potassium conductance through PKC activation because Bis-1 (360 nM), a selective PKC inhibitor, abolished the effect of the peptide. Injections performed in different fibers of the same ventricle showed a variable effect of Ang II on action potential duration and generated spontaneous rhythmicity. The effect of intracellular Ang II on action potential duration and cardiac refractoriness remains for more than 1 h after interruption of the intracellular injection of the peptide. PMID:21744071

  19. Angiotensin II increases glomerular permeability by β-arrestin mediated nephrin endocytosis

    PubMed Central

    Königshausen, Eva; Zierhut, Ulf M.; Ruetze, Martin; Potthoff, Sebastian A.; Stegbauer, Johannes; Woznowski, Magdalena; Quack, Ivo; Rump, Lars C.; Sellin, Lorenz

    2016-01-01

    Glomerular permeability and subsequent albuminuria are early clinical markers for glomerular injury in hypertensive nephropathy. Albuminuria predicts mortality and cardiovascular morbidity. AT1 receptor blockers protect from albuminuria, cardiovascular morbidity and mortality. A blood pressure independent, molecular mechanism for angiotensin II (Ang II) dependent albuminuria has long been postulated. Albuminuria results from a defective glomerular filter. Nephrin is a major structural component of the glomerular slit diaphragm and its endocytosis is mediated by β-arrestin2. Ang II stimulation increases nephrin-β-arrestin2 binding, nephrin endocytosis and glomerular permeability in mice. This Ang II effect is mediated by AT1-receptors. AT1-receptor mutants identified G-protein signaling to be essential for this Ang II effect. Gαq knockdown and phospholipase C inhibition block Ang II mediated enhanced nephrin endocytosis. Nephrin Y1217 is the critical residue controlling nephrin binding to β-arrestin under Ang II stimulation. Nephrin Y1217 also mediates cytoskeletal anchoring to actin via nck2. Ang II stimulation decreases nephrin nck2 binding. We conclude that Ang II weakens the structural integrity of the slit diaphragm by increased nephrin endocytosis and decreased nephrin binding to nck2, which leads to increased glomerular permeability. This novel molecular mechanism of Ang II supports the use of AT1-receptor blockers to prevent albuminuria even in normotensives. PMID:28004760

  20. Melatonin attenuates angiotensin II-induced abdominal aortic aneurysm through the down-regulation of matrix metalloproteinases.

    PubMed

    Kong, Jing; Zhang, Ya; Liu, Shanshan; Li, Hongxuan; Liu, Shangming; Wang, Jingjing; Qin, Xiaoteng; Jiang, Xiuxin; Yang, Jianmin; Zhang, Cheng; Zhang, Wencheng

    2017-02-04

    Abdominal aortic aneurysm (AAA) affects more than 5% of the population in developed countries and the pharmacotherapies for AAA are limited. Here, we explored whether melatonin regulates the development of AAA. In smooth muscle cells, melatonin treatment decreases angiotensin II-induced matrix metalloproteinase 2 (MMP2) and MMP9 expression. Human antigen R (HuR) could bind with the adenylateuridylate-rich elements of MMP2 and MMP9 mRNAs 3' untranslated region, resulting in the increased stability of MMP2 and MMP9 mRNAs. HuR is required for angiotensin II-induced MMP2 and MMP9 expression. Moreover, melatonin suppresses angiotensin II-induced HuR expression through inhibiting NF-κB signaling, leading to decreased MMP2 and MMP9 levels. Finally, melatonin attenuates the development of AAA in ApoE-/- mice infused with angiotensin II in vivo. These data support a role of HuR in the development of AAA and possible therapeutic roles for melatonin and/or HuR inhibition in AAA.

  1. Captopril avoids hypertension, the increase in plasma angiotensin II but increases angiotensin 1-7 and angiotensin II-induced perfusion pressure in isolated kidney in SHR.

    PubMed

    Castro-Moreno, P; Pardo, J P; Hernández-Muñoz, R; López-Guerrero, J J; Del Valle-Mondragón, L; Pastelín-Hernández, G; Ibarra-Barajas, M; Villalobos-Molina, R

    2012-10-01

    We investigated captopril effects, an ACE inhibitor, on hypertension development, on Ang II and Ang-(1-7) plasma concentrations, on Ang II-induced contraction in isolated kidneys, and on kidney AT1R from spontaneously hypertensive (SHR) rats. Five weeks-old SHR and Wistar Kyoto (WKY) rats were treated with captopril at 30 mg/kg/day, in drinking water for 2 or 14 weeks. Systolic blood pressure (SBP) was measured, and isolated kidneys were tested for perfusion pressure and AT1R expression; while Ang II and Ang-(1-7) concentrations were determined in plasma. Captopril did not modify SBP in WKY rats and avoided its increase as SHR aged. Plasma Ang-II concentration was ∼4-5 folds higher in SHR rats, and captopril reduced it (P<0.05); while captopril increased Ang-(1-7) by ∼2 fold in all rat groups. Captopril increased Ang II-induced pressor response in kidneys of WKY and SHR rats, phenomenon not observed in kidneys stimulated with phenylephrine, a α₁-adrenoceptor agonist. Captopril did not modify AT1R in kidney cortex and medulla among rat strains and ages. Data indicate that captopril increased Ang II-induced kidney perfusion pressure but not AT₁R density in kidney of WKY and SHR rats, due to blockade of angiotensin II synthesis; however, ACE inhibitors may have other actions like activating signaling processes that could contribute to their diverse effects.

  2. Control of glomerular filtration rate: role of intrarenally formed angiotensin II.

    PubMed

    Kastner, P R; Hall, J E; Guyton, A C

    1984-06-01

    This study was designed to investigate the role of intrarenally formed angiotensin II (ANG II) in controlling glomerular filtration rate (GFR) during reduction of renal artery pressure (RAP). The experimental design prevented renin released by the kidney from entering the systemic circulation and therefore prevented changes in circulating ANG II from influencing GFR control. In dogs with only a functional intrarenal renin-angiotensin system (RAS), GFR and renal blood flow (RBF) were not significantly altered by RAP reduction to 70 mmHg. After blockade of intrarenal ANG II formation with SQ 14225, reduction of RAP to 70 mmHg decreased GFR and filtration fraction to 75.6 +/- 7.0 and 59.0 +/- 4.1% of control, respectively, while RBF remained at 129.3 +/- 8.8% of control. Calculated efferent arteriolar resistance decreased considerably more when RAP was reduced after SQ 14225, whereas preglomerular resistance decreased to about the same level as observed prior to SQ 14225 infusion. After return of endogenously produced ANG II by recirculation of the renal venous blood or after infusion of ANG II (following SQ 14225) at a rate that restored RBF to the control level (with RAP held at 70 mmHg in each case), GFR, filtration fraction, and calculated efferent resistance were restored to control levels, but preglomerular resistance did not change. These results suggest that intrarenal ANG II formation plays an important role in maintaining GFR during reductions in RAP by constricting efferent arterioles.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Effects of angiotensin II on arginine-vasopressin in physiological and pathological situations in man.

    PubMed

    Padfield, P L; Morton, J J

    1977-08-01

    Studies were designed to determine whether angiotensin II has a direct stimulatory effect on arginine-vasopressin in man and to determine the role, if any, played by angiotensin II in the control of vasopressin release in physiological and pathological conditions. Acute infusion of angiotensin II in normal volunteers produced small but definite increases in plasma levels of arginine-vasopressin (5-4+/-0-3(S.E.M.) to 6-4+/-0-2 pg/ml) only when plasma angiotensin II levels were supraphysiological. Concurrent measurements of plasma arginine-vasopressin and angiotensin II were made during acute changes in fluid balance and posture in normal volunteers and in clinical conditions characterized by high plasma levels of angiotensin II (Addison's disease and Bartter's syndrome). The results of these studies allow us to conclude that there is little to suggest a direct effect of angiotensin II which is likely to be relevant to the normal physiological control of arginine-vasopressin in man.

  4. Angiotensin II dependent cardiac remodeling in the eel Anguilla anguilla involves the NOS/NO system.

    PubMed

    Filice, Mariacristina; Amelio, Daniela; Garofalo, Filippo; David, Sabrina; Fucarino, Alberto; Jensen, Frank Bo; Imbrogno, Sandra; Cerra, Maria Carmela

    2017-05-01

    Angiotensin II (AngII), the principal effector of the Renin-Angiotensin System (RAS), plays an important role in controlling mammalian cardiac morpho-functional remodelling. In the eel Anguilla anguilla, one month administration of AngII improves cardiac performance and influences the expression and localization of molecules which regulate cell growth. To deeper investigate the morpho-functional chronic influences of AngII on the eel heart and the molecular mechanisms involved, freshwater eels (A. anguilla) were intraperitoneally injected for 2 months with AngII (1 nmol g BW(-1)). Then the isolated hearts were subjected to morphological and western blotting analyses, and nitrite measurements. If compared to control animals, the ventricle of AngII-treated hearts showed an increase in compacta thickness, vascularization, muscle mass and fibrosis. Structural changes were paralleled by a higher expression of AT2 receptor and a negative modulation of the ERK1-2 pathway, together with a decrease in nitrite concentration, indicative of a reduced Nitric Oxide Synthase (NOS)-dependent NO production. Moreover, immunolocalization revealed, particularly on the endocardial endothelium (EE) of AngII-treated hearts, a significant reduction of phosphorylated NOS detected by peNOS antibody accompanied by an increased expression of the eNOS disabling protein NOSTRIN, and a decreased expression of the positive regulators of NOS activity, pAkt and Hsp90. On the whole, results suggest that, in the eel, AngII modulates cardiac morpho-functional plasticity by influencing the molecular mechanisms that control NOS activity and the ERK1-2 pathway.

  5. Properly timed exposure to central ANG II prevents behavioral sensitization and changes in angiotensin receptor expression

    PubMed Central

    Santollo, Jessica; Whalen, Philip E.; Speth, Robert C.; Clark, Stewart D.

    2014-01-01

    Previous studies show that the angiotensin type 1 receptor (AT1R) is susceptible to rapid desensitization, but that more chronic treatments that stimulate ANG II lead to sensitization of several responses. It is unclear, however, if the processes of desensitization and sensitization interact. To test for differences in AT1R expression associated with single or repeated injections of ANG II, we measured AT1R mRNA in nuclei that control fluid intake of rats given ANG II either in a single injection or divided into three injections spaced 20 min apart. Rats given a single injection of ANG II had more AT1R mRNA in the subfornical organ (SFO) and the periventricular tissue surrounding the anteroventral third ventricle (AV3V) than did controls. The effect was not observed, however, when the same cumulative dose of ANG II was divided into multiple injections. Behavioral tests found that single daily injections of ANG II sensitized the dipsogenic response to ANG II, but a daily regimen of four injections did not cause sensitization. Analysis of 125I-Sar1-ANG II binding revealed a paradoxical decrease in binding in the caudal AV3V and dorsal median preoptic nucleus after 5 days of single daily injections of ANG II; however, this effect was absent in rats treated for 5 days with four daily ANG II injections. Taken together, these data suggest that a desensitizing treatment regimen prevents behavior- and receptor-level effects of repeated daily ANG II. PMID:25354729

  6. Norepinephrine uptake by rat jejunum: Modulation by angiotensin II

    SciTech Connect

    Suvannapura, A.; Levens, N.R. )

    1988-02-01

    Angiotensin II (ANG II) is believed to stimulate sodium and water absorption from the small intestine by enhancing sympathetic nerve transmission. This study is designed to determine whether ANG II can enhance sympathetic neurotransmission within the small intestine by inhibition norepinephrine (NE) uptake. Intracellular NE accumulation by rat jejunum was concentration dependent and resolved into high- and low-affinity components. The high-affinity component (uptake 1) exhibited a Michaelis constant (K{sub m}) of 1.72 {mu}M and a maximum velocity (V{sub max}) of 1.19 nmol {center dot} g{sup {minus}1} {center dot} 10 min{sup {minus}1}. The low-affinity component (uptake 2) exhibited a K{sub m} of 111.1 {mu}M and a V{sub max} of 37.1 nmol {center dot} g{sup {minus}1} {center dot} 10 min{sup {minus}1}. Cocaine, an inhibitor of neuronal uptake, inhibited the intracellular accumulation of label by 80%. Treatment of animals with 6-hydroxydopamine, which depletes norepinephrine from sympathetic terminals, also attenuated NE uptake by 60%. Thus accumulation within sympathetic nerves constitutes the major form of ({sup 3}H)NE uptake into rat jejunum. ANG II inhibited intracellular ({sup 3}H)NE uptake in a concentration-dependent manner. At a dose of 1 mM, ANG II inhibited intracellular ({sup 3}H)NE accumulation by 60%. Cocaine failed to potentiate the inhibition of ({sup 3}H)NE uptake produced by ANG II. Thus ANG II appears to prevent ({sup 3}H)NE accumulation within rat jejunum by inhibiting neuronal uptake.

  7. Relationship between angiotensin-(1-7) and angiotensin II correlates with hemodynamic changes in human liver cirrhosis

    PubMed Central

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

    2009-01-01

    AIM: To measure circulating angiotensins at different stages of human cirrhosis and to further evaluate a possible relationship between renin angiotensin system (RAS) components and hemodynamic changes. METHODS: Patients were allocated into 4 groups: mild-to-moderate liver disease (MLD), advanced liver disease (ALD), patients undergoing liver transplantation, and healthy controls. Blood was collected to determine plasma renin activity (PRA), angiotensin (Ang) I, Ang II, and Ang-(1-7) levels using radioimmunoassays. During liver transplantation, hemodynamic parameters were determined and blood was simultaneously obtained from the portal vein and radial artery in order to measure RAS components. RESULTS: PRA and angiotensins were elevated in ALD when compared to MLD and controls (P < 0.05). In contrast, Ang II was significantly reduced in MLD. Ang-(1-7)/Ang II ratios were increased in MLD when compared to controls and ALD. During transplantation, Ang II levels were lower and Ang-(1-7)/Ang II ratios were higher in the splanchnic circulation than in the peripheral circulation (0.52 ± 0.08 vs 0.38 ± 0.04, P < 0.02), whereas the peripheral circulating Ang II/Ang I ratio was elevated in comparison to splanchnic levels (0.18 ± 0.02 vs 0.13 ± 0.02, P < 0.04). Ang-(1-7)/Ang II ratios positively correlated with cardiac output (r = 0.66) and negatively correlated with systemic vascular resistance (r = -0.70). CONCLUSION: Our findings suggest that the relationship between Ang-(1-7) and Ang II may play a role in the hemodynamic changes of human cirrhosis. PMID:19469002

  8. The Hippo pathway is controlled by Angiotensin II signaling and its reactivation induces apoptosis in podocytes

    PubMed Central

    Wennmann, D O; Vollenbröker, B; Eckart, A K; Bonse, J; Erdmann, F; Wolters, D A; Schenk, L K; Schulze, U; Kremerskothen, J; Weide, T; Pavenstädt, H

    2014-01-01

    The Hippo pathway fulfills a crucial function in controlling the balance between proliferation, differentiation and apoptosis in cells. Recent studies showed that G protein-coupled receptors (GPCRs) serve as upstream regulators of Hippo signaling, that either activate or inactivate the Hippo pathway via the large tumor suppressor kinase (LATS) and its substrate, the co-transcription factor Yes-associated protein (YAP). In this study, we focused on the Angiotensin II type 1 receptor (AT1R), which belongs to the GPCR family and has an essential role in the control of blood pressure and water homeostasis. We found that Angiotensin II (Ang II) inactivates the pathway by decreasing the activity of LATS kinase; therefore, leading to an enhanced nuclear shuttling of unphosphorylated YAP in HEK293T cells. This shuttling of YAP is actin-dependent as disruption of the actin cytoskeleton inhibited dephosphorylation of LATS and YAP. Interestingly, in contrast to HEK293T cells, podocytes, which are a crucial component of the glomerular filtration barrier, display a predominant nuclear YAP localization in vivo and in vitro. Moreover, stimulation with Ang II did not alter Hippo pathway activity in podocytes, which show a deactivated pathway. Reactivation of the LATS kinase activity in podocytes resulted in an increased cytoplasmic YAP localization accompanied by a strong induction of apoptosis. Thus, our work indicates that the control of LATS activation and subsequent YAP localization is important for podocyte homeostasis and survival. PMID:25393475

  9. Angiotensin type 1a receptor deficiency decreases amyloid β-protein generation and ameliorates brain amyloid pathology

    PubMed Central

    Liu, Junjun; Liu, Shuyu; Matsumoto, Yukino; Murakami, Saki; Sugakawa, Yusuke; Kami, Ayako; Tanabe, Chiaki; Maeda, Tomoji; Michikawa, Makoto; Komano, Hiroto; Zou, Kun

    2015-01-01

    Alzheimer’s disease is characterized by neuronal loss and cerebral accumulation of amyloid-β protein (Aβ) and lowering the generation of Aβ is a pivotal approach in the strategy of Alzheimer’s disease treatment. Midlife hypertension is a major risk factor for the future onset of sporadic Alzheimer’s disease and the use of some antihypertensive drugs may decrease the incidence of Alzheimer’s disease. However, it is largely unknown how the blood pressure regulation system is associated with the pathogenesis of Alzheimer’s disease. Here we found that the deficiency of angiotensin type 1a receptor (AT1a), a key receptor for regulating blood pressure, significantly decreased Aβ generation and amyloid plaque formation in a mouse model of Alzheimer’s disease. The lack of AT1a inhibited the endocleavage of presenilin-1 (PS1), which is essential for γ-secretase complex formation and Aβ generation. Notably, the ligand of AT1a, angiotensin II, enhanced Aβ generation, PS1 endocleavage and γ-secretase complex formation. Our results suggest that AT1a activation is closely associated with Aβ generation and brain amyloid accumulation by regulating γ-secretase complex formation. Thus, removal of life style factors or stresses that stimulate AT1a to elevate blood pressure may decrease Aβ generation and brain amyloid accumulation, thereby preventing the pathogenesis of Alzheimer’s disease. PMID:26154270

  10. Inhibition of Angiotensin II receptors during pregnancy induces malformations in developing rat kidney.

    PubMed

    Sánchez, Susana I; Seltzer, Alicia M; Fuentes, Lucia B; Forneris, Myriam L; Ciuffo, Gladys M

    2008-06-24

    Evidence suggests that Angiotensin II plays an important role in the complex process of renal organogenesis. Rat kidney organogenesis starts between E13-14 and lasts up to 2 weeks after birth. The present study demonstrates histologic modifications and changes in receptor localisation in animals born from mothers treated with Angiotensin II, Losartan or PD123319 (1.0 mg/kg/day) during late pregnancy. Angiotensin II-treated animals exhibited very well developed tubules in the renal medulla in coincidence with higher AT(1) binding. Control animals exhibited angiotensin AT(2) binding in the outer stripe of the outer medulla, while in the Angiotensin II-treated animals binding was observed to the inner stripe. In Angiotensin II-treated 1-week-old animals, the nephrogenic zone contained fewer immature structures, and more developed collecting tubules than control animals. Treatment with Losartan resulted in severe renal abnormalities. For newborn and 1-week-old animals, glomeruli exhibited altered shape and enlarged Bowman spaces, in concordance with a loss of [(125)I]Angiotensin II binding in the cortex. Blockade with PD123319 led to an enlarged nephrogenic zone with increased number of immature glomeruli, and less glomeruli in the juxtamedullary area. Autoradiography showed a considerable loss of AT(1) binding in the kidney cortex of PD123319-treated animals at both ages. The present results show for the first time histomorphological and receptor localisation alterations following treatment with low doses of Losartan and PD123319 during pregnancy. These observations confirm previous assumptions that in the developing kidney Angiotensin II exerts stimulatory effects through AT(1) receptors that might be counterbalanced by angiotensin AT(2) receptors.

  11. Angiotensin-(1–7) Suppresses Hepatocellular Carcinoma Growth and Angiogenesis via Complex Interactions of Angiotensin II Type 1 Receptor, Angiotensin II Type 2 Receptor and Mas Receptor

    PubMed Central

    Liu, Yanping; Li, Bin; Wang, Ximing; Li, Guishuang; Shang, Rui; Yang, Jianmin; Wang, Jiali; Zhang, Meng; Chen, Yuguo; Zhang, Yun; Zhang, Cheng; Hao, Panpan

    2015-01-01

    We recently confirmed that angiotensin II (Ang II) type 1 receptor (AT1R) was overexpressed in hepatocellular carcinoma tissue using a murine hepatoma model. Angiotensin(Ang)-(1–7) has been found beneficial in ameliorating lung cancer and prostate cancer. Which receptor of Ang-(1–7) is activated to mediate its effects is much speculated. This study was designed to investigate the effects of Ang-(1–7) on hepatocellular carcinoma, as well as the probable mechanisms. H22 hepatoma-bearing mice were randomly divided into five groups for treatment: mock group, low-dose Ang-(1–7), high-dose Ang-(1–7), high-dose Ang-(1–7) + A779 and high-dose Ang-(1–7) + PD123319. Ang-(1–7) treatment inhibited tumor growth time- and dose-dependently by arresting tumor proliferation and promoting tumor apoptosis as well as inhibiting tumor angiogenesis. The effects of Ang-(1–7) on tumor proliferation and apoptosis were reversed by coadministration with A779 or PD123319, whereas the effects on tumor angiogenesis were completely reversed by A779 but not by PD123319. Moreover, Ang-(1–7) downregulated AT1R mRNA, upregulated mRNA levels of Ang II type 2 receptor (AT2R) and Mas receptor (MasR) and p38-MAPK phosphorylation and suppressed H22 cell–endothelial cell communication. Thus, Ang-(1–7) administration suppresses hepatocellular carcinoma via complex interactions of AT1R, AT2R and MasR and may provide a novel and promising approach for the treatment of hepatocellular carcinoma. PMID:26225830

  12. Angiotensin-(1-7) Suppresses Hepatocellular Carcinoma Growth and Angiogenesis via Complex Interactions of Angiotensin II Type 1 Receptor, Angiotensin II Type 2 Receptor and Mas Receptor.

    PubMed

    Liu, Yanping; Li, Bin; Wang, Ximing; Li, Guishuang; Shang, Rui; Yang, Jianmin; Wang, Jiali; Zhang, Meng; Chen, Yuguo; Zhang, Yun; Zhang, Cheng; Hao, Panpan

    2015-07-27

    We recently confirmed that angiotensin II (Ang II) type 1 receptor (AT1R) was overexpressed in hepatocellular carcinoma tissue using a murine hepatoma model. Angiotensin(Ang)-(1-7) has been found beneficial in ameliorating lung cancer and prostate cancer. Which receptor of Ang-(1-7) is activated to mediate its effects is much speculated. This study was designed to investigate the effects of Ang-(1-7) on hepatocellular carcinoma, as well as the probable mechanisms. H22 hepatoma-bearing mice were randomly divided into five groups for treatment: mock group, low-dose Ang-(1-7), high-dose Ang-(1-7), high-dose Ang-(1-7) + A779 and high-dose Ang-(1-7) + PD123319. Ang-(1-7) treatment inhibited tumor growth time- and dose-dependently by arresting tumor proliferation and promoting tumor apoptosis as well as inhibiting tumor angiogenesis. The effects of Ang-(1-7) on tumor proliferation and apoptosis were reversed by coadministration with A779 or PD123319, whereas the effects on tumor angiogenesis were completely reversed by A779 but not by PD123319. Moreover, Ang-(1-7) downregulated AT1R mRNA, upregulated mRNA levels of Ang II type 2 receptor (AT2R) and Mas receptor (MasR) and p38-MAPK phosphorylation and suppressed H22 cell-endothelial cell communication. Thus, Ang-(1-7) administration suppresses hepatocellular carcinoma via complex interactions of AT1R, AT2R and MasR and may provide a novel and promising approach for the treatment of hepatocellular carcinoma.

  13. Angiotensin II-Activated Protein Kinase D Mediates Acute Aldosterone Secretion

    PubMed Central

    Shapiro, Brian A.; Olala, Lawrence; Arun, Senthil Nathan; Parker, Peter M.; George, Mariya V.; Bollag, Wendy B.

    2009-01-01

    Summary Dysregulation of the renin-angiotensin II (AngII)-aldosterone system can contribute to cardiovascular disease, such that an understanding of this system is critical. Diacylglycerol-sensitive serine/threonine protein kinase D (PKD) is activated by AngII in several systems, including the human adrenocortical carcinoma cell line NCI H295R, where this enzyme enhances chronic (24 hours) AngII-evoked aldosterone secretion. However, the role of PKD in acute AngII-elicited aldosterone secretion has not been previously examined. In primary cultures of bovine adrenal glomerulosa cells, which secrete detectable quantities of aldosterone in response to secretagogues within minutes, PKD was activated in response to AngII, but not an elevated potassium concentration or adrenocorticotrophic hormone. This activation was time- and dose-dependent and occurred through the AT1, but not the AT2, receptor. Adenovirus-mediated overexpression of constitutively-active PKD resulted in enhanced AngII-induced aldosterone secretion; whereas overexpression of a dominant-negative PKD construct decreased AngII-stimulated aldosterone secretion. Thus, we demonstrate for the first time that PKD mediates acute AngII-induced aldosterone secretion. PMID:19961896

  14. Endothelial AT₁ and AT₂ pathways in aortic responses to angiotensin II after stress and ethanol consumption in rats.

    PubMed

    Baptista, Rafaela de Fátima Ferreira; Chies, Agnaldo Bruno; Taipeiro, Elane de Fátima; Cordellini, Sandra

    2014-12-01

    Stress and ethanol are important cardiovascular risk factors. Their vascular and blood pressure (BP) effects were evaluated alone and in combination. Adult male Wistar rats (8-10 per group) were separated into control, ethanol (ethanol 20% in drinking water for 6 weeks), stress (restraint 1 h/d 5 d/week for 6 weeks), and ethanol/stress (in combination) groups. Systolic BP was evaluated weekly. Concentration-response curves for contractile responses to angiotensin II in the absence and the presence of losartan (AT1-blocker), PD123-319 (AT2-blocker), L-NAME (nitric oxide synthase inhibitor), or indomethacin (cyclooxygenase inhibitor) were obtained in isolated intact and endothelium-denuded aortas. Effective concentration 50% (EC50) and maximum response (MR) were compared among groups using MANOVA/Tukey tests. Stress and stress plus ethanol increased BP. Ethanol and stress, alone and in combination, did not alter angiotensin responses of intact aortas. PD123-319 decreased MR to angiotensin II in intact aortas from the ethanol and ethanol/stress groups relative to control in the presence of PD123-319. Losartan increased MR to angiotensin II in intact aortas from the stress and ethanol/stress groups relative to control in the presence of losartan. None of the protocols altered angiotensin responses of denuded aortas. Neither indomethacin nor L-NAME altered angiotensin responses of intact aortas from the experimental groups. Thus ethanol and ethanol plus stress may alter endothelial signaling via AT1-receptors, without changing systemic BP. Stress and stress plus ethanol may alter endothelial signaling via AT2-receptors, and thereby increase BP. Knowledge of such vascular changes induced by stress and/or ethanol may contribute to understanding adverse cardiovascular effects of stress and ethanol consumption in humans.

  15. Activation of Central PPAR-γ Attenuates Angiotensin II-Induced Hypertension

    PubMed Central

    Yu, Yang; Xue, Bao-Jian; Wei, Shun-Guang; Zhang, Zhi-Hua; Beltz, Terry G; Guo, Fang; Johnson, Alan Kim; Felder, Robert B

    2015-01-01

    Inflammation and renin-angiotensin system activity in the brain contribute to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. We recently reported that activation of brain peroxisome proliferator-activated receptor (PPAR)-γ in heart failure rats reduced inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorated the peripheral manifestations of heart failure. We hypothesized that activation of brain PPAR-γ might have beneficial effects in angiotensin II-induced hypertension. Sprague-Dawley rats received a 2-week subcutaneous infusion of angiotensin II (120 ng/kg/min) combined with a continuous intracerebroventricular infusion of vehicle, the PPAR-γ agonist pioglitazone (3 nmol/h) or the PPAR-γ antagonist GW9662 (7 nmol/h). Angiotensin II+vehicle rats had increased mean blood pressure, increased sympathetic drive as indicated by the mean blood pressure response to ganglionic blockade, and increased water consumption. PPAR-γ mRNA in subfornical organ and hypothalamic paraventricular nucleus was unchanged, but PPAR-γ DNA binding activity was reduced. mRNA for interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2 and angiotensin II type-1 receptor was augmented in both nuclei, and hypothalamic paraventricular nucleus neuronal activity was increased. The plasma vasopressin response to a 6-hour water restriction also increased. These responses to angiotensin II were exacerbated by GW9662 and ameliorated by pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA binding activity in subfornical organ and hypothalamic paraventricular nucleus. Pioglitazone and GW9662 had no effects on control rats. The results suggest that activating brain PPAR-γ to reduce central inflammation and brain renin-angiotensin system activity may be a useful adjunct in the treatment of angiotensin II-dependent hypertension. PMID:26101342

  16. Activation of central PPAR-γ attenuates angiotensin II-induced hypertension.

    PubMed

    Yu, Yang; Xue, Bao-Jian; Wei, Shun-Guang; Zhang, Zhi-Hua; Beltz, Terry G; Guo, Fang; Johnson, Alan Kim; Felder, Robert B

    2015-08-01

    Inflammation and renin-angiotensin system activity in the brain contribute to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. We recently reported that activation of brain peroxisome proliferator-activated receptor (PPAR)-γ in heart failure rats reduced inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorated the peripheral manifestations of heart failure. We hypothesized that the activation of brain PPAR-γ might have beneficial effects in angiotensin II-induced hypertension. Sprague-Dawley rats received a 2-week subcutaneous infusion of angiotensin II (120 ng/kg per minute) combined with a continuous intracerebroventricular infusion of vehicle, the PPAR-γ agonist pioglitazone (3 nmol/h) or the PPAR-γ antagonist GW9662 (7 nmol/h). Angiotensin II+vehicle rats had increased mean blood pressure, increased sympathetic drive as indicated by the mean blood pressure response to ganglionic blockade, and increased water consumption. PPAR-γ mRNA in subfornical organ and hypothalamic paraventricular nucleus was unchanged, but PPAR-γ DNA-binding activity was reduced. mRNA for interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2, and angiotensin II type 1 receptor was augmented in both nuclei, and hypothalamic paraventricular nucleus neuronal activity was increased. The plasma vasopressin response to a 6-hour water restriction also increased. These responses to angiotensin II were exacerbated by GW9662 and ameliorated by pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA-binding activity in subfornical organ and hypothalamic paraventricular nucleus. Pioglitazone and GW9662 had no effects on control rats. The results suggest that activating brain PPAR-γ to reduce central inflammation and brain renin-angiotensin system activity may be a useful adjunct in the treatment of angiotensin II-dependent hypertension.

  17. Mitochondrial aldehyde dehydrogenase prevents ROS-induced vascular contraction in angiotensin-II hypertensive mice.

    PubMed

    Choi, Hyehun; Tostes, Rita C; Webb, R Clinton

    2011-01-01

    Mitochondrial aldehyde dehydrogenase (ALDH2) is an enzyme that detoxifies aldehydes to carboxylic acids. ALDH2 deficiency is known to increase oxidative stress, which is the imbalance between reactive oxygen species (ROS) generation and antioxidant defense activity. Increased ROS contribute to vascular dysfunction and structural remodeling in hypertension. We hypothesized that ALDH2 plays a protective role to reduce vascular contraction in angiotensin-II (AngII) hypertensive mice. Endothelium-denuded aortic rings from C57BL6 mice, treated with AngII (3.6 μg/kg/min, 14 days), were used to measure isometric force development. Rings treated with daidzin (10 μmol/L), an ALDH2 inhibitor, potentiated contractile responses to phenylephrine (PE) in AngII mice. Tempol (1 mmol/L) and catalase (600 U/mL) attenuated the augmented contractile effect of daidzin. In normotensive mice, contraction to PE in the presence of the daidzin was not different from control, untreated values. AngII aortic rings transfected with ALDH2 recombinant protein decreased contractile responses to PE compared with control. These data suggest that ALDH2 reduces vascular contraction in AngII hypertensive mice. Because tempol and catalase blocked the contractile response of the ALDH2 inhibitor, ROS generation by AngII may be decreased by ALDH2, thereby preventing ROS-induced contraction.

  18. Can intradermal administration of angiotensin II influence human heat loss responses during whole body heat stress?

    PubMed

    Fujii, Naoto; Meade, Robert D; Paull, Gabrielle; McGinn, Ryan; Foudil-bey, Imane; Akbari, Pegah; Kenny, Glen P

    2015-05-01

    It is unclear if angiotensin II, which can increase the production of reactive oxygen species (oxidative stress), modulates heat loss responses of cutaneous blood flow and sweating. We tested the hypothesis that angiotensin II-induced increases in oxidative stress impair cutaneous perfusion and sweating during rest and exercise in the heat. Eleven young (24 ± 4 yr) healthy adults performed two 30-min cycling bouts at a fixed rate of metabolic heat production (400 W) in the heat (35°C). The first and second exercises were followed by a 20- and 40-min recovery. Four microdialysis fibers were placed in the forearm skin for continuous administration of either: 1) lactated Ringer (control), 2) 10 μM angiotensin II, 3) 10 mM ascorbate (an antioxidant), or 4) a combination of 10 μM angiotensin II + 10 mM ascorbate. Cutaneous vascular conductance (CVC; laser-Doppler perfusion units/mean arterial pressure) and sweating (ventilated capsule) were evaluated at each skin site. Compared with control, angiotensin II reduced both CVC and sweating at baseline resting and during each recovery in the heat (all P < 0.05). However, during both exercise bouts, there were no differences in CVC or sweating between the treatment sites (all P > 0.05). When ascorbate was coinfused with angiotensin II, the effect of angiotensin II on sweating was abolished (all P > 0.05); however, its effect on CVC at baseline resting and during each recovery remained intact (all P < 0.05). We show angiotensin II impairs cutaneous perfusion independent of oxidative stress, while it impairs sweating through increasing oxidative stress during exposure to an ambient heat stress before and following exercise.

  19. Can intradermal administration of angiotensin II influence human heat loss responses during whole body heat stress?

    PubMed Central

    Fujii, Naoto; Meade, Robert D.; Paull, Gabrielle; McGinn, Ryan; Foudil-bey, Imane; Akbari, Pegah

    2015-01-01

    It is unclear if angiotensin II, which can increase the production of reactive oxygen species (oxidative stress), modulates heat loss responses of cutaneous blood flow and sweating. We tested the hypothesis that angiotensin II-induced increases in oxidative stress impair cutaneous perfusion and sweating during rest and exercise in the heat. Eleven young (24 ± 4 yr) healthy adults performed two 30-min cycling bouts at a fixed rate of metabolic heat production (400 W) in the heat (35°C). The first and second exercises were followed by a 20- and 40-min recovery. Four microdialysis fibers were placed in the forearm skin for continuous administration of either: 1) lactated Ringer (control), 2) 10 μM angiotensin II, 3) 10 mM ascorbate (an antioxidant), or 4) a combination of 10 μM angiotensin II + 10 mM ascorbate. Cutaneous vascular conductance (CVC; laser-Doppler perfusion units/mean arterial pressure) and sweating (ventilated capsule) were evaluated at each skin site. Compared with control, angiotensin II reduced both CVC and sweating at baseline resting and during each recovery in the heat (all P < 0.05). However, during both exercise bouts, there were no differences in CVC or sweating between the treatment sites (all P > 0.05). When ascorbate was coinfused with angiotensin II, the effect of angiotensin II on sweating was abolished (all P > 0.05); however, its effect on CVC at baseline resting and during each recovery remained intact (all P < 0.05). We show angiotensin II impairs cutaneous perfusion independent of oxidative stress, while it impairs sweating through increasing oxidative stress during exposure to an ambient heat stress before and following exercise. PMID:25767030

  20. Angiotensin II has acute effects on TRPC6 channels in podocytes of freshly isolated glomeruli

    PubMed Central

    Ilatovskaya, Daria V.; Palygin, Oleg; Chubinskiy-Nadezhdin, Vladislav; Negulyaev, Yuri A.; Ma, Rong; Birnbaumer, Lutz; Staruschenko, Alexander

    2014-01-01

    A key role for podocytes in the pathogenesis of proteinuric renal diseases has been established. Angiotensin II causes depolarization and increased intracellular calcium concentration in podocytes; members of the cation TRPC channels family, particularly TRPC6, are proposed as proteins responsible for calcium flux. Angiotensin II evokes calcium transient through TRPC channels and mutations in the gene encoding the TRPC6 channel result in the development of focal segmental glomerulosclerosis. Here we examined the effects of angiotensin II on intracellular calcium ion levels and endogenous channels in intact podocytes of freshly isolated decapsulated mouse glomeruli. An ion channel with distinct TRPC6 properties was identified in wild type, but was absent in TRPC6 knockout mice. Single channel electrophysiological analysis found that angiotensin II acutely activated native TRPC-like channels in both podocytes of freshly isolated glomeruli and TRPC6 channels transiently overexpressed in CHO cells; the effect was mediated by changes in the channel open probability. Angiotensin II evoked intracellular calcium transients in the wild type podocytes, which was blunted in TRPC6 knockout glomeruli. Pan-TRPC inhibitors gadolinium and SKF 96365 reduced the response in wild type glomerular epithelial cells, whereas the transient in TRPC6 knockout animals was not affected. Thus, angiotensin II-dependent activation of TRPC6 channels in podocytes may have a significant role in the development of kidney diseases. PMID:24646854

  1. Increased intracellular free calcium and sensitivity to angiotensin II in platelets of preeclamptic women.

    PubMed

    Haller, H; Oeney, T; Hauck, U; Distler, A; Philipp, T

    1989-04-01

    Preeclampsia is characterized by a generalized vasoconstriction and increased vascular sensitivity to angiotensin II. Intracellular free calcium, implicated in vascular smooth muscle contraction, has been found to be elevated in platelets of other hypertensive disorders. We therefore measured intracellular free calcium concentrations by using the fluorescent probe quin-2 in platelets of six patients with preeclampsia and compared them to measurements in ten normotensive pregnant women and ten age-matched nonpregnant women. Intracellular free calcium was also determined in the preeclamptic women after delivery. We found that intracellular free calcium was slightly elevated in normal pregnancy (102 +/- 13 nmol/L v 87 +/- 17 nmol/L) but was markedly increased in preeclampsia (138 +/- 13 nmol/L, P less than .05). This increase disappeared six weeks after delivery (84 + 10 nmol/L, P less than .01). To investigate whether the increased intracellular free calcium was related to angiotensin II, the platelets were exposed to thrombin and angiotensin II in vitro. Exposure to thrombin and angiotensin II caused a dose-dependent increase in intracellular free calcium. The intracellular response to thrombin was not significantly different in the three groups. However, stimulation with angiotensin II revealed an increased response in intracellular free calcium in preeclampsia (P less than .05) that disappeared after delivery. Our findings show a sustained increase in platelet intracellular free calcium in preeclampsia and suggest a functional alteration of the angiotensin II receptor in this disease.

  2. Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonist attenuate tumor growth via polarization of neutrophils toward an antitumor phenotype

    PubMed Central

    Shrestha, Sanjeeb; Noh, Jae Myoung; Kim, Shin-Yeong; Ham, Hwa-Yong; Kim, Yeon-Ja; Yun, Young-Jin; Kim, Min-Ju; Kwon, Min-Soo; Song, Dong-Keun; Hong, Chang-Won

    2016-01-01

    ABSTRACT Tumor microenvironments polarize neutrophils to protumoral phenotypes. Here, we demonstrate that the angiotensin converting enzyme inhibitors (ACEis) and angiotensin II type 1 receptor (AGTR1) antagonist attenuate tumor growth via polarization of neutrophils toward an antitumoral phenotype. The ACEis or AGTR1 antagonist enhanced hypersegmentation of human neutrophils and increased neutrophil cytotoxicity against tumor cells. This neutrophil hypersegmentation was dependent on the mTOR pathway. In a murine tumor model, ACEis and AGTR1 antagonist attenuated tumor growth and enhanced neutrophil hypersegmentation. ACEis inhibited tumor-induced polarization of neutrophils to a protumoral phenotype. Neutrophil depletion reduced the antitumor effect of ACEi. Together, these data suggest that the modulation of Ang II pathway attenuates tumor growth via polarization of neutrophils to an antitumoral phenotype. PMID:26942086

  3. 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.

  4. Angiotensin II natriuresis and anti-natriuresis: role of renal artery pressure in anaesthetized dogs.

    PubMed

    Olsen, M E; Hall, J E; Montaini, J P; Guyton, A C

    1984-12-01

    The aim of this study was to determine the role of changes in renal artery pressure (RAP), renal haemodynamics, and tubular reabsorption in mediating the natriuretic and anti-natriuretic actions of angiotensin II (ANG II). In anaesthetized dogs, endogenous ANG II formation was blocked with SQ-14225 and ANG II was infused intravenously at rates of 5-1215 ng/kg/min while RAP was either servo-controlled at the normal level or permitted to increase. When RAP was servo-controlled to prevent a rise in RAP, ANG II infusion at all rates from 5-1215 ng/kg/min decreased urinary sodium excretion (INaV) and fractional sodium excretion (FENa), while increasing fractional reabsorption of lithium (FRLi), an index of proximal tubule fractional sodium reabsorption (FRDNa). When RAP was permitted to increase, ANG II infusion rates up to 45 ng/kg/min decreased UNaV, and FENam while increasing FRLi and FRDNa greater than However, at 135 ng/kg/min and above UNaV and FENE increased while FRLi and FRDNa decreased when RAP was allowed to rise, even though renal blood flow and filtration fraction were not substantially different from the values observed when RAP was servo-controlled. Filtered sodium load was slightly higher when RAP was permitted to increase during ANG II infusion, compared to the dogs in which RAP was servo-controlled, although the differences were not statistically significant. Thus, even very large doses of ANG II cause anti-natriuresis when RAP is prevented from increasing. The natriuretic effect of high doses of ANG II is caused by increased RAP which decreases fractional sodium reabsorption in proximal and distal tubules and causes slight increase in sodium delivery to the tubules.

  5. Pressor responsiveness to angiotensin II in female mice is enhanced with age: role of the angiotensin type 2 receptor

    PubMed Central

    2014-01-01

    Background The pressor response to angiotensin II (AngII) is attenuated in adult females as compared to males via an angiotensin type 2 receptor (AT2R)-dependent pathway. We hypothesized that adult female mice are protected against AngII-induced hypertension via an enhanced AT2R-mediated pathway and that in reproductively senescent females this pathway is no longer operative. Methods Mean arterial pressure was measured via telemetry in 4-month-old (adult) and 16-month-old (aged) and aged ovariectomized (aged-OVX) wild-type and AT2R knockout (AT2R-KO) female mice during baseline and 14-day infusion of vehicle (saline) or AngII (600 ng/kg/min s.c.). Real-time reverse transcription polymerase chain reaction (RT-PCR) was used to determine renal gene expression of angiotensin receptors and angiotensin-converting enzyme 2 in response to 14-day treatment with vehicle or AngII. Results Basal mean arterial pressure was similar between the groups. The pressor response to AngII was augmented in adult AT2R-KO compared to adult wild-type mice (29 ± 3 mmHg versus 10 ± 4 mmHg, respectively, on day 14 as compared to basal mean arterial pressure, P = 0.002). In wild-type mice, pressor responsiveness to AngII was augmented with age, such that the pressor response to AngII was similar between aged AT2R-KO and wild-type female mice (31 ± 4 mmHg versus 34 ± 3 mmHg, respectively, on day 14, P = 0.9). There were no significant differences in pressor responsiveness to AngII between aged and aged-OVX mice. Vehicle-treated aged wild-type mice had a lower renal AT2R/AT1R balance as compared to adult counterparts. In response to AngII, the renal AT2R/AT1R balance in aged wild-type females was greater than that observed in vehicle-treated aged wild-type females and adult wild-type females, yet the protective effects of AT2R activation were not restored. Conclusions The protective role of the AT2R depressor pathway is lost with age in female mice. Therefore

  6. 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.

  7. Autoradiographic localization of angiotensin II receptors in rat brain.

    PubMed Central

    Mendelsohn, F A; Quirion, R; Saavedra, J M; Aguilera, G; Catt, K J

    1984-01-01

    The 125I-labeled agonist analog [1-sarcosine]-angiotensin II ( [Sar1]AII) bound with high specificity and affinity (Ka = 2 X 10(9) M-1) to a single class of receptor sites in rat brain. This ligand was used to analyze the distribution of AII receptors in rat brain by in vitro autoradiography followed by computerized densitometry and color coding. A very high density of AII receptors was found in the subfornical organ, paraventricular and periventricular nuclei of the hypothalamus, nucleus of the tractus solitarius, and area postrema. A high concentration of receptors was found in the suprachiasmatic nucleus of the hypothalamus, lateral olfactory tracts, nuclei of the accessory and lateral olfactory tracts, triangular septal nucleus, subthalamic nucleus, locus coeruleus, and inferior olivary nuclei. Moderate receptor concentrations were found in the organum vasculosum of the lamina terminalis, median preoptic nucleus, medial habenular nucleus, lateral septum, ventroposterior thalamic nucleus, median eminence, medial geniculate nucleus, superior colliculus, subiculum, pre- and parasubiculum, and spinal trigeminal tract. Low concentrations of sites were seen in caudate-putamen, nucleus accumbens, amygdala, and gray matter of the spinal cord. These studies have demonstrated that AII receptors are distributed in a highly characteristic anatomical pattern in the brain. The high concentrations of AII receptors at numerous physiologically relevant sites are consistent with the emerging evidence for multiple roles of AII as a neuropeptide in the central nervous system. Images PMID:6324205

  8. Angiotensin II-noradrenergic interactions in renovascular hypertensive rats.

    PubMed Central

    Zimmerman, J B; Robertson, D; Jackson, E K

    1987-01-01

    This study tested the hypothesis that interactions of endogenous angiotensin II (AII) with the noradrenergic neuroeffector junction are important in renin-dependent hypertension. In the in situ blood-perfused rat mesentery, in normal rats exogenous AII potentiated mesenteric vascular responses to periarterial (sympathetic) nerve stimulation (PNS) more than vascular responses to exogenous norepinephrine (NE). In 2-kidney-1-clip (2K-1C) rats with renovascular hypertension mesenteric vascular responses to PNS and NE were greater than in sham-operated rats, and renovascular hypertension mimicked the effects of exogenous AII with respect to enhancing responses to PNS more than responses to NE. In 2K-1C rats, but not in sham-operated rats, 1-Sar-8-Ile-AII markedly suppressed vascular responses to PNS, without influencing responses to NE. Finally, 1-Sar-8-Ile-AII attenuated sympathetic nerve stimulation-induced neuronal spillover of NE in 2K-1C rats, but not in sham-operated rats. These data indicate that renovascular hypertension enhances noradrenergic neurotransmission, and that this enhancement is mediated in part by AII-induced facilitation of NE release. PMID:3301900

  9. Autoradiographic localization of angiotensin II receptors in rat brain

    SciTech Connect

    Mendelsohn, F.A.O.; Quirion, R.; Saavedra, J.M.; Aguilera, G.; Catt, K.J.

    1984-03-01

    The /sup 125/I-labeled agonist analog (1-sarcosine)-angiotensin II ((Sar/sup 1/)AII) bound with high specificity and affinity (K/sub a/ = 2 x 10/sup 9/ M/sup -1/) to a single class of receptor sites in rat brain. This ligand was used to analyze the distribution of AII receptors in rat brain by in vitro autoradiography followed by computerized densitometry and color coding. A very high density of AII receptors was found in the subfornical organ, paraventricular and periventricular nuclei of the hypothalamus, nucleus of the tractus solitarius, and area postrema. A high concentration of receptors was found in the suprachiasmatic nucleus of the hypothalamus, lateral olfactory tracts, nuclei of the accessory and lateral olfactory tracts, triangular septal nucleus, subthalamic nucleus, locus coeruleus, and inferior olivary nuclei. Moderate receptor concentrations were found in the organum vasculosum of the lamina terminalis, median preoptic nucleus, medial habenular nucleus, lateral septum, ventroposterior thalamic nucleus, median eminence, medial geniculate nucleus, superior colliculus, subiculum, pre- and parasubiculum, and spinal trigeminal tract. Low concentrations of sites were seen in caudate-putamen, nucleus accumbens, amygdala, and gray matter of the spinal cord. These studies have demonstrated that AII receptors are distributed in a highly characteristic anatomical pattern in the brain. The high concentrations of AII receptors at numerous physiologically relevant sites are consistent with the emerging evidence for multiple roles of AII as a neuropeptide in the central nervous system. 75 references, 2 figures.

  10. Angiotensin 1-7 Receptor and Angiotensin II Receptor 2 Blockades Prevent the Increased Serum and Kidney Nitric Oxide Levels in Response to Angiotensin II Administration: Gender-Related Difference

    PubMed Central

    Safari, Tahereh; Nematbakhsh, Mehdi

    2013-01-01

    Background: The angiotensin II (Ang II) receptor 2 (AT2R) and angiotensin 1-7 receptor (masR) expression in the kidney are gender-related. We attempted to compare the response of nitric oxide (NO) production to Ang II administration, with and without AT2R and masR blockades, using A-779 and PD123319 in male and female rats. Methods: Anesthetized and catheterized male and female Wistar rats were subjected to one-hour continuous infusion of Ang II (~20 μg/kg/hour), with and without masR and AT2R blockades. The level of the NO metabolite (nitrite) was measured before and after the experiment in rat serum and in the homogenized kidney tissue. Results: The basal data indicated that no sex difference in the serum level of nitrite could be detected before Ang II infusion. However, administration of Ang II in male and female rats caused a gender difference in the nitrite level, which resulted in the serum level of the nitrite significantly increasing in males (P < 0.05) when compared with the females. In addition, masR blockade or co-blockade of masR and AT2R in male rats abolished the gender difference related to the effect of Ang II on nitrite production. In the presence of masR and AT2R, or when masR alone was blocked, the level of nitrite in the kidney, in response to the Ang II infusion was not significantly different between the two sexes. On the contrary, masR and AT2R co-blockades significantly decreased the kidney nitrite concentration response to Ang II administration in both male and female rats (P < 0.05), but no sex difference was detected. Conclusions: The renal vasculature of male rats may provide more response to Ang II administration-induced NO, which is dependent on masR and AT2R. During dual masR + AT2R blockades, the kidney NO formation wasreduced in a non-gender related manner. PMID:23626887

  11. 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.

  12. Debate: angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers--a gap in evidence-based medicine.

    PubMed

    Ball, Stephen G; White, William B

    2003-05-22

    In this article, 2 leading physicians debate the strength of outcome data on the efficacy of angiotensin-converting enzyme (ACE) inhibitors versus angiotensin II receptor blockers (ARBs) for reducing the incidence of cardiovascular, cerebrovascular, and renovascular events. Dr. Stephen G. Ball notes that the efficacy of ACE inhibitors for reducing the risk for myocardial infarction independent of their effects on blood pressure is controversial. In the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril treatment in high-risk patients was associated with a 20% reduction in the risk for myocardial infarction; mean reduction in blood pressure was 3 mm Hg for systolic blood pressure and 1 mm Hg for diastolic blood pressure. The HOPE investigators propose that the 20% reduction was much greater than would be expected based on the observed blood pressure reduction. However, a meta-regression analysis of blood pressure reduction in >20 antihypertensive therapy outcome trials found that the reduction in myocardial infarction risk with ramipril observed in HOPE was consistent with the modest blood pressure reduction seen with that agent. Nevertheless, there are convincing data for prevention of myocardial infarction with ACE inhibitors in patients with heart failure, including those with heart failure after myocardial infarction, as well as supportive evidence from studies in patients with diabetes mellitus and concomitant hypertension. On the other hand, Dr. William B. White takes the position that ARBs are well-tolerated antihypertensive agents that specifically antagonize the angiotensin II type 1 (AT(1)) receptor and provide a more complete block of the pathologic effects of angiotensin II-which are mediated via the AT(1) receptor-than ACE inhibitors. The Evaluation of Losartan in the Elderly (ELITE) II study and the Valsartan Heart Failure Trial (ValHeFT) suggest that ARBs reduce the risk for mortality in patients with congestive heart failure. The Losartan

  13. Dietary sodium intake regulates angiotensin II type 1, mineralocorticoid receptor, and associated signaling proteins in heart.

    PubMed

    Ricchiuti, Vincent; Lapointe, Nathalie; Pojoga, Luminita; Yao, Tham; Tran, Loc; Williams, Gordon H; Adler, Gail K

    2011-10-01

    Liberal or high-sodium (HS) intake, in conjunction with an activated renin-angiotensin-aldosterone system, increases cardiovascular (CV) damage. We tested the hypothesis that sodium intake regulates the type 1 angiotensin II receptor (AT(1)R), mineralocorticoid receptor (MR), and associated signaling pathways in heart tissue from healthy rodents. HS (1.6% Na(+)) and low-sodium (LS; 0.02% Na(+)) rat chow was fed to male healthy Wistar rats (n=7 animals per group). Protein levels were assessed by western blot and immunoprecipitation analysis. Fractionation studies showed that MR, AT(1)R, caveolin-3 (CAV-3), and CAV-1 were located in both cytoplasmic and membrane fractions. In healthy rats, consumption of an LS versus a HS diet led to decreased cardiac levels of AT(1)R and MR. Decreased sodium intake was also associated with decreased cardiac levels of CAV-1 and CAV-3, decreased immunoprecipitation of AT(1)R-CAV-3 and MR-CAV-3 complexes, but increased immunoprecipitation of AT(1)R/MR complexes. Furthermore, decreased sodium intake was associated with decreased cardiac extracellular signal-regulated kinase (ERK), phosphorylated ERK (pERK), and pERK/ERK ratio; increased cardiac striatin; decreased endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (peNOS), but increased peNOS/eNOS ratio; and decreased cardiac plasminogen activator inhibitor-1. Dietary sodium restriction has beneficial effects on the cardiac expression of factors associated with CV injury. These changes may play a role in the cardioprotective effects of dietary sodium restriction.

  14. Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors.

    PubMed

    Wang, Lei; de Kloet, Annette D; Pati, Dipanwita; Hiller, Helmut; Smith, Justin A; Pioquinto, David J; Ludin, Jacob A; Oh, S Paul; Katovich, Michael J; Frazier, Charles J; Raizada, Mohan K; Krause, Eric G

    2016-06-01

    Over-activation of the brain renin-angiotensin system (RAS) has been implicated in the etiology of anxiety disorders. Angiotensin converting enzyme 2 (ACE2) inhibits RAS activity by converting angiotensin-II, the effector peptide of RAS, to angiotensin-(1-7), which activates the Mas receptor (MasR). Whether increasing brain ACE2 activity reduces anxiety by stimulating central MasR is unknown. To test the hypothesis that increasing brain ACE2 activity reduces anxiety-like behavior via central MasR stimulation, we generated male mice overexpressing ACE2 (ACE2 KI mice) and wild type littermate controls (WT). ACE2 KI mice explored the open arms of the elevated plus maze (EPM) significantly more than WT, suggesting increasing ACE2 activity is anxiolytic. Central delivery of diminazene aceturate, an ACE2 activator, to C57BL/6 mice also reduced anxiety-like behavior in the EPM, but centrally administering ACE2 KI mice A-779, a MasR antagonist, abolished their anxiolytic phenotype, suggesting that ACE2 reduces anxiety-like behavior by activating central MasR. To identify the brain circuits mediating these effects, we measured Fos, a marker of neuronal activation, subsequent to EPM exposure and found that ACE2 KI mice had decreased Fos in the bed nucleus of stria terminalis but had increased Fos in the basolateral amygdala (BLA). Within the BLA, we determined that ∼62% of GABAergic neurons contained MasR mRNA and expression of MasR mRNA was upregulated by ACE2 overexpression, suggesting that ACE2 may influence GABA neurotransmission within the BLA via MasR activation. Indeed, ACE2 overexpression was associated with increased frequency of spontaneous inhibitory postsynaptic currents (indicative of presynaptic release of GABA) onto BLA pyramidal neurons and central infusion of A-779 eliminated this effect. Collectively, these results suggest that ACE2 may reduce anxiety-like behavior by activating central MasR that facilitate GABA release onto pyramidal neurons within the

  15. Angiotensin II attenuates synaptic GABA release and excites paraventricular-rostral ventrolateral medulla output neurons.

    PubMed

    Li, De-Pei; Pan, Hui-Lin

    2005-06-01

    The hypothalamic paraventricular nucleus (PVN) neurons regulate sympathetic outflow through projections to the spinal cord and rostral ventrolateral medulla (RVLM). Although the PVN-RVLM pathway is important for the action of brain angiotensin II (Ang II) on autonomic control, the cellular mechanisms involved are not fully known. In this study, we examined the effect of Ang II on the excitability and synaptic inputs to RVLM-projecting PVN neurons. PVN neurons were retrogradely labeled by FluoSpheres injected into the RVLM of rats. Whole-cell patch-clamp recordings were performed on labeled PVN neurons in brain slices. Ang II significantly increased the firing rate of PVN neurons from 3.63 +/- 0.65 to 6.10 +/- 0.75 Hz (P < 0.05, n = 9), and such an effect was eliminated by an AT(1) receptor antagonist, losartan. Furthermore, inclusion of a G protein inhibitor, guanosine 5'-O-(2-thiodiphosphate, in the pipette internal solution did not alter the excitatory effect of Ang II on labeled PVN neurons. Application of 0.5 to 5 microM Ang II significantly decreased the amplitude of evoked GABAergic inhibitory postsynaptic currents (IPSCs) in a dose-dependent manner. Also, 2 microM Ang II significantly decreased the frequency of miniature IPSCs (mIPSCs) from 3.89 +/- 0.84 to 2.06 +/- 0.45 Hz (P < 0.05, n = 11), but did not change the amplitude and decay time constant of mIPSCs. By contrast, Ang II had no significant effect on glutamatergic excitatory postsynaptic currents at the concentrations that inhibited IPSCs. In addition, Ang II failed to excite PVN neurons in the presence of bicuculline. Collectively, this study provides important new information that Ang II excites RVLM-projecting PVN neurons through attenuation of GABAergic synaptic inputs.

  16. Glomerular angiotensin II receptors in gentamicin-induced renal failure in the rat.

    PubMed

    Esquerro, E; Rivas-Cabãnero, L; López-Novoa, J M

    1995-11-01

    We evaluated the properties of glomerular angiotensin II receptors in renal glomeruli isolated from control rats and from rats with gentamicin-induced renal failure. There were no differences in the affinity of angiotensin II for its receptor between glomeruli from control and those from rats treated with gentamicin. Angiotensin II receptor density was lower in glomeruli from rats with renal failure than in those from control rats (985 +/- 71 in gentamicin treated rats vs. 1602 +/- 213 fmol/mg prot in controls). No significant differences were observed in renin activity in the supernatant from glomeruli isolated from control rats (3.74 +/- 0.29 ng angiotensin l/mL h) and those isolated from rats with gentamicin-induced renal failure (2.99 +/- 0.29 ng angiotensin l/mL h, p > 0.1). These findings do not support the contention of a role of angiotensin II in the development and maintenance of gentamicin-induced ARF.

  17. Molecular mechanisms and signaling pathways of angiotensin II-induced muscle wasting: potential therapeutic targets for cardiac cachexia.

    PubMed

    Yoshida, Tadashi; Tabony, A Michael; Galvez, Sarah; Mitch, William E; Higashi, Yusuke; Sukhanov, Sergiy; Delafontaine, Patrice

    2013-10-01

    Cachexia is a serious complication of many chronic diseases, such as congestive heart failure (CHF) and chronic kidney disease (CKD). Many factors are involved in the development of cachexia, and there is increasing evidence that angiotensin II (Ang II), the main effector molecule of the renin-angiotensin system (RAS), plays an important role in this process. Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme (ACE) inhibitor treatment improves weight loss. In rodent models, an increase in systemic Ang II leads to weight loss through increased protein breakdown, reduced protein synthesis in skeletal muscle and decreased appetite. Ang II activates the ubiquitin-proteasome system via generation of reactive oxygen species and via inhibition of the insulin-like growth factor-1 signaling pathway. Furthermore, Ang II inhibits 5' AMP-activated protein kinase (AMPK) activity and disrupts normal energy balance. Ang II also increases cytokines and circulating hormones such as tumor necrosis factor-α, interleukin-6, serum amyloid-A, glucocorticoids and myostatin, which regulate muscle protein synthesis and degradation. Ang II acts on hypothalamic neurons to regulate orexigenic/anorexigenic neuropeptides, such as neuropeptide-Y, orexin and corticotropin-releasing hormone, leading to reduced appetite. Also, Ang II may regulate skeletal muscle regenerative processes. Several clinical studies have indicated that blockade of Ang II signaling via ACE inhibitors or Ang II type 1 receptor blockers prevents weight loss and improves muscle strength. Thus the RAS is a promising target for the treatment of muscle atrophy in patients with CHF and CKD. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

  18. Effect of dietary fiber on the level of free angiotensin II receptor blocker in vitro.

    PubMed

    Iwazaki, Ayano; Takahashi, Kazuhiro; Tamezane, Yui; Tanaka, Kenta; Nakagawa, Minami; Imai, Kimie; Nakanishi, Kunio

    2014-01-01

    The interaction between angiotensin II type 1 (AT1) receptor blockers (ARBs), such as losartan potassium (LO), candesartan (CA), and telmisartan (TE), and dietary fiber was studied as to the level of free ARB in vitro. When ARB was incubated with soluble (sodium alginate, pectin, and glucomannan) or insoluble (cellulose and chitosan) dietary fiber, the levels of free LO, TE, and CA decreased. This resulted only from mixing the dietary fiber with the ARBs and differed among the types of dietary fiber, and the pH and electrolytes in the mixture. The levels of free LO and TE tended to decrease with a higher concentration of sodium chloride in pH 1.2 fluid. These results suggest that it is important to pay attention to the possible interactions between ARBs and dietary fiber.

  19. Neuroprotective effect of angiotensin II type 2 receptor during cerebral ischemia/reperfusion

    PubMed Central

    Ma, Chun-ye; Yin, Lin

    2016-01-01

    Angiotensin II type 2 receptor (AT2R) activation has been shown to protect against stroke, but its precise mechanism remains poorly understood. We investigated whether the protective effect of AT2R against ischemia/reperfusion injury is mediated by the suppression of immune and inflammatory responses. Rat models of middle cerebral artery occlusion were intraperitoneally injected with physiological saline, the AT2R agonist CGP42112 (1 mg/kg per day) or antagonist PD123319 (1 mg/kg per day). In the CGP42112 group, AT2R expression increased, the infarct area decreased, interleukin-1β and tumor necrosis factor-α expression decreased, and interleukin-10 expression increased compared with the saline group. Antagonisin AT2R using PD123319 produced the opposite effects. These results indicate that AT2R activation suppresses immune and inflammatory responses, and protects against cerebral ischemia/reperfusion injury. PMID:27630693

  20. Angiotensin II AT1 receptor antagonists inhibit platelet adhesion and aggregation by nitric oxide release.

    PubMed

    Kalinowski, Leszek; Matys, Tomasz; Chabielska, Ewa; Buczko, Włodzimierz; Malinski, Tadeusz

    2002-10-01

    This study investigated the process of nitric oxide (NO) release from platelets after stimulation with different angiotensin II type 1 (AT1)-receptor antagonists and its effect on platelet adhesion and aggregation. Angiotensin II AT1-receptor antagonist-stimulated NO release in platelets was compared with that in human umbilical vein endothelial cells by using a highly sensitive porphyrinic microsensor. In vitro and ex vivo effects of angiotensin II AT1-receptor antagonists on platelet adhesion to collagen and thromboxane A2 analog U46619-induced aggregation were evaluated. Losartan, EXP3174, and valsartan alone caused NO release from platelets and endothelial cells in a dose-dependent manner in the range of 0.01 to 100 micro mol/L, which was attenuated by NO synthase inhibitor N(G)-nitro-L-arginine methyl ester. The angiotensin II AT1-receptor antagonists had more than 70% greater potency in NO release in platelets than in endothelial cells. The degree of inhibition of platelet adhesion (collagen-stimulated) and aggregation (U46619-stimulated) elicited by losartan, EXP3174, and valsartan, either in vitro or ex vivo, closely correlated with the NO levels produced by each of these drugs alone. The inhibiting effects of angiotensin II AT1-receptor antagonists on collagen-stimulated adhesion and U46619-stimulated aggregation of platelets were significantly reduced by pretreatment with N(G)-nitro-L-arginine methyl ester. Neither the AT2 receptor antagonist PD123319, the cyclooxygenase synthase inhibitor indomethacin, nor the selective thromboxane A2/prostaglandin H2 receptor antagonist SQ29,548 had any effect on angiotensin II AT1-receptor antagonist-stimulated NO release in platelets and endothelial cells. The presented studies clearly indicate a crucial role of NO in the arterial antithrombotic effects of angiotensin II AT1-receptor antagonists.

  1. [Angiotensin II inhibitors for the diagnosis and treatment of hypertension].

    PubMed

    Brunner, H R; Gavras, H

    1976-12-11

    Specific antagonists of the renin angiotensin system have been used to investigate the role of this hormonal system in blood pressure homeostasis and in different types of experimental and clinical hypertension. Using this approach it was possible to show that renin via angiotensin participates actively in blood pressure maintenace, particularly following sodium depletion. Such antagonists, if available for oral administration and taken together with a diuretic, would be useful therapeutically.

  2. Effect of Lysyl Oxidase Inhibition on Angiotensin II-Induced Arterial Hypertension, Remodeling, and Stiffness

    PubMed Central

    Eberson, Lance S.; Sanchez, Pablo A.; Majeed, Beenish A.; Tawinwung, Supannikar; Secomb, Timothy W.; Larson, Douglas F.

    2015-01-01

    It is well accepted that angiotensin II (Ang II) induces altered vascular stiffness through responses including both structural and material remodeling. Concurrent with remodeling is the induction of the enzyme lysyl oxidase (LOX) through which ECM proteins are cross-linked. The study objective was to determine the effect of LOX mediated cross-linking on vascular mechanical properties. Three-month old mice were chronically treated with Ang II with or without the LOX blocker, β -aminopropionitrile (BAPN), for 14 days. Pulse wave velocity (PWV) from Doppler measurements of the aortic flow wave was used to quantify in vivo vascular stiffness in terms of an effective Young’s modulus. The increase in effective Young’s modulus with Ang II administration was abolished with the addition of BAPN, suggesting that the material properties are a major controlling element in vascular stiffness. BAPN inhibited the Ang II induced collagen cross-link formation by 2-fold and PWV by 44% (P<0.05). Consistent with this observation, morphometric analysis showed that BAPN did not affect the Ang II mediated increase in medial thickness but significantly reduced the adventitial thickness. Since the hypertensive state contributes to the measured in vivo PWV stiffness, we removed the Ang II infusion pumps on Day 14 and achieved normal arterial blood pressures. With pump removal we observed a decrease of the PWV in the Ang II group to 25% above that of the control values (P=0.002), with a complete return to control values in the Ang II plus BAPN group. In conclusion, we have shown that the increase in vascular stiffness with 14 day Ang II administration results from a combination of hypertension-induced wall strain, adventitial wall thickening and Ang II mediated LOX ECM cross-linking, which is a major material source of vascular stiffening, and that the increased PWV was significantly inhibited with co-administration of BAPN. PMID:25875748

  3. Angiotensin II stimulates expression of the chemokine RANTES in rat glomerular endothelial cells. Role of the angiotensin type 2 receptor.

    PubMed Central

    Wolf, G; Ziyadeh, F N; Thaiss, F; Tomaszewski, J; Caron, R J; Wenzel, U; Zahner, G; Helmchen, U; Stahl, R A

    1997-01-01

    Glomerular influx of monocytes/macrophages (M/M) occurs in many immune- and non-immune-mediated renal diseases. The mechanisms targeting M/M into the glomerulus are incompletely understood, but may involve stimulated expression of chemokines. We investigated whether angiotensin II (ANG II) induces the chemokine RANTES in cultured glomerular endothelial cells of the rat and in vivo. ANG II stimulated mRNA and protein expression of RANTES in cultured glomerular endothelial cells. The ANG II-induced RANTES protein was chemotactic for human monocytes. Surprisingly, the ANG II-stimulated RANTES expression was transduced by AT2 receptors because the AT2 receptor antagonists PD 123177 and CGP-42112A, but not an AT1 receptor blocker, abolished the induced RANTES synthesis. Intraperitoneal infusion of ANG II (500 ng/h) into naive rats for 4 d significantly stimulated glomerular RANTES mRNA and protein expression compared with solvent-infused controls. Immunohistochemistry revealed induction of RANTES protein mainly in glomerular endothelial cells and small capillaries. Moreover, ANG II- infused animals exhibited an increase in glomerular ED-1- positive cells compared with controls. Oral treatment with PD 123177 (50 mg/liter drinking water) attenuated the glomerular M/M influx without normalizing the slightly elevated systolic blood pressure caused by ANG II infusion, suggesting that the effects on blood pressure and RANTES induction can be separated. We conclude that the vasoactive peptide ANG II may play an important role in glomerular chemotaxis of M/M through local induction of the chemokine RANTES. The observation that the ANG II- mediated induction of RANTES is transduced by AT2 receptors may influence the decision as to which substances might be used for the therapeutic interference with the activity of the renin-angiotensin system. PMID:9276721

  4. Perioperative management of patients treated with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers: a quality improvement audit.

    PubMed

    Vijay, A; Grover, A; Coulson, T G; Myles, P S

    2016-05-01

    Previous studies have shown that patients continuing angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers on the day of surgery are more likely to have significant intraoperative hypotension, higher rates of postoperative acute kidney injury, and lower incidences of postoperative atrial fibrillation. However, many of these studies were prone to bias and confounding, and questions remain over the validity of these outcomes. This observational, before-and-after quality improvement audit aimed to assess the effect of withholding these medications on the morning of surgery. We recruited 323 participants, with 83 (26%) having their preoperative angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) withheld on the day of surgery. There were only very small Spearman rank-order correlations between time since last dose of these medications (rho -0.12, P=0.057) and intraoperative and recovery room intravenous fluid administration (rho -0.11, P=0.042). There was no statistically significant difference between the continued or withheld groups in vasopressor (metaraminol use 3.5 [1.5-8.3] mg versus 3.5 [1.5-8.5] mg, P=0.67) or intravenous fluid administration (1000 ml [800-1500] ml versus 1000 [800-1500] ml, P=0.096), nor rates of postoperative acute kidney injury (13% vs 18%, P=0.25) or atrial fibrillation (15% versus 18%, P=0.71). This audit found no significant differences in measured outcomes between the continued or withheld ACEi/ARB groups. This finding should be interpreted with caution due to the possibility of confounding and an insufficient sample size. However, as the finding is in contrast to many previous studies, future prospective randomised clinical trials are required to answer this important question.

  5. Advanced Glycation End Products Activate a Chymase-Dependent Angiotensin II Generating Pathway in Diabetic Complications

    PubMed Central

    Koka, Vijay; Wang, Wansheng; Huang, Xiao Ru; Kim-Mitsuyama, Shokei; Truong, Luan D.; Lan, Hui Y

    2006-01-01

    Background: Angiotensin II is a key mediator of diabetes-related vascular disease. It is now recognized that in addition to angiotensin converting enzyme (ACE), chymase is an important alternative angiotensin II generating enzyme in hypertension and diabetes. However, the mechanism of induction of chymase in diabetes remains unknown. Methods and Results: Here we report that chymase is upregulated in coronary and renal arteries in patients with diabetes by immunohistochemistry. Upregulation of vascular chymase is associated with deposition of advanced glycation end products (AGEs), increase in expression of the receptor for AGEs (RAGE), and activation of ERK1/2 MAP kinase. In vitro, AGEs can induce chymase expression and chymase-dependent angiotensin II generation in human vascular smooth muscle cells via the RAGE-ERK1/2 MAP kinase-dependent mechanism. This is confirmed by blockade of AGE-induced vascular chymase expression with a neutralizing RAGE antibody and an inhibitor to ERK1/2, and by overexpression of the dominant negative-ERK1/2. Compared to ACE, chymase contributes to the majority of angiotensin II production (more than 70%, p<0.01) in response to AGEs. Further more, AGE-induced Angiotensin II production is blocked by the anti-RAGE antibody and by inhibition of ERK1/2 MAP kinase activities. Conclusions: Advanced glycation end products, a hallmark of diabetes, induce chymase via the RAGE-ERK1/2 MAP kinase pathway. Chymase initiates an important alternative angiotensin II generating pathway in diabetes and may play a critical role in diabetic vascular disease. PMID:16520412

  6. Characterization of angiotensin II binding sites in African Green monkey uterus

    SciTech Connect

    Petersen, E.P.; Wright, J.W.; Harding, J.W.

    1985-01-14

    The observation that there are significant differences in the concentration, affinity, and specificity of both central nervous system (CNS) and peripheral angiotensin receptors among several different mammalian species, including the African Green monkey, led to the detailed analysis of /sup 125/I-angiotensin II binding in the uterus of the African Green monkey. The B/sub max/ for angiotensin receptors in uterine tissue from this species is 56.6 +/- 8.7 fmole per mg protein. The K/sub d/ for angiotensin II is .601 +/- .108 mM. The specificity of the receptor is similar to that reported for the uterus of the rat and dog. These results indicate that the angiotensin II receptors, although nearly absent from the CNS of the African Green monkey, are found in the uterus and are very similar to uterine receptors previously characterized in the rat and dog and support the use of these species as appropriate models for studying the biochemistry of angiotensin binding in the uterus. 25 references, 1 figure, 2 tables.

  7. 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

  8. Angiotensin II and NADPH oxidase increase ADMA in vascular smooth muscle cells.

    PubMed

    Luo, Zaiming; Teerlink, Tom; Griendling, Kathy; Aslam, Shakil; Welch, William J; Wilcox, Christopher S

    2010-09-01

    Asymmetrical dimethylarginine inhibits nitric oxide synthase, cationic amino acid transport, and endothelial function. Patients with cardiovascular risk factors often have endothelial dysfunction associated with increased plasma asymmetrical dimethylarginine and markers of reactive oxygen species. We tested the hypothesis that reactive oxygen species, generated by nicotinamide adenine dinucleotide phosphate oxidase, enhance cellular asymmetrical dimethylarginine. Incubation of rat preglomerular vascular smooth muscle cells with angiotensin II doubled the activity of nicotinamide adenine dinucleotide phosphate oxidase but decreased the activities of dimethylarginine dimethylaminohydrolase by 35% and of cationic amino acid transport by 20% and doubled cellular (but not medium) asymmetrical dimethylarginine concentrations (P<0.01). This was blocked by tempol or candesartan. Cells stably transfected with p22(phox) had a 50% decreased protein expression and activity of dimethylarginine dimethylaminohydrolase despite increased promoter activity and mRNA. The decreased DDAH protein expression and the increased asymmetrical dimethylarginine concentration in p22(phox)-transfected cells were prevented by proteosomal inhibition. These cells had enhanced protein arginine methylation, a 2-fold increased expression of protein arginine methyltransferase-3 (P<0.05) and a 30% reduction in cationic amino acid transport activity (P<0.05). Asymmetrical dimethylarginine was increased from 6+/-1 to 16+/-3 micromol/L (P<0.005) in p22(phox)-transfected cells. Thus, angiotensin II increased cellular asymmetrical dimethylarginine via type 1 receptors and reactive oxygen species. Nicotinamide adenine dinucleotide phosphate oxidase increased cellular asymmetrical dimethylarginine by increasing enzymes that generate it, enhancing the degradation of enzymes that metabolize it, and reducing its cellular transport. This could underlie increases in cellular asymmetrical dimethylarginine during

  9. Evidence for extracellular, but not intracellular, generation of angiotensin II in the rat adrenal zona glomerulosa

    SciTech Connect

    Urata, H.; Khosla, M.C.; Bumpus, M.; Husain, A. )

    1988-11-01

    Based on the observation that high levels of renin and angiotensin II (Ang II) are found in the adrenal zona glomerulosa (ZG), it has been postulated that Ang II is formed intracellularly by the renin-converting enzyme cascade in this tissue. To test this hypothesis, the authors examined renin-angiotensin system components in subcellular fractions of the rat adrenal ZG. Renin activity and immunoreactive-Ang II (IR-Ang II) were observed in vesicular fractions but were not colocalized. In addition, angiotensinogen, angiotensin I, and converting enzyme were not observed in the renin or IR-Ang II-containing vesicular fractions. These data do not support the hypothesis that Ang II is formed intracellularly within the renin-containing vesicles of the ZG. Rather, since modulatable renin release from adrenal ZG slices was observed and renin activity was found in dense vesicular fractions (33-39% sucrose), it is likely that Ang II formation in the ZG is extracellular and initiated by the release of vesicular renin. In ZG lysomal fractions {sup 125}I-labeled Ang II was degraded to {sup 125}I-labeled des-(Phe{sup 8})Ang II. Since Ang II antibodies do not recognize des-(Phe{sup 8})Ang II, these finding explain why IR-Ang II in the ZG is due predominantly to Ang II and not to its C-terminal immunoreactive fragments.

  10. Safflor yellow B suppresses angiotensin II-mediated human umbilical vein cell injury via regulation of Bcl-2/p22{sup phox} expression

    SciTech Connect

    Wang, Chaoyun; He, Yanhao; Yang, Ming; Sun, Hongliu; Zhang, Shuping; Wang, Chunhua

    2013-11-15

    Intracellular reactive oxygen species (ROS) are derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Angiotensin II (Ang II) can cause endothelial dysfunction by promoting intracellular ROS generation. Safflor yellow B (SYB) effectively inhibits ROS generation by upregulating Bcl-2 expression. In this study, we examined the effects of SYB on Ang II-induced injury to human umbilical vein endothelial cells (HUVECs), and elucidated the roles of NADPH oxidase and Bcl-2. We treated cultured HUVECs with Ang II, SYB, and Bcl-2 siRNA, and determined NADPH oxidase activity and ROS levels. Furthermore, cellular and mitochondrial physiological states were evaluated, and the expression levels of target proteins were analyzed. Ang II significantly enhanced intracellular ROS levels, caused mitochondrial membrane dysfunction, and decreased cell viability, leading to apoptosis. This was associated with increased expression of AT1R and p22{sup phox}, increased NADPH oxidase activity, and an increased ratio of Bax/Bcl-2, leading to decreases in antioxidant enzyme activities, which were further strengthened after blocking Bcl-2. Compared to Ang II treatment alone, co-treatment with SYB significantly reversed HUVEC injury. Taken together, these results demonstrate that SYB could significantly protect endothelial cells from Ang II-induced cell damage, and that it does so by upregulating Bcl-2 expression and inhibiting ROS generation. - Highlights: • Angiotensin II depresses mitochondria physiological function. • Angiotensin II activates NADPH oxidase via up-regulating expresion of p22{sup phox}. • Bcl-2 plays a pivotal role in improving mitochondria function and regulates ROS level. • Inhibitor of Bcl-2 promotes angiotensin II mediated HUVEC injury. • SYB attenuates angiotensin II mediated HUVEC injury via up regulating Bcl-2 expression.

  11. Angiotensin II receptor blocker telmisartan attenuates aortic stiffening and remodelling in STZ-diabetic rats

    PubMed Central

    2014-01-01

    Background Prevention or attenuation of diabetic vascular complications includes anti-hypertensive treatment with renin-angiotensin system inhibitors on account of their protective effects beyond blood pressure reduction. The present study aimed to investigate the effects of telmisartan, an angiotensin II type 1 receptor blocker (ARB), on blood pressure, aortic stiffening, and aortic remodelling in experimental type 1 diabetes in rats. Methods Diabetes was induced by streptozotocin (STZ) (65 mg/kg) in male Wistar rats. One diabetic group was treated for 10 weeks with telmisartan (10 mg/kg/day p/o). Pressure-independent aortic pulse wave velocity (PWV) was measured under anaesthesia after intravenous infusion of phenylephrine and nitroglycerine. Aortic wall samples were collected for histomorphometrical analysis. Results Untreated diabetes imposed differential effects on aortic stiffening, as demonstrated by increased isobaric PWV over a range of high blood pressures, but not at lower blood pressures. This was associated with loss and disruption of elastin fibres and an increase in collagen fibres in the aortic media. Treatment with telmisartan decreased resting blood pressure, reduced aortic stiffness, and partially prevented the degradation of elastin network within the aortic wall. Conclusions Telmisartan improved the structural and functional indices of aortic stiffening induced by untreated STZ-diabetes, demonstrating the importance of ARBs in the therapeutic approach to diabetic vascular complications. PMID:24920962

  12. Synthesis and evaluation of novel angiotensin II receptor 1 antagonists as anti-hypertension drugs.

    PubMed

    Bao, Xiaolu; Zhu, Weibo; Zhang, Ruijing; Wen, Caihong; Wang, Li; Yan, Yijia; Tang, Hesheng; Chen, Zhilong

    2016-05-01

    Three new angiotensin II receptor 1 antagonists, 1, 2 and 3 were designed, synthesized and evaluated. The AT1 receptor-binding assays in vitro showed that all the synthesized compounds had nanomolar affinity for the AT1 receptor. From which compound 3 was found to be the most potent ligands with an IC50 value of 2.67±0.23 nM. Biological evaluation in vivo revealed that all the compounds could cause significant decrease on MBP in a dose dependent manner in spontaneously hypertensive rats, and compound 3 especially showed an efficient and long-lasting effect in reducing blood pressure, whose maximal response lowered 41 mmHg of MBP at 10mg/kg and 62 mmHg at 15 mg/kg after oral administration, the significant anti-hypertensive effect lasted beyond 12 h, which is better than the reference compound losartan. The pharmacokinetic experiments showed that compound 3 could be absorbed efficiently and metabolized smoothly both in blood and in tissues in Wistar rats. The acute toxicity assay suggested that it has low toxicity with the LD50 value of 2974.35 mg/kg. These results demonstrate that compound 3 is a potent angiotensin AT1 receptor antagonist which could be considered as a novel anti-hypertension candidate and deserved for further investigation.

  13. Nitrosonifedipine ameliorates angiotensin II-induced vascular remodeling via antioxidative effects.

    PubMed

    Sakurada, Takumi; Ishizawa, Keisuke; Imanishi, Masaki; Izawa-Ishizawa, Yuki; Fujii, Shoko; Tominaga, Erika; Tsuneishi, Teppei; Horinouchi, Yuya; Kihira, Yoshitaka; Ikeda, Yasumasa; Tomita, Shuhei; Aihara, Ken-ichi; Minakuchi, Kazuo; Tsuchiya, Koichiro; Tamaki, Toshiaki

    2013-01-01

    Nifedipine is unstable under light and decomposes to a stable nitroso analog, nitrosonifedipine (NO-NIF). The ability of NO-NIF to block calcium channels is quite weak compared with that of nifedipine. Recently, we have demonstrated that NO-NIF reacts with unsaturated fatty acid leading to generate NO-NIF radical, which acquires radical scavenging activity. However, the effects of NO-NIF on the pathogenesis related with oxidative stress, such as atherosclerosis and hypertension, are unclear. In this study, we investigated the effects of NO-NIF on angiotensin II (Ang II)-induced vascular remodeling. Ang II-induced thickening and fibrosis of aorta were inhibited by NO-NIF in mice. NO-NIF decreased reactive oxygen species (ROS) in the aorta and urinary 8-hydroxy-20-deoxyguanosine. Ang II-stimulated mRNA expressions of p22(phox), CD68, F4/80, monocyte chemoattractant protein-1, and collagen I in the aorta were inhibited by NO-NIF. Moreover, NO-NIF inhibited Ang II-induced cell migration and proliferation of vascular smooth muscle cells (VSMCs). NO-NIF reduced Ang II-induced ROS to the control level detected by dihydroethidium staining and lucigenin chemiluminescence assay in VSMCs. NO-NIF suppressed phosphorylations of Akt and epidermal growth factor receptor induced by Ang II. However, NO-NIF had no effects on intracellular Ca(2+) increase and protein kinase C-δ phosphorylation induced by Ang II in VSMCs. The electron paramagnetic resonance spectra indicated the continuous generation of NO-NIF radical of reaction with cultured VSMCs. These findings suggest that NO-NIF improves Ang II-induced vascular remodeling via the attenuation of oxidative stress.

  14. Calpain-10 Activity Underlies Angiotensin II-Induced Aldosterone Production in an Adrenal Glomerulosa Cell Model

    PubMed Central

    Seremwe, Mutsa; Schnellmann, Rick G.

    2015-01-01

    Aldosterone is a steroid hormone important in the regulation of blood pressure. Aberrant production of aldosterone results in the development and progression of diseases including hypertension and congestive heart failure; therefore, a complete understanding of aldosterone production is important for developing more effective treatments. Angiotensin II (AngII) regulates steroidogenesis, in part through its ability to increase intracellular calcium levels. Calcium can activate calpains, proteases classified as typical or atypical based on the presence or absence of penta-EF-hands, which are involved in various cellular responses. We hypothesized that calpain, in particular calpain-10, is activated by AngII in adrenal glomerulosa cells and underlies aldosterone production. Our studies showed that pan-calpain inhibitors reduced AngII-induced aldosterone production in 2 adrenal glomerulosa cell models, primary bovine zona glomerulosa and human adrenocortical carcinoma (HAC15) cells, as well as CYP11B2 expression in the HAC15 cells. Although AngII induced calpain activation in these cells, typical calpain inhibitors had no effect on AngII-elicited aldosterone production, suggesting a lack of involvement of classical calpains in this process. However, an inhibitor of the atypical calpain, calpain-10, decreased AngII-induced aldosterone production. Consistent with this result, small interfering RNA (siRNA)-mediated knockdown of calpain-10 inhibited aldosterone production and CYP11B2 expression, whereas adenovirus-mediated overexpression of calpain-10 resulted in increased AngII-induced aldosterone production. Our results indicate that AngII-induced activation of calpain-10 in glomerulosa cells underlies aldosterone production and identify calpain-10 or its downstream pathways as potential targets for the development of drug therapies for the treatment of hypertension. PMID:25836666

  15. Humid heat exposure induced oxidative stress and apoptosis in cardiomyocytes through the angiotensin II signaling pathway.

    PubMed

    Wang, Xiaowu; Yuan, Binbin; Dong, Wenpeng; Yang, Bo; Yang, Yongchao; Lin, Xi; Gong, Gu

    2015-05-01

    Exposure to humid heat stress leads to the initiation of serious physiological dysfunction that may result in heat-related diseases, including heat stroke, heat cramp, heat exhaustion, and even death. Increasing evidences have shown that the humid heat stress-induced dysfunction of the cardiovascular system was accompanied with severe cardiomyocyte injury; however, the precise mechanism of heat stress-induced injury of cardiomyocyte remains unknown. In the present study, we hypothesized that humid heat stress promoted oxidative stress through the activation of angiotensin II (Ang II) in cardiomyocytes. To test our hypothesis, we established mouse models of humid heat stress. Using the animal models, we found that Ang II levels in serum were significantly up-regulated and that the Ang II receptor AT1 was increased in cardiomyocytes. The antioxidant ability in plasma and heart tissues which was detected by the ferric reducing/antioxidant power assay was also decreased with the increased ROS production under humid heat stress, as was the expression of antioxidant genes (SOD2, HO-1, GPx). Furthermore, we demonstrated that the Ang II receptor antagonist, valsartan, effectively relieved oxidative stress, blocked Ang II signaling pathway and suppressed cardiomyocyte apoptosis induced by humid heat stress. In addition, overexpression of antioxidant genes reversed cardiomyocyte apoptosis induced by Ang II. Overall, these results implied that humid heat stress increased oxidative stress and caused apoptosis of cardiomyocytes through the Ang II signaling pathway. Thus, targeting the Ang II signaling pathway may provide a promising approach for the prevention and treatment of cardiovascular diseases caused by humid heat stress.

  16. Measurement and characterization of angiotensin peptides in plasma

    SciTech Connect

    Hermann, K.; Ganten, D.; Unger, T.; Bayer, C.; Lang, R.E.

    1988-06-01

    We report a method for the extraction of angiotensin peptides from plasma with a mixture of acetone, 1 mol/L HCl, and water (40/1/5 by vol). The method is highly reproducible for the measurement of angiotensin I and angiotensin II in small sample volumes, with analytical recoveries of about 80% for both peptides. We investigated the influence of sample handling and found a standard procedure for blood collection, plasma preparation, and extraction was essential. The method was used to measure angiotensin I and II in rat and human plasma. In rat plasma, the mean (+/- SEM) concentrations of angiotensin I and angiotensin II were determined to be 67 (+/- 8) and 14 (+/- 1) pmol/L (n = 10), respectively. Neither angiotensin I nor angiotensin II was detectable 24 h after bilateral nephrectomy. Acute oral administration of the converting-enzyme inhibitor ramipril caused a significant increase of angiotensin I from 85 (+/- 6) to 257 (+/- 33) pmol/L (n = 10; P less than 0.001) and a significant decrease of angiotensin II from 12 (+/- 1) to 7 (+/- 0.4) pmol/L in rat plasma (n = 9; P less than 0.001). In human plasma, angiotensin I and angiotensin II values of 21 (+/- 1) and 6.6 (+/- 0.5) pmol/L (n = 10) were found. A single oral dose of the diuretic furosemide increased angiotensin I significantly from 21 (+/- 1) to 32 (+/- 1.7) pmol/L (n = 5); P less than 0.001), whereas angiotensin II remained unchanged, 6.6 (+/- 0.5) vs 6.4 (+/- 0.4) pmol/L (n = 5). Extracted peptides could be identified as (IIe5)-angiotensin I and (IIe5)-angiotensin II by HPLC in combination with specific radioimmunoassays for angiotensin I and angiotensin II.

  17. Effect of des-aspartate-angiotensin I on the actions of angiotensin II in the isolated renal and mesenteric vasculature of hypertensive and STZ-induced diabetic rats.

    PubMed

    Dharmani, M; Mustafa, M R; Achike, F I; Sim, M K

    2005-07-15

    The present study investigated the action of des-aspartate-angiotensin I (DAA-I) on the pressor action of angiotensin II in the renal and mesenteric vasculature of WKY, SHR and streptozotocin (STZ)-induced diabetic rats. Angiotensin II-induced a dose-dependent pressor response in the renal vasculature. Compared to the WKY, the pressor response was enhanced in the SHR and reduced in the STZ-induced diabetic rat. DAA-I attenuated the angiotensin II pressor action in renal vasculature of WKY and SHR. The attenuation was observed for DAA-I concentration as low as 10(-18) M and was more prominent in SHR. However, the ability of DAA-I to reduce angiotensin II response was lost in the STZ-induced diabetic kidney. Instead, enhancement of angiotensin II pressor response was seen at the lower doses of the octapeptide. The effect of DAA-I was not inhibited by PD123319, an AT2 receptor antagonist, and indomethacin, a cyclo-oxygenase inhibitor in both WKY and SHR, indicating that its action was not mediated by angiotensin AT2 receptor and prostaglandins. The pressor responses to angiotensin II in mesenteric vascular bed were also dose-dependent but smaller in magnitude compared to the renal vasculature. The responses were significantly smaller in SHR but no significant difference was observed between STZ-induced diabetic and WKY rat. Similarly, PD123319 and indomethacin had no effect on the action of DAA-I. The findings reiterate a regulatory role for DAA-I in vascular bed of the kidney and mesentery. By being active at circulating level, DAA-I subserves a physiological role. This function appears to be present in animals with diseased state of hypertension and diabetes. It is likely that DAA-I functions are modified to accommodate the ongoing vascular remodeling.

  18. Properties of angiotensin II receptors in glial cells from the adult corpus callosum.

    PubMed Central

    Matute, C; Pulakat, L; Río, C; Valcárcel, C; Miledi, R

    1994-01-01

    The existence and the properties of angiotensin II receptors in the adult bovine and human corpus callosum (CC) were investigated by using Xenopus oocytes and primary glial cell cultures. In oocytes injected with CC mRNA, angiotensin II elicited oscillatory Cl- currents due to activation of the inositol phosphate/Ca(2+)-receptor-channel coupling system. The receptors expressed in oocytes and in CC cultures were pharmacologically similar to the AT1 receptor type as assayed by binding. Northern blot analysis and in situ hybridization studies in sections from CC and in glial cultures revealed that the receptors were molecularly related to the AT1 receptor and that they were present in astrocytes. In these cells, activation of the receptors with angiotensin II increased de novo DNA synthesis, promoted the release of aldosterone, and induced c-Fos expression. These findings indicate that CC astrocytes possess functional AT1 receptors that participate in various physiological processes. Images PMID:8170986

  19. Protective effect of angiotensin II-induced increase in nitric oxide in the renal medullary circulation.

    PubMed

    Zou, A P; Wu, F; Cowley, A W

    1998-01-01

    This study examined the effect of intravenous infusion of subpressor doses of angiotensin (Ang II) on renal medullary blood flow (MBF), medullary partial oxygen pressure (PO2), and nitric oxide (NO) concentration under normal conditions and during reduction of the medullary nitric oxide synthase (NOS) activity in anesthetized rats. With laser Doppler flowmetry and polarographic measurement of PO2 with microelectrodes, Ang II (5 ng/kg per minute) did not alter renal cortical and medullary blood flows or medullary PO2. N(omega)-nitro-L-arginine methyl ester (L-NAME) was infused into the renal medullary interstitial space at a dose of 1.4 microg/kg per minute, a dose that did not significantly alter basal levels of MBF or PO2. Intravenous infusion of Ang II at the same dose in the presence of L-NAME decreased MBF by 23% and medullary PO2 by 28%, but it had no effect on cortical blood flow or arterial blood pressure. An in vivo microdialysis-oxyhemoglobin NO trapping technique was used in other rats to determine tissue NO concentrations using the same protocol. Ang II infusion increased tissue NO concentrations by 85% in the renal cortex and 150% in the renal medulla. Renal medullary interstitial infusion of L-NAME (1.4 microg/kg per minute) reduced medullary NO concentrations and substantially blocked Ang II-induced increases in NO concentrations in the renal medulla, but not in the renal cortex. Tissue slices of the renal cortex and medulla were studied to determine the effects of Ang II and L-NAME on the nitrite/nitrate production. Ang II stimulated the nitrite/nitrate production predominately in the renal medulla, which was significantly attenuated by L-NAME. We conclude that small elevations of circulating Ang II levels increase medullary NO production and concentrations, which plays an important role in buffering the vasoconstrictor effects of this peptide and in maintaining a constancy of MBF.

  20. Angiotensin II limits NO production by upregulating arginase through a p38 MAPK - ATF-2 pathway

    PubMed Central

    Shatanawi, Alia; Lemtalsi, Tahira; Yao, Lin; Patel, Chintan; Caldwell, Ruth B.; Caldwell, R. William

    2014-01-01

    Enhanced vascular arginase activity can impair endothelium-dependent vasorelaxation by decreasing L-arginine availability to endothelial nitric oxide (NO) synthase, thereby reducing NO production and uncoupling NOS function. Elevated angiotensin II (Ang II) is a key component of endothelial dysfunction in many cardiovascular diseases and has been linked to elevated arginase activity. In this study we explored the signaling pathway leading to increased arginase expression/activity in response to Ang II in bovine aortic endothelial cells (BAEC). Our previous studies indicate involvement of p38 mitogen activated protein kinase (MAPK) in Ang II-induced arginase upregulation and reduced NO production. In this study, we further investigated the Ang II-transcriptional regulation of arginase 1 in endothelial cells. Our results indicate the involvement of ATF-2 transcription factor of the AP1 family in arginase 1 upregulation and in limiting NO production. Using small interfering RNA (siRNA) targeting ATF-2, we showed that this transcription factor is required for Ang II-induced arginase 1 gene upregulation and increased arginase 1 expression and activity, leading to reduced NO production. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay further confirmed the involvement of ATF-2. Moreover, our data indicate that p38 MAPK phosphorylates ATF-2 in response to Ang II. Collectively, our results indicate that Ang II increases endothelial arginase activity/expression through a p38 MAPK/ATF-2 pathway leading to reduced endothelial NO production. These signaling steps might be therapeutic targets for preventing vascular endothelial dysfunction associated with elevated arginase activity/expression. PMID:25446432

  1. Role of Jagged1-Hey1 Signal in Angiotensin II-induced Impairment of Myocardial Angiogenesis

    PubMed Central

    Guan, Ai-Li; He, Tao; Shao, Yi-Bing; Chi, Yi-Fan; Dai, Hong-Yan; Wang, Yan; Xu, Li; Yang, Xuan; Ding, Hua-Min; Cai, Shang-Lang

    2017-01-01

    Background: Angiotensin II (Ang II) is a major contributor to the development of heart failure. However, the molecular and cellular mechanisms that underlie this process remain elusive. Inadequate angiogenesis in the myocardium leads to a transition from cardiac hypertrophy to dysfunction, and our previous study showed that Ang II significantly impaired the angiogenesis response. The current study was designed to examine the role of Jagged1-Notch signaling in the effect of Ang II during impaired angiogenesis and cardiac hypertrophy. Methods: Ang II was subcutaneously infused into 8-week-old male C57BL/6 mice at a dose of 200 ng·kg−1·min−1 for 2 weeks using Alzet micro-osmotic pumps. N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine tert-butyl ester (DAPT), a γ-secretase inhibitor, was injected subcutaneously during Ang II infusion at a dose of 10.0 mg·kg−1·d−1. Forty mice were divided into four groups (n = 10 per group): control group; Ang II group, treated with Ang II; DAPT group, treated with DAPT; and Ang II + DAPT group, treated with both Ang II and DAPT. At the end of experiments, myocardial (left ventricle [LV]) tissue from each experimental group was evaluated using immunohistochemistry, Western blotting, and real-time polymerase chain reaction. Data were analyzed using one-way analysis of variance test followed by the least significant difference method or independent samples t-test. Results: Ang II treatment significantly induced cardiac hypertrophy and impaired the angiogenesis response compared to controls, as shown by hematoxylin and eosin (HE) staining and immunohistochemistry for CD31, a vascular marker (P < 0.05 for both). Meanwhile, Jagged1 protein was significantly increased, but gene expression for both Jag1 and Hey1 was decreased in the LV following Ang II treatment, compared to that in controls (relative ratio for Jag1 gene: 0.45 ± 0.13 vs. 0.84 ± 0.15; relative ratio for Hey1 gene: 0.51 ± 0.08 vs. 0.91 ± 0.09; P < 0

  2. Effect of Angiotensin II and Small GTPase Ras Signaling Pathway Inhibition on Early Renal Changes in a Murine Model of Obstructive Nephropathy

    PubMed Central

    Rodríguez-Peña, Ana B.; Fuentes-Calvo, Isabel; Docherty, Neil G.; Arévalo, Miguel; Grande, María T.; Eleno, Nélida; Pérez-Barriocanal, Fernando; López-Novoa, José M.

    2014-01-01

    Tubulointerstitial fibrosis is a major feature of chronic kidney disease. Unilateral ureteral obstruction (UUO) in rodents leads to the development of renal tubulointerstitial fibrosis consistent with histopathological changes observed in advanced chronic kidney disease in humans. The purpose of this study was to assess the effect of inhibiting angiotensin II receptors or Ras activation on early renal fibrotic changes induced by UUO. Animals either received angiotensin II or underwent UUO. UUO animals received either losartan, atorvastatin, and farnesyl transferase inhibitor (FTI) L-744,832, or chaetomellic acid A (ChA). Levels of activated Ras, phospho-ERK1/2, phospho-Akt, fibronectin, and α-smooth muscle actin were subsequently quantified in renal tissue by ELISA, Western blot, and/or immunohistochemistry. Our results demonstrate that administration of angiotensin II induces activation of the small GTPase Ras/Erk/Akt signaling system, suggesting an involvement of angiotensin II in the early obstruction-induced activation of renal Ras. Furthermore, upstream inhibition of Ras signalling by blocking either angiotensin AT1 type receptor or by inhibiting Ras prenylation (atorvastatin, FTI o ChA) reduced the activation of the Ras/Erk/Akt signaling system and decreased the early fibrotic response in the obstructed kidney. This study points out that pharmacological inhibition of Ras activation may hold promise as a future strategy in the prevention of renal fibrosis. PMID:25101263

  3. pK(a) determination of angiotensin II receptor antagonists (ARA II) by spectrofluorimetry.

    PubMed

    Cagigal, E; González, L; Alonso, R M; Jiménez, R M

    2001-10-01

    The acid-base equilibrium constants of a new family of antihypertensive drugs, the angiotensin II receptor antagonists (ARA II), Losartan, Irbesartan, Valsartan, Candesartan cilexetil, its metabolite Candesartan M1 and Telmisartan were determined by spectrofluorimetry. Relative fluorescent intensity (I(F,rel))-pH data were treated by graphical (derivatives and curve-fitting) and numerical methods (LETAGROP SPEFO). The resultant pK(a) values at an ionic strength of 0.5 M were (3.15+/-0.07) for Losartan, (4.70+/-0.06) for Irbesartan, (4.90+/-0.09) for Valsartan, (6.0+/-0.1) for Candesartan cilexetil, (3.9+/-0.1) for Candesartan M1, and (4.45+/-0.09) for Telmisartan.

  4. Phosphodiesterase 5 inhibition ameliorates angiotensin II-dependent hypertension and renal vascular dysfunction.

    PubMed

    Thieme, Manuel; Sivritas, Sema H; Mergia, Evanthia; Potthoff, Sebastian A; Yang, Guang; Hering, Lydia; Grave, Katharina; Hoch, Henning; Rump, Lars C; Stegbauer, Johannes

    2017-03-01

    Changes in renal hemodynamics have a major impact on blood pressure (BP). Angiotensin (Ang) II has been shown to induce vascular dysfunction by interacting with phosphodiesterase (PDE)1 and PDE5. The predominant PDE isoform responsible for renal vascular dysfunction in hypertension is unknown. Here, we measured the effects of PDE5 (sildenafil) or PDE1 (vinpocetine) inhibition on renal blood flow (RBF), BP, and renal vascular function in normotensive and hypertensive mice. During acute short-term Ang II infusion, sildenafil decreased BP and increased RBF in C57BL/6 (WT) mice. In contrast, vinpocetine showed no effect on RBF and BP. Additionally, renal cGMP levels were significantly increased after acute sildenafil but not after vinpocetine infusion, indicating a predominant role of PDE5 in renal vasculature. Furthermore, chronic Ang II infusion (500 ng·kg(-1)·min(-1)) increased BP and led to impaired NO-dependent vasodilation in kidneys of WT mice. Additional treatment with sildenafil (100 mg·kg(-1)·day(-1)) attenuated Ang II-dependent hypertension and improved NO-mediated vasodilation. During chronic Ang II infusion, urinary nitrite excretion, a marker for renal NO generation, was increased in WT mice, whereas renal cGMP generation was decreased and restored after sildenafil treatment, suggesting a preserved cGMP signaling after PDE5 inhibition. To investigate the dependency of PDE5 effects on NO/cGMP signaling, we next analyzed eNOS-KO mice, a mouse model characterized by low vascular NO/cGMP levels. In eNOS-KO mice, chronic Ang II infusion increased BP but did not impair NO-mediated vasodilation. Moreover, sildenafil did not influence BP or vascular function in eNOS-KO mice. These results highlight PDE5 as a key regulator of renal hemodynamics in hypertension.

  5. Impaired endothelial function and microvascular asymmetrical dimethylarginine in angiotensin II-infused rats: effects of tempol.

    PubMed

    Wang, Dan; Luo, Zaiming; Wang, Xiaoyan; Jose, Pedro A; Falck, John R; Welch, William J; Aslam, Shakil; Teerlink, Tom; Wilcox, Christopher S

    2010-11-01

    Angiotensin (Ang) II causes endothelial dysfunction, which is associated with cardiovascular risk. We investigated the hypothesis that Ang II increases microvascular reactive oxygen species and asymmetrical dimethylarginine and switches endothelial function from vasodilator to vasoconstrictor pathways. Acetylcholine-induced endothelium-dependent responses of mesenteric resistance arterioles were assessed in a myograph and vascular NO and reactive oxygen species by fluorescent probes in groups (n=6) of male rats infused for 14 days with Ang II (200 ng/kg per minute) or given a sham infusion. Additional groups of Ang or sham-infused rats were given oral Tempol (2 mmol · L(-1)). Ang II infusion increased mean blood pressure (119±5 versus 89±7 mm Hg; P<0.005) and plasma malondialdehyde (0.57±0.02 versus 0.37±0.05 μmol · L(-1); P<0.035) and decreased maximal endothelium-dependent relaxation (18±5% versus 54±6%; P<0.005) and hyperpolarizing (19±3% versus 29±3%; P<0.05) responses and NO activity (0.9±0.1 versus 1.6±0.2 U; P<0.01) yet enhanced endothelium-dependent contraction responses (23±5% versus 5±5%; P<0.05) and reactive oxygen species production (0.82±0.05 versus 0.15±0.03 U; P<0.01). Ang II decreased the expression of dimethylarginine dimethylaminohydrolase 2 and increased asymmetrical dimethylarginine in vessels (450±50 versus 260±35 pmol/mg of protein; P<0.01) but not plasma. Tempol prevented any significant changes with Ang II. In conclusion, Ang redirected endothelial responses from relaxation to contraction, reduced vascular NO, and increased asymmetrical dimethylarginine. These effects were dependent on reactive oxygen species and could, therefore, be targeted with effective antioxidant therapy.

  6. Angiotensin II-induced dilated cardiomyopathy in Balb/c but not C57BL/6J mice.

    PubMed

    Peng, Hongmei; Yang, Xiao-Ping; Carretero, Oscar A; Nakagawa, Pablo; D'Ambrosio, Martin; Leung, Pablo; Xu, Jiang; Peterson, Edward L; González, Germán E; Harding, Pamela; Rhaleb, Nour-Eddine

    2011-08-01

    Balb/c mice, which are T-helper lymphocyte 2 (Th2) responders, are highly susceptible to infectious and non-infectious heart diseases, whereas C57BL/6 mice (Th1 responders) are not. Angiotensin II (Ang II) is not only a vasopressor but also a pro-inflammatory factor that leads to cardiac hypertrophy, fibrosis and dysfunction. We hypothesized that Ang II exacerbates cardiac damage in Balb/c but not in C57BL/6 mice even though both strains have a similar level of hypertension. Twelve-week-old male C57BL/6J and Balb/c mice received either vehicle or Ang II (1.4 mg kg(-1) day(-1), s.c. via osmotic minipump) for 8 weeks. At baseline, Balb/c mice exhibited the following: (1) a lower heart rate; (2) an enlarged left ventricular chamber; (3) a lower ejection fraction and shortening fraction; and (4) twice the left ventricular collagen deposition of age-matched C57BL/6J mice. Angiotensin II raised systolic blood pressure (to ∼150 mmHg) and induced cardiomyocyte hypertrophy in a similar manner in both strains. While C57BL/6J mice developed compensatory concentric hypertrophy and fibrosis in response to Ang II, Balb/c mice demonstrated severe left ventricular chamber dilatation, wall thinning and fibrosis, leading to congestive heart failure as evidenced by dramatically decreased ejection fraction and lung congestion (significant increase in lung weight), which are both characteristic of dilated cardiomyopathy. Our study suggests that the Th phenotype plays an active role in cardiac remodelling and function both in basal conditions and in hypertension. Angiotensin II-induced dilated cardiomyopathy in Balb/c mice is an ideal animal model for studying the impact of the adaptive immune system on cardiac remodelling and function and for testing strategies to prevent or treat hypertension-associated heart failure.

  7. Protective effects of coenzyme Q10 against angiotensin II-induced oxidative stress in human umbilical vein endothelial cells.

    PubMed

    Tsuneki, Hiroshi; Tokai, Emi; Suzuki, Takashi; Seki, Takayuki; Okubo, Kyosuke; Wada, Tsutomu; Okamoto, Tadashi; Koya, Sakuji; Kimura, Ikuko; Sasaoka, Toshiyasu

    2013-02-15

    Angiotensin II is the major effector in the renin-angiotensin system, and angiotensin II-induced oxidative stress and endothelial dysfunction are profoundly implicated in the pathogenesis of hypertension and cardiovascular disease. In the present study, we investigated the effect of an antioxidant reagent, coenzyme Q10, on angiotensin II-induced oxidative stress in human umbilical vein endothelial cells (HUVEC) to assess its potential usefulness for antioxidant therapy. Treatment of HUVEC with coenzyme Q10 (1-10μM) increased its intracellular levels in a concentration-dependent manner. Coenzyme Q10 (10μM) prevented the actions of angiotensin II (100nM): overproduction of reactive oxygen species, increases in expression of p22(phox) and Nox2 subunits of NADPH oxidase, and inhibition of insulin-induced nitric oxide production. In addition, coenzyme Q10 prevented angiotensin II-induced upregulation of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in HUVEC, and inhibited their adhesion to U937 monocytic cells. Moreover, treatment of HUVEC with coenzyme Q10 effectively ameliorated angiotensin II-induced increases in expression of Nox2 subunit of NADPH oxidase, ICAM-1, and VCAM-1. These results provide the first in vitro evidence that coenzyme Q10 is an efficient antioxidant reagent to improve angiotensin II-induced oxidative stress and endothelial dysfunction, possibly relevant to the causes of cardiovascular disease.

  8. Metformin inhibits angiotensin II-induced differentiation of cardiac fibroblasts into myofibroblasts.

    PubMed

    Bai, Jian; Zhang, Na; Hua, Ying; Wang, Bingjian; Ling, Lin; Ferro, Albert; Xu, Biao

    2013-01-01

    Differentiation of cardiac fibroblasts into myofibroblasts is a critical event in the progression of cardiac fibrosis that leads to pathological cardiac remodeling. Metformin, an antidiabetic agent, exhibits a number of cardioprotective properties. However, much less is known regarding the effect of metformin on cardiac fibroblast differentiation. Thus, in the present study, we examined the effect of metformin on angiotensin (Ang) II-induced differentiation of cardiac fibroblasts into myofibroblasts and its underlying mechanism. Adult rat cardiac fibroblasts were stimulated with Ang II (100 nM) in the presence or absence of metformin (10-200 µM). Ang II stimulation induced the differentiation of cardiac fibroblasts into myofibroblasts, as indicated by increased expression of α-smooth muscle actin (α-SMA) and collagen types I and III, and this effect of Ang II was inhibited by pretreatment of cardiac fibroblasts with metformin. Metformin also decreased Ang II-induced reactive oxygen species (ROS) generation in cardiac fibroblasts via inhibiting the activation of the PKC-NADPH oxidase pathway. Further experiments using PKC inhibitor calphostin C and NADPH oxidase inhibitor apocynin confirmed that inhibition of the PKC-NADPH oxidase pathway markedly attenuated Ang II-induced ROS generation and myofibroblast differentiation. These data indicate that metformin inhibits Ang II-induced myofibroblast differentiation by suppressing ROS generation via the inhibition of the PKC-NADPH oxidase pathway in adult rat cardiac fibroblasts. Our results provide new mechanistic insights regarding the cardioprotective effects of metformin and provide an efficient therapeutic strategy to attenuate cardiac fibrosis.

  9. Protection of protease-activated receptor 2 mediated vasodilatation against angiotensin II-induced vascular dysfunction in mice

    PubMed Central

    2011-01-01

    Background Under conditions of cardiovascular dysfunction, protease-activated receptor 2 (PAR2) agonists maintain vasodilatation activity, which has been attributed to increased cyclooxygenase-2, nitric oxide synthase and calcium-activated potassium channel (SK3.1) activities. Protease-activated receptor 2 agonist mediated vasodilatation is unknown under conditions of dysfunction caused by angiotensin II. The main purpose of our study was to determine whether PAR2-induced vasodilatation of resistance arteries was attenuated by prolonged angiotensin II treatment in mice. We compared the vasodilatation of resistance-type arteries (mesenteric) from angiotensin II-treated PAR2 wild-type mice (WT) induced by PAR2 agonist 2-furoyl-LIGRLO-amide (2fly) to the responses obtained in controls (saline treatment). We also investigated arterial vasodilatation in angiotensin II-treated PAR2 deficient (PAR2-/-) mice. Results 2fly-induced relaxations of untreated arteries from angiotensin II-treated WT were not different than saline-treated WT. Treatment of arteries with nitric oxide synthase inhibitor and SK3.1 inhibitor (L-NAME + TRAM-34) blocked 2fly in angiotensin II-treated WT. Protein and mRNA expression of cyclooxygenase-1 and -2 were increased, and cyclooxygenase activity increased the sensitivity of arteries to 2fly in only angiotensin II-treated WT. These protective vasodilatation mechanisms were selective for 2fly compared with acetylcholine- and nitroprusside-induced relaxations which were attenuated by angiotensin II; PAR2-/- were protected against this attenuation of nitroprusside. Conclusions PAR2-mediated vasodilatation of resistance type arteries is protected against the negative effects of angiotensin II-induced vascular dysfunction in mice. In conditions of endothelial dysfunction, angiotensin II induction of cyclooxygenases increases sensitivity to PAR2 agonist and the preserved vasodilatation mechanism involves activation of SK3.1. PMID:21955547

  10. Activating types 1 and 2 angiotensin II receptors modulate the hypertrophic differentiation of chondrocytes☆

    PubMed Central

    Tsukamoto, Ichiro; Inoue, Shinji; Teramura, Takeshi; Takehara, Toshiyuki; Ohtani, Kazuhiro; Akagi, Masao

    2013-01-01

    A local tissue-specific renin–angiotensin system (local RAS) has been identified in many organs. However, no report has described the role of a local RAS in the hypertrophic differentiation of chondrocytes. To examine the role of a local RAS in the hypertrophic differentiation, we activated angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R) separately in the cell line ATDC5, which involves differentiation from mesenchymal stem cells to hypertrophic chondrocytes. Activation of AT1R suppressed and activation of AT2R enhanced the expression of markers of hypertrophic differentiation, including type X collagen, matrix metalloproteinase 13 and runt-related transcription factor 2. PMID:23905010

  11. Angiotensin II Facilitates Fibrogenic Effect of TGF-β1 through Enhancing the Down-Regulation of BAMBI Caused by LPS: A New Pro-Fibrotic Mechanism of Angiotensin II

    PubMed Central

    Shi, Xiao-Lan; Zhao, Xu-Wen; Luo, Hai-Hua; Li, Xu

    2013-01-01

    Angiotensin II has progressively been considered to play an important role in the development of liver fibrosis, although the mechanism isn't fully understood. The aim of this study was to investigate a possible pro-fibrotic mechanism, by which angiotensin II would enhance the pro-fibrotic effect of transforming growth factor beta 1 (TGF-β1) through up-regulation of toll-like receptor 4 (TLR4) and enhancing down-regulation of TGF-β1 inhibitory pseudo-receptor—BAMBI caused by LPS in hepatic stellate cells (HSCs). Firstly, the synergistic effects of angiotensin II, TGF-β1 and LPS on collagen 1α production were confirmed in vitro by ELISA, in which angiotensin II, LPS and TGF-β1 were treated sequentially, and in vivo by immunofluorescence, in the experiments single or multiple intra-peritoneally implanted osmotic mini-pumps administrating angiotensin II or LPS combined with intra-peritoneal injections of TGF-β1 were used. We also found that only LPS and TGF-β1 weren't enough to induce obvious fibrogenesis without angiotensin II. Secondly, to identify the reason of why angiotensin II is so important, the minute level of TLR4 in activated HSCs - T6 and primary quiescent HSCs of rat, up-regulation of TLR4 by angiotensin II and blockage by different angiotensin II receptor type 1 (AT1) blockers in HSCs were assayed by western blotting in vitro and immunofluorescence in vivo. Finally, BAMBI expression level, which is regulated by LPS-TLR4 pathway, was detected by qRT-PCR and results showed angiotensin II enhanced the down-regulation of BAMBI mRNA caused by LPS in vitro and in vivo, and TLR4 neutralization antibody blocked this interactive effect. These data demonstrated that angiotensin II enhances LPS-TLR4 pathway signaling and further down-regulates expression of BAMBI through up-regulation of TLR4, which results in facilitation of pro-fibrotic activity of TGF-β1. Angiotensin II, LPS and TGF-β1 act synergistically during hepatic fibrogenesis, showing

  12. Elastase-2, an angiotensin II-generating enzyme, contributes to increased Ang II in resistance arteries of mice with myocardial infarction.

    PubMed

    Becari, Christiane; Silva, Marcondes A B; Durand, Marina T; Prado, Cibele M; Oliveira, Eduardo B; Ribeiro, Mauricio S; Salgado, Helio C; Salgado, Maria Cristina O; Tostes, Rita C

    2017-02-21

    Angiotensin II (Ang II), whose generation largely depends on angiotensin-converting enzyme activity, mediates most of the renin-angiotensin-system effects. Elastase-2 (ELA-2), a chymotrypsin-serine protease elastase family member 2A, alternatively generates Ang II in rat arteries. Myocardial infarction (MI) leads to intense RAS activation, but mechanisms involved on Ang II-generation in resistance arteries are unknown. We hypothesized that ELA-2 contributes to vascular Ang II generation and to cardiac damage in mice submitted to MI. Concentration-effect curves to Ang I and Ang II were performed in mesenteric resistance arteries from male wild type (WT) and ELA-2 knockout (ELA-2KO) mice submitted to left anterior descending coronary artery ligation (myocardial infarction, MI). MI size was similar in WT (29.5 ± 9 %) and ELA-2KO (32 ± 4%) mice. Ejection fraction and fractional shortening after MI similarly decreased in both strains. However, MI decreased stroke volume and cardiac output in WT, but not in ELA-2KO mice. Ang I-induced contractions increased in WT mice submitted to MI (MI-WT) compared to Sham-WT mice. No differences were observed in Ang I reactivity between arteries from Sham-ELA-2KO and ELA-2KO submitted to MI (MI-ELA-2KO). Ang I contractions increased in arteries from MI-WT vs. MI-ELA-2KO mice. Chymostatin attenuated Ang I-induced vascular contractions in WT mice (P < 0.05), but did not affect Ang I responses in ELA-2KO arteries. These results provide the first evidence that ELA-2 contributes to increased Ang II formation in resistance arteries and modulates cardiac function after MI, implicating ELA-2 as a key player in ACE-independent dysregulation of the RAS.

  13. Sex differences in the development of angiotensin II-induced hypertension in conscious mice.

    PubMed

    Xue, Baojian; Pamidimukkala, Jaya; Hay, Meredith

    2005-05-01

    Sex has an important influence on blood pressure (BP) regulation. There is increasing evidence that sex hormones interfere with the renin-angiotensin system. Thus the purpose of this study was to determine whether there are sex differences in the development of ANG II-induced hypertension in conscious male and female mice. We used telemetry implants to measure aortic BP and heart rate (HR) in conscious, freely moving animals. ANG II (800 ng.kg(-1).min(-1)) was delivered via an osmotic pump implanted subcutaneously. Our results showed baseline BP in male and female mice to be similar. Chronic systemic infusion of ANG II induced a greater increase in BP in male (35.1 +/- 5.7 mmHg) than in female mice (7.2 +/- 2.0 mmHg). Gonadectomy attenuated ANG II-induced hypertension in male mice (15.2 +/- 2.4 mmHg) and augmented it in female mice (23.1 +/- 1.0 mmHg). Baseline HR was significantly higher in females relative to males (630.1 +/- 7.9 vs. 544.8 +/- 16.2 beats/min). In females, ANG II infusion significantly decreased HR. However, the increase in BP with ANG II did not result in the expected decrease in HR in either intact male or gonadectomized mice. Moreover, the slope of the baroreflex bradycardia to phenylephrine was blunted in males (-5.6 +/- 0.3 to -2.9 +/- 0.5) but not in females (-6.5 +/- 0.5 to -5.6 +/- 0.3) during infusion of ANG II, suggesting that, in male mice, infusion of ANG II results in a resetting of the baroreflex control of HR. Ganglionic blockade resulted in greater reduction in BP on day 7 after ANG II infusion in males compared with females (-61.0 +/- 8.9 vs. -36.6 +/- 6.6 mmHg), suggesting an increased contribution of sympathetic nerve activity in arterial BP maintenance in male mice. Together, these data indicate that there are sex differences in the development of chronic ANG II-induced hypertension in conscious mice and that females may be protected from the increases in BP induced by ANG II.

  14. Candesartan cilexetil protects against loss of autoregulatory efficiency in angiotensin II-infused rats.

    PubMed

    Inscho, E W; Imig, J D; Deichmann, P C; Cook, A K

    1999-01-01

    Renal autoregulatory efficiency is compromised in angiotensin-II (AngII)-dependent Goldblatt hypertension. The current studies were performed to assess renal autoregulatory capability in AngII-infused hypertensive rats and to determine the effect of chronic candesartan cilexetil treatment on autoregulatory behavior. Rats received chronic infusion of AngII (60 ng/min) or vehicle via an osmotic minipump implanted subcutaneously in the dorsum of the neck. Selected rats received the novel AT1 receptor blocker candesartan cilexetil (1.0 mg/kg per d) in the drinking water. Systolic BP averaged 118+/-1 mmHg (n=34) before pump implantation. Chronic AngII infusion for 6 d increased arterial pressure to 151+/-4 mmHg. Candesartan cilexetil administration prevented the AngII-dependent increase in systolic BP. Microvascular autoregulation experiments were performed in vitro using the blood-perfused juxtamedullary nephron technique combined with videomicroscopy. Renal perfusion pressure was set at 100 mmHg during the control period before being decreased to 65 mmHg. Afferent arteriolar diameter was measured continuously as the perfusion pressure was increased from 65 mmHg to 170 mmHg in 15-mmHg increments. Afferent arteriolar diameter in sham-treated rats was 120% of control at a perfusion pressure of 65 mmHg and decreased to 76% of the control diameter at 170 mmHg (n=6). This behavior is consistent with normal autoregulatory behavior. Arterioles from rats receiving chronic infusion of AngII exhibited compromised renal microvascular autoregulatory efficiency. Afferent arteriolar diameter in AngII-treated kidneys varied from 103 to 100% (n=6) of the control diameter over the same pressure range of 65 to 170 mmHg. This blunting of autoregulatory behavior was prevented by AT1 receptor blockade. In animals receiving AngII + candesartan cilexetil, stepwise changes in perfusion pressure elicited changes in afferent arteriolar diameter between 120 and 84% after 6 d of treatment (n=6

  15. Role of p47phox in Vascular Oxidative Stress and Hypertension Caused by Angiotensin II

    PubMed Central

    Landmesser, Ulf; Cai, Hua; Dikalov, Sergey; McCann, Louise; Hwang, Jinah; Jo, Hanjoong; Holland, Steven M.; Harrison, David G.

    2016-01-01

    Hypertension caused by angiotensin II is dependent on vascular superoxide (O2·–) production. The nicotin-amide adenine dinucleotide phosphate (NAD[P]H) oxidase is a major source of vascular O2·– and is activated by angiotensin II in vitro. However, its role in angiotensin II–induced hypertension in vivo is less clear. In the present studies, we used mice deficient in p47phox, a cytosolic subunit of the NADPH oxidase, to study the role of this enzyme system in vivo. In vivo, angiotensin II infusion (0.7 mg/kg per day for 7 days) increased systolic blood pressure from 105±2 to 151±6 mm Hg and increased vascular O2·– formation 2- to 3-fold in wild-type (WT) mice. In contrast, in p47phox−/− mice the hypertensive response to angiotensin II infusion (122±4 mm Hg; P<0.05) was markedly blunted, and there was no increase of vascular O2·– production. In situ staining for O2·– using dihydroethidium revealed a marked increase of O2·–production in both endothelial and vascular smooth muscle cells of angiotensin II–treated WT mice, but not in those of p47phox−/− mice. To directly examine the role of the NAD(P)H oxidase in endothelial production of O2·–, endothelial cells from WT and p47phox−/− mice were cultured. Western blotting confirmed the absence of p47phox in p47phox−/− mice. Angiotensin II increased O2·– production in endothelial cells from WT mice, but not in those from p47phox−/− mice, as determined by electron spin resonance spectroscopy. These results suggest a pivotal role of the NAD(P)H oxidase and its subunit p47phox in the vascular oxidant stress and the blood pressure response to angiotensin II in vivo. PMID:12364355

  16. Direct Activation of ENaC by Angiotensin II: Recent Advances and New Insights

    PubMed Central

    Zaika, Oleg; Mamenko, Mykola; Staruschenko, Alexander

    2012-01-01

    Angiotensin II (Ang II) is the principal effector of the renin-angiotensin-aldosterone system (RAAS). It initiates myriad processes in multiple organs integrated to increase circulating volume and elevate systemic blood pressure. In the kidney, Ang II stimulates renal tubular water and salt reabsorption causing antinatriuresis and antidiuresis. Activation of RAAS is known to enhance activity of the epithelial Na+ channel (ENaC) in the aldosterone-sensitive distal nephron. In addition to its well described stimulatory actions on aldosterone secretion, Ang II is also capable to directly increase ENaC activity. In this brief review, we discuss recent findings about non-classical Ang II actions on ENaC and speculate about its relevance for renal sodium handling. PMID:23180052

  17. Angiotensin II receptor type 1 blockers suppress the cell proliferation effects of angiotensin II in breast cancer cells by inhibiting AT1R signaling.

    PubMed

    Du, Ning; Feng, Jiang; Hu, Li-Juan; Sun, Xin; Sun, Hai-Bing; Zhao, Yang; Yang, Yi-Ping; Ren, Hong

    2012-06-01

    Chronic stress and a high-fat diet are well-documented risk factors associated with the renin-angiotensin system in the development of breast cancer. The angiotensin II type 1 receptor (AT1R) is a novel component of the renin-angiotensin system. Several recent studies have focused on the function of AT1R in cell proliferation during cancer development. Thus, we hypothesized that angiotensin II (Ang Ⅱ) can promote proliferation of breast cancer via activated AT1R; the activation of AT1R may play an important role in promoting breast cancer growth, and AT1R blocker (ARB) may suppress the promotional effect on proliferation by antagonizing AT1R. The expression level of AT1R was found to be significantly upregulated in breast cancer cells by immunohistochemistry, but no correlation between AT1R expression and ER/PR/Her-2 expression was observed. The AT1R(+)-MCF-7 cell line exhibited high expression of AT1R protein, and we generated the AT1R(-)-MCF-7 cell line using RNA interference. ARBs, and in particular irbesartan, effectively inhibited the effects of Ang II on cell proliferation, cell cycle development and downstream AT1R signaling events, including the activation of the Ras-Raf-MAPK pathway and the transcription factors NF-κB and CREB. Irbesartan also significantly altered p53, PCNA and cyclin D1 expression, which was also influenced by activated AT1R in AT1R(+)-MCF-7 cells. These results suggest that ARBs may be useful as a novel preventive and therapeutic strategy for treating breast cancer.

  18. Angiotensin II Levels in Gingival Tissues from Healthy Individuals, Patients with Nifedipine Induced Gingival Overgrowth and Non Responders on Nifedipine

    PubMed Central

    Balaji, Anitha; Balaji, Thodur Madapusi

    2015-01-01

    Context The Renin Angiotensin system has been implicated in the pathogenesis of Drug Induced Gingival Overgrowth (DIGO), a fibrotic condition, caused by Phenytoin, Nifedipine and Cyclosporine. Aim This study quantified Angiotensin II levels in gingival tissue samples obtained from healthy individuals, patients on Nifedipine manifesting/not manifesting drug induced gingival overgrowth. Materials and Methods Gingival tissue samples were obtained from healthy individuals (n=24), patients on nifidipine manifesting gingival overgrowth (n= 18) and patients on nifidipine not manifesting gingival overgrowth (n=8). Angiotensin II levels were estimated in the samples using a commercially available ELISA kit. Results Angiotensin II levels were significantly elevated in patients on Nifedipine manifesting gingival overgrowth compared to the other 2 groups (p<0.01). Conclusion The results of the study give an insight into the role played by Angiotensin II in the pathogenesis of drug induced gingival overgrowth. PMID:26436057

  19. Alterations in Responses to Bradykinin, Angiotensin I, and Angiotensin II During the Induction Phase of One-Kidney, One-Wrapped Hypertension and Associated Arterial Disease in Rabbits

    PubMed Central

    Campbell, Wallace G.; Donohue, John A.; Duket, Lea H.

    1980-01-01

    During the induction phase of low-renin, one-kidney, one-wrapped hypertension in rabbits,serum angiotensin converting enzyme (ACE) activity is depressed and correlates inversely with the degree of necrotic arterial disease that develops. Responses to the vasoactive polypeptides, bradykinin (BK), angiotensin I (AI), angiotensin II (AII), the ACE blocker teprotide, and the AII antagonist 1-sar-8-ile AII were studied. Responses to BK, AII, and AI showed significant changes in both magnitude and duration (recovery time). Recovery time for depressor responses to BK in hypertensive rabbits was approximately three times that in the control period. One-wrapped, two-kidney control rabbits without hypertension-associated arterial disease showed no change in BK recovery time, although serum ACE activity was significantly depressed. In the experimental period BK recovery time correlated directly with the degree of arterial disease and indirectly with the final serum ACE activity. Duration of the pressor responses after AII correlated directly with the degree of arterial disease and indirectly with final serum ACE activity. In untreated hypertensive rabbits the percentage of increases in blood pressure after AI relative to control animals were decreased, and for all hypertensive rabbits' the increase in blood pressure correlated directly with the final serum ACE activity. Long-term treatment with teprotide moderated the hypertension but had little effect on serum ACE activity or the responses to BK, AII, and AI. Short-term infusions of 1-sar-8-ile AII and teprotide caused significant decreases in blood pressure in both the control and experimental periods, although no change in response to either polypeptide occurred. These studies support other evidence that pressor components of the renin-angiotensin system do not sustain the elevation of blood pressure in this form of experimental hypertension. Alterations in response patterns following AII and AI suggest that a

  20. Angiotensin II stimulates superoxide production by nitric oxide synthase in thick ascending limbs.

    PubMed

    Gonzalez-Vicente, Agustin; Saikumar, Jagannath H; Massey, Katherine J; Hong, Nancy J; Dominici, Fernando P; Carretero, Oscar A; Garvin, Jeffrey L

    2016-02-01

    Angiotensin II (Ang II) causes nitric oxide synthase (NOS) to become a source of superoxide (O2 (-)) via a protein kinase C (PKC)-dependent process in endothelial cells. Ang II stimulates both NO and O2 (-) production in thick ascending limbs. We hypothesized that Ang II causes O2 (-) production by NOS in thick ascending limbs via a PKC-dependent mechanism. NO production was measured in isolated rat thick ascending limbs using DAF-FM, whereas O2 (-) was measured in thick ascending limb suspensions using the lucigenin assay. Consistent stimulation of NO was observed with 1 nmol/L Ang II (P < 0.001; n = 9). This concentration of Ang II-stimulated O2 (-) production by 50% (1.77 ± 0.26 vs. 2.62 ± 0.36 relative lights units (RLU)/s/μg protein; P < 0.04; n = 5). In the presence of the NOS inhibitor L-NAME, Ang II-stimulated O2 (-) decreased from 2.02 ± 0.29 to 1.10 ± 0.11 RLU/s/μg protein (P < 0.01; n = 8). L-arginine alone did not change Ang II-stimulated O2 (-) (2.34 ± 0.22 vs. 2.29 ± 0.29 RLU/s/μg protein; n = 5). In the presence of Ang II plus the PKC α/β1 inhibitor Gö 6976, L-NAME had no effect on O2 (-) production (0.78 ± 0.23 vs. 0.62 ± 0.11 RLU/s/μg protein; n = 7). In the presence of Ang II plus apocynin, a NADPH oxidase inhibitor, L-NAME did not change O2 (-) (0.59 ± 0.04 vs. 0.61 ± ×0.08 RLU/s/μg protein; n = 5). We conclude that: (1) Ang II causes NOS to produce O2 (-) in thick ascending limbs via a PKC- and NADPH oxidase-dependent process; and (2) the effect of Ang II is not due to limited substrate.

  1. Endothelium-Dependent Relaxation and Angiotensin II Sensitivity in Experimental Preeclampsia

    PubMed Central

    van der Graaf, Anne Marijn; Wiegman, Marjon J.; Plösch, Torsten; Zeeman, Gerda G.; van Buiten, Azuwerus; Henning, Robert H.; Buikema, Hendrik; Faas, Marijke M.

    2013-01-01

    Objective We investigated endothelial dysfunction and the role of angiotensin (Ang)-II type I (AT1-R) and type II (AT2-R) receptor in the changes in the Ang-II sensitivity in experimental preeclampsia in the rat. Methods Aortic rings were isolated from low dose lipopolysaccharide (LPS) infused pregnant rats (experimental preeclampsia; n=9), saline-infused pregnant rats (n=8), and saline (n=8) and LPS (n=8) infused non-pregnant rats. Endothelium-dependent acetylcholine--mediated relaxation was studied in phenylephrine-preconstricted aortic rings in the presence of vehicle, NG-nitro-L-arginine methyl ester and/or indomethacin. To evaluate the role for AT1-R and AT2-R in Ang-II sensitivity, full concentration response curves were obtained for Ang-II in the presence of losartan or PD123319. mRNA expression of the AT1-R and AT2-R, eNOS and iNOS, COX1 and COX2 in aorta were evaluated using real-time RT-PCR. Results The role of vasodilator prostaglandins in the aorta was increased and the role of endothelium-derived hyperpolarizing factor and response of the AT1-R and AT2-R to Ang-II was decreased in pregnant saline infused rats as compared with non-pregnant rats. These changes were not observed during preeclampsia. Conclusion Pregnancy induced adaptations in endothelial function, which were not observed in the rat model for preeclampsia. This role of lack of pregnancy induced endothelial adaptation in the pathophysiology of experimental preeclampsia needs further investigation. PMID:24223202

  2. Limiting angiotensin II signaling with a cell penetrating peptide mimicking the second intracellular loop of the angiotensin II type I receptor

    PubMed Central

    Yu, Jun; Taylor, Linda; Mierke, Dale; Berg, Eric; Shia, Michael; Fishman, Jordan; Sallum, Christine; Polgar, Peter

    2010-01-01

    A cell-penetrating peptide consisting of the second intracellular loop (IC2) of the Angiotensin II (AngII) type I receptor (AT1) linked to the HIV transactivating regulatory protein (TAT) domain was used to identify the role of this motif for intracellular signal transduction. HEK-293 cells stably transfected with AT1R cDNA and primary cultures of human pulmonary artery smooth muscle cells expressing endogenous AT1 receptor were exposed to the cell-penetrating peptide construct and the effect on angiotensin II signaling determined. The AT1 IC2 peptide effectively inhibited AngII stimulated phosphatidylinositol turnover and calcium influx. It also limited the activation of Akt/PKB as determined by an inhibition of phosphorylation of Akt at Ser473 and completely abolished the AngII dependent activation of the transcriptional factor NFκB. In contrast, the AT1 IC2 peptide had no effect on AngII/AT1 receptor activation of ERK. These results illustrate the potential of using cell penetrating peptides to both delineate receptor-mediated signal transduction as well as to selectively regulate G protein coupled receptor signaling. PMID:20492449

  3. Impact of Angiotensin I-converting Enzyme Inhibitors and Angiotensin II Type-1 Receptor Blockers on Survival of Patients with NSCLC

    PubMed Central

    Miao, Lili; Chen, Wei; Zhou, Ling; Wan, Huanying; Gao, Beili; Feng, Yun

    2016-01-01

    It has been shown that angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) can decrease tumor growth and tumor-associated angiogenesis and inhibit metastasis. Epidermal growth factor receptor (EGFR) mutations are found in approximately 30% of patients with advanced non-small cell lung cancer (NSCLC) in East Asia and in 10–15% of such patients in Western countries. We retrospectively identified 228 patients with histologically confirmed advanced NSCLC and 73 patients with early stage disease; 103 of these patients took antihypertensive drugs, and 112 received treatment with EGFR tyrosine kinase inhibitors (TKIs). There was a significant difference in progression-free survival after first-line therapy (PFS1) between the ACEI/ARB group and the non-ACEI/ARB group. For the patients treated with TKIs, there was a significant difference in PFS but not in overall survival (OS) between the ACEI/ARB group and the non-ACEI/ARB group. For the patients with advanced NSCLC, there was a significant difference in PFS1 between the ACEI/ARB group and the non-ACEI/ARB group. ACEI/ARB in combination with standard chemotherapy or TKIs had a positive effect on PFS1 or OS, regardless of whether the lung cancer was in the early or advanced stage. PMID:26883083

  4. The role of IL-6 in the physiologic versus hypertensive blood pressure actions of angiotensin II

    PubMed Central

    Manhiani, M Marlina; Seth, Dale M; Banes-Berceli, Amy K L; Satou, Ryosuke; Navar, L Gabriel; Brands, Michael W

    2015-01-01

    Angiotensin II (AngII) is a critical physiologic regulator of volume homeostasis and mean arterial pressure (MAP), yet it also is known to induce immune mechanisms that contribute to hypertension. This study determined the role of interleukin-6 (IL-6) in the physiologic effect of AngII to maintain normal MAP during low-salt (LS) intake, and whether hypertension induced by plasma AngII concentrations measured during LS diet required IL-6. IL-6 knockout (KO) and wild-type (WT) mice were placed on LS diet for 7 days, and MAP was measured 19 h/day with telemetry. MAP was not affected by LS in either group, averaging 101 ± 4 and 100 ± 4 mmHg in WT and KO mice, respectively, over the last 3 days. Seven days of ACEI decreased MAP ∼25 mmHg in both groups. In other KO and WT mice, AngII was infused at 200 ng/kg per minute to approximate plasma AngII levels during LS. Surgical reduction of kidney mass and high-salt diet were used to amplify the blood pressure effect. The increase in MAP after 7 days was not different, averaging 20 ± 5 and 22 ± 6 mmHg in WT and KO mice, respectively. Janus Kinase 2 (JAK2)/signal transducer of activated transcription (STAT3) phosphorylation were not affected by LS, but were increased by AngII infusion at 200 and 800 ng/kg per minute. These data suggest that physiologic levels of AngII do not activate or require IL-6 to affect blood pressure significantly, whether AngII is maintaining blood pressure on LS diet or causing blood pressure to increase. JAK2/STAT3 activation, however, is tightly associated with AngII hypertension, even when caused by physiologic levels of AngII. PMID:26486161

  5. Determinants and Changes Associated with Aldosterone Breakthrough after Angiotensin II Receptor Blockade in Patients with Type 2 Diabetes with Overt Nephropathy

    PubMed Central

    Moranne, Olivier; Bakris, George; Fafin, Coraline; Favre, Guillaume; Pradier, Christian

    2013-01-01

    Summary Background and objectives Inhibition of the renin-angiotensin-aldosterone system decreases proteinuria and slows estimated GFR decline in patients with type 2 diabetes mellitus with overt nephropathy. Serum aldosterone levels may increase during renin-angiotensin-aldosterone system blockade. The determinants and consequences of this aldosterone breakthrough remain unknown. Design, setting, participants, & measurements This study examined the incidence, determinants, and changes associated with aldosterone breakthrough in a posthoc analysis of a randomized study that compared the effect of two angiotensin II receptor blockers in patients with type 2 diabetes mellitus with overt nephropathy. Results Of 567 of 860 participants included in this posthoc analysis, 28% of participants developed aldosterone breakthrough, which was defined by an increase greater than 10% over baseline values of serum aldosterone levels after 1 year of angiotensin II receptor blocker treatment. Factors independently associated with aldosterone breakthrough at 1 year were lower serum aldosterone and potassium levels at baseline, higher decreases in sodium intake, systolic BP, and estimated GFR from baseline to 1 year, and use of losartan versus telmisartan. Aldosterone breakthrough at 6 months was not sustained at 1 year in 69% of cases, and it did not predict estimated GFR decrease and proteinuria increase between 6 months and 1 year. Conclusions Aldosterone breakthrough is a frequent event 1 year after initiating renin-angiotensin-aldosterone system blockade, particularly in participants exposed to intensive lowering of BP with sodium depletion and short-acting angiotensin II receptor blockers. Short-term serum aldosterone level increases at 6 months are not associated with negative kidney outcomes between 6 months and 1 year. PMID:23929924

  6. Reactive oxygen species mediate angiotensin II-induced transcytosis of low-density lipoprotein across endothelial cells

    PubMed Central

    Bian, Fang; Cui, Jun; Zheng, Tao; Jin, Si

    2017-01-01

    The retention of plasma low-density lipoprotein (LDL) particles to subendothelial spaces through transcytosis across the endothelium is the initial step of atherosclerosis (AS). Angiotensin II (Ang II), as the principal effector molecule of the renin-angiotensin system (RAS), is implicated in several important steps of AS development. However, whether or not Ang II can directly exert a pro-atherogenic effect by promoting LDL transcytosis across endothelial barriers, has not been defined. In the present study, we found that Ang II upregulated intracellular reactive oxygen species (ROS) levels in endothelial cells (ECs) by measuring fluorescence of 2′,7′-dichlorofluorescein (DCF-DA). Based on our transcytosis model, we observed that Ang II significantly accelerated LDL transcytosis, whereas transcytosis inhibitor methyl-β-cyclodextrin (MβCD) and ROS inhibitor dithiothreitol (DTT), markedly blocked the Ang II-stimulated increase in LDL transcytosis. Confocal imaging analysis revealed that both LDL uptake by cells and LDL retention in human umbilical venous walls were highly elevated after Ang II exposure, while MβCD and DTT significantly inhibited the effects of Ang II. What is more, proteins involved in caveolae-mediated transcytosis, including LDL receptor (LDLR), caveolin-1 and cavin-1, were associated with Ang II-induced LDL transcytosis across the ECs. Nevertheless, this process was independent of clathrin in our study. Of note, ROS inhibitor, DTT, markedly decreased the expression levels of those proteins. Consequently, ROS are critical mediators in Ang II-induced LDL transcytosis. Hopefully, these findings will provide novel insight into the crosstalk between dyslipidemia and RAS in atherogenesis. PMID:28204818

  7. Different reactivity to angiotensin II of peripheral and renal arteries in spontaneously hypertensive rats: effect of acute and chronic angiotensin converting enzyme inhibition

    NASA Technical Reports Server (NTRS)

    Guidi, E.; Hollenberg, N. K.

    1986-01-01

    We assessed renal blood flow and pressor responses to graded angiotensin II doses in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats ingesting a diet containing 1.6% sodium basally and after acute and chronic angiotensin converting enzyme (ACE) inhibition with captopril. In the basal state the pressor response to angiotensin II was enhanced (P<0.0005) and the renal vascular response was blunted (P<0.005) in SHR compared with WKY rats. After acute captopril administration the pressor response was enhanced in both strains, and the difference between them was maintained, while the renal vascular response was enhanced in both, but more in SHR, so that the renal vascular response in the SHR became larger than in WKY (P<0.0001). Chronic captopril treatment blunted both pressor and renal responses in WKY rats, but only the pressor response in SHR. The renal vessels of SHR seem to be different from those of WKY rats in reaction to exogenous angiotensin II, and in response to both acute administration of captopril (probably acting through blockade of angiotensin II production) and chronic administration of captopril (probably acting mainly through accumulation of kinin or production of prostaglandins).

  8. Changes in blood pressure and dipsogenic responsiveness to angiotensin II during chronic exposure of rats to cold.

    PubMed

    Fregly, M J; Shechtman, O; van Bergen, P; Reeber, C; Papanek, P E

    1991-04-01

    Hypertension accompanies chronic exposure of rats to cold (5-6 degrees C). Systolic, diastolic, and mean blood pressures become elevated, and hypertrophy of the heart occurs. A previous study from this laboratory suggested that the renin-angiotensin system may play a role. The present study was carried out to assess this further. Thus, in addition to measurement of systolic blood pressure at intervals during exposure to cold, plasma renin activity and the dipsogenic responsiveness to acute administration of angiotensin II were also measured to assess the functional status of the renin-angiotensin system. The results showed a significant (p less than 0.05) increase in systolic blood pressure during the third week of exposure to cold. In contrast, plasma renin activity (PRA) increased within the first week of exposure to cold, and declined thereafter to reach the level of the control by the third week of exposure to cold. By the fourth week, PRA decreased to a level significantly (p less than 0.05) below that of the control group. The responsiveness to acute administration of angiotensin II (AII), as assessed by the drinking response, increased significantly (p less than 0.05) by the third week of exposure to cold and remained significantly elevated during the fourth week. There was a significant (p less than 0.01) direct relationship between dipsogenic responsiveness to AII and blood pressure in the cold-treated (r = .57), but not the control group (r = .12). There was also a significant (r = -.91) indirect linear relationship between PRA and dipsogenic responsiveness to AII. Cold-treated rats had significant increases in urinary norepinephrine output and weights of heart, kidneys, adrenals, and brown adipose tissue characteristic of rats acclimated to cold.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Intrarenal angiotensin II and its contribution to the genesis of chronic hypertension

    PubMed Central

    Navar, L Gabriel; Prieto, Minolfa C; Satou, Ryousuke; Kobori, Hiroyuki

    2011-01-01

    The increased activity of intrarenal renin–angiotensin system (RAS) in a setting of elevated arterial pressure elicits renal vasoconstriction, increased sodium reabsorption, proliferation, fibrosis and renal injury. Increases in intrarenal and interstitial angiotensin (Ang) II levels are due to increased AT1 receptor mediated Ang II uptake and stimulation of renal angiotensinogen (AGT) mRNA and protein expression. Augmented proximal tubule AGT production increases tubular AGT secretion and spillover of AGT into the distal nephron and urine. Increased renin formation by principal cells of the collecting ducts forms Ang I from AGT thus increasing Ang II. The catalytic actions of renin and prorenin are enhanced by prorenin receptors (PRRs) on the intercalated cells. The resultant increased intrarenal Ang II levels contribute to the genesis of chronic hypertension. PMID:21339086

  10. TRPM8 downregulation by angiotensin II in vascular smooth muscle cells is involved in hypertension.

    PubMed

    Huang, Fang; Ni, Min; Zhang, Jing-Ming; Li, Dong-Jie; Shen, Fu-Ming

    2017-04-01

    Angiotensin II (Ang II)-induced injury of vascular smooth muscle cells (VSMCs) serves an important role in hypertension and other cardiovascular disorders. Transient receptor potential melastatin 8 (TRPM8) is a thermally‑regulated Ca2+‑permeable channel that is activated by reduced body temperature. Although several recent studies have revealed the regulatory effect of TRPM8 in vascular tone and hypertension, the precise role of TRPM8 in dysfunction of vascular smooth muscle cells (VSMCs) induced by Ang II remains elusive. In the present study, the possible function of TRPM8 in Ang II‑induced VSMCs malfunction in vivo and in vitro was investigated. In the aortae from rats that had undergone a two‑kidney one‑clip operation, which is a widely‑used renovascular hypertension model, the mRNA and protein levels of TRPM8 were reduced. In addition, exogenous Ang II treatment decreased TRPM8 mRNA and protein expression levels in primary cultures of rat VSMCs. TRPM8 activation by menthol, a pharmacological agonist, in VSMCs, significantly attenuated the Ang II‑induced increase in reactive oxygen species and H2O2 production. In addition, TRPM8 activation reduced the Ang II‑induced upregulation of NADPH oxidase (NOX) 1 and NOX4 in VSMCs. Furthermore, TRPM8 activation relieved the Ang II‑induced activation of ras homolog gene family, member A‑rho associated protein kinase 2 and janus kinase 2 signaling pathways in VSMCs. In conclusion, the results presented in the current study indicated that TRPM8 downregulation by Ang II in VSMCs may be involved in hypertension.

  11. Angiotensin II, independent of plasma renin activity, contributes to the hypertension of autonomic failure.

    PubMed

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

    2013-03-01

    At least half of primary autonomic failure patients exhibit supine hypertension, despite profound impairments in sympathetic activity. Although the mechanisms underlying this hypertension are unknown, plasma renin activity is often undetectable, suggesting renin-angiotensin (Ang) pathways are not involved. However, because aldosterone levels are preserved, we tested the hypothesis that Ang II is intact and contributes to the hypertension of autonomic failure. Indeed, circulating Ang II was paradoxically increased in hypertensive autonomic failure patients (52±5 pg/mL, n=11) compared with matched healthy controls (27±4 pg/mL, n=10; P=0.002), despite similarly low renin activity (0.19±0.06 versus 0.34±0.13 ng/mL per hour, respectively; P=0.449). To determine the contribution of Ang II to supine hypertension in these patients, we administered the AT(1) receptor blocker losartan (50 mg) at bedtime in a randomized, double-blind, placebo-controlled study (n=11). Losartan maximally reduced systolic blood pressure by 32±11 mm Hg at 6 hours after administration (P<0.05), decreased nocturnal urinary sodium excretion (P=0.0461), and did not worsen morning orthostatic tolerance. In contrast, there was no effect of captopril on supine blood pressure in a subset of these patients. These findings suggest that Ang II formation in autonomic failure is independent of plasma renin activity, and perhaps Ang-converting enzyme. Furthermore, these studies suggest that elevations in Ang II contribute to the hypertension of autonomic failure, and provide rationale for the use of AT(1) receptor blockers for treatment of these patients.

  12. Antiangiogenic effect of angiotensin II type 2 receptor in ischemia-induced angiogenesis in mice hindlimb.

    PubMed

    Silvestre, Jean-Sébastien; Tamarat, Radia; Senbonmatsu, Takaaki; Icchiki, Toshihiro; Ebrahimian, Teni; Iglarz, Marc; Besnard, Sandrine; Duriez, Micheline; Inagami, Tadashi; Lévy, Bernard I

    2002-05-31

    This study examined the potential role of angiotensin type 2 (AT(2)) receptor on angiogenesis in a model of surgically induced hindlimb ischemia. Ischemia was produced by femoral artery ligature in both wild-type and AT(2) gene-deleted mice (Agtr2(-)/Y). After 28 days, angiogenesis was quantitated by microangiography, capillary density measurement, and laser Doppler perfusion imaging. Protein levels of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), Bax, and Bcl-2 were determined by Western blot analysis in hindlimbs. The AT(2) mRNA level (assessed by semiquantitative RT-PCR) was increased in the ischemic hindlimb of wild-type mice. Angiographic vessel density and laser Doppler perfusion data showed significant improvement in ischemic/nonischemic leg ratio, 1.9- and 1.7-fold, respectively, in Agtr2(-)/Y mice compared with controls. In ischemic leg of Agtr2(-)/Y mice, revascularization was associated with an increase in the antiapoptotic protein content, Bcl-2 (211% of basal), and a decrease (60% of basal) in the number of cell death, determined by TUNEL method. Angiotensin II treatment (0.3 mg/kg per day) raised angiogenic score, blood perfusion, and both VEGF and eNOS protein content in ischemic leg of wild-type control but did not modulate the enhanced angiogenic response observed in untreated Agtr2(-)/Y mice. Finally, immunohistochemistry analysis revealed that VEGF was mainly localized to myocyte, whereas eNOS-positive staining was mainly observed in the capillary of ischemic leg of both wild-type and AT(2)-deficient mice. This study demonstrates for the first time that the AT(2) receptor subtype may negatively modulate ischemia-induced angiogenesis through an activation of the apoptotic process.

  13. Gestational therapy with an angiotensin II receptor antagonist and transient renal failure in a premature infant.

    PubMed

    Bass, J Kirk; Faix, Roger G

    2006-07-01

    The fetotoxic effects of angiotensin converting enzyme inhibitors when used during the second half of pregnancy are well known. The more recently developed angiotensin II receptor antagonists appear to yield similar fetal abnormalities. We report a premature infant born to a 41-year-old mother with a long history of infertility who had received losartan therapy for hypertension throughout an undetected pregnancy. Ultrasound examination 2 days prior to delivery identified a single fetus at 29 weeks gestation, anhydramnios, and an empty fetal bladder. The neonatal course was complicated by oliguria, hyperkalemia, marked renal dysfunction, respiratory failure, joint contractures, and a large anterior fontanelle with widely separated sutures. Hypotension (mean arterial pressure<25 torr) on day 1 responded to volume expansion, dopamine, and hydrocortisone. Serum creatinine reached a maximum of 2.7 mg/dL on day 6 and decreased to 0.4 by day 56. No formal urinalysis was performed, but the urine was reported to be visually clear throughout the course. Although a renal ultrasound on day 2 was normal, a follow-up study at 7 months revealed bilateral generalized parenchymal echogenicity, consistent with medical renal disease. Since then, weight and length have been at the 5th percentile or less, with apparent renal tubular acidosis necessitating the addition of sodium citrate supplements. This case emphasizes the importance of maintaining a high index of suspicion for potential pregnancy when contemplating the use of a drug of this class, and considering serial testing for pregnancy when using such drugs, even in patients with a longstanding history of infertility.

  14. Life and death in the microcirculation: a role for angiotensin II

    NASA Technical Reports Server (NTRS)

    Greene, A. S.; Cowley, A. W. (Principal Investigator)

    1998-01-01

    OBJECTIVE: Angiotensin II (ANGII) plays a critical role in the maintenance of the microcirculation and in the anatomical loss of microvessels (rarefaction) that occurs in low renin forms of hypertension and in animals fed a high-salt diet. Elevations in sodium intake can trigger a series of hemodynamic and hormonal responses culminating in a substantial rarefaction of small arterioles and capillaries in both normal and reduced renal mass hypertensive rats. METHODS: Immunohistochemistry, Northern blot, and reverse transcription-polymerase chain reaction (RT-PCR) analysis of microdissected blood vessels were used to localize ANGII receptors in the microcirculation. Chronic infusion of ANGII and other physiologic and pharmacologic manipulations of the reninangiotensin system in rats was combined with morphologic and mathematical analysis of the network architecture. RESULTS: We have shown that rarefaction of the microcirculation can cause an increase in total peripheral resistance, reduced tissue perfusion, decreased oxygen delivery, and impaired organ function. Although the mechanisms by which this occurs are not well understood, a number of key observations point to a role for the renin-angiotensin system in this effect. First, ANGII infused systemically at subpressor levels, or locally into the skeletal muscle interstitium, can induce significant microvessel growth. Second, localization of ANGII receptor proteins by immunohistochemistry and Western blotting and RNA localization by RT-PCR confirm the presence of AT1 receptors, which are growth-stimulatory, and AT2 receptors, which are growth-inhibitory in the microcirculation. Third, maintenance of ANGII at normal levels during periods of hypertension or high-salt diet completely eliminates rarefaction. CONCLUSIONS: Taken together, these results support the hypothesis that ANGII acting through AT1- and AT2-receptor mechanisms modulate vessel density during high-salt diet and hypertension.

  15. Chymase-dependent production of angiotensin II: an old enzyme in old hearts.

    PubMed

    Froogh, Ghezal; Pinto, John T; Le, Yicong; Kandhi, Sharath; Aleligne, Yeabsra; Huang, An; Sun, Dong

    2017-02-01

    Age-dependent alteration of the renin-angiotensin system (RAS) and generation of angiotensin II (Ang II) are well documented. By contrast, RAS-independent generation of Ang II in aging and its responses to exercise have not been explored. To this end, we examined the effects of chymase, a secretory serine protease, on the angiotensin-converting enzyme (ACE)-independent conversion of Ang I to Ang II. We hypothesized that age-dependent alteration of cardiac Ang II formation is chymase dependent in nature and is prevented by exercise training. Experiments were conducted on hearts isolated from young (3 mo), aged sedentary (24 mo), and aged rats chronically exercised on a treadmill. In the presence of low Ang I levels and downregulation of ACE expression/activity, cardiac Ang II levels were significantly higher in aged than young rats, suggesting an ACE-independent response. Aged hearts also displayed significantly increased chymase expression and activity, as well as upregulation of tryptase, a biological marker of mast cells, confirming a mast cell-sourced increase in chymase. Coincidently, cardiac superoxide produced from NADPH oxidase (Nox) was significantly enhanced in aged rats and was normalized by exercise. Conversely, a significant reduction in cardiac expression of ACE2 followed by lower Ang 1-7 levels and downregulation of the Mas receptor (binding protein of Ang 1-7) in aged rats were completely reversed by exercise. In conclusion, local formation of Ang II is increased in aged hearts, and chymase is primarily responsible for this increase. Chronic exercise is able to normalize the age-dependent alterations via compromising chymase/Ang II/angiotensin type 1 receptor/Nox actions while promoting ACE2/Ang 1-7/MasR signaling.

  16. Angiotensin-(1-7) Decreases Cell Growth and Angiogenesis of Human Nasopharyngeal Carcinoma Xenografts.

    PubMed

    Pei, Nana; Wan, Renqiang; Chen, Xinglu; Li, Andrew; Zhang, Yanling; Li, Jinlong; Du, Hongyan; Chen, Baihong; Wei, Wenjin; Qi, Yanfei; Zhang, Yi; Katovich, Michael J; Sumners, Colin; Zheng, Haifa; Li, Hongwei

    2016-01-01

    Angiotensin-(1-7) [Ang-(1-7)] is an endogenous, heptapeptide hormone acting through the Mas receptor (MasR), with antiproliferative and antiangiogenic properties. Recent studies have shown that Ang-(1-7) has an antiproliferative action on lung adenocarcinoma cells and prostate cancer cells. In this study, we report that MasR levels were significantly upregulated in nasopharyngeal carcinoma (NPC) specimens and NPC cell lines. Viral vector-mediated expression of Ang-(1-7) dramatically suppressed NPC cell proliferation and migration in vitro. These effects were completely blocked by the specific Ang-(1-7) receptor antagonist A-779, suggesting that they are mediated by the Ang-(1-7) receptor Mas. In this study, Ang-(1-7) not only caused a significant reduction in the growth of human nasopharyngeal xenografts, but also markedly decreased vessel density, suggesting that the heptapeptide inhibits angiogenesis to reduce tumor size. Mechanistic investigations revealed that Ang-(1-7) inhibited the expression of the proangiogenic factors VEGF and PlGF. Taken together, the data suggest that upregulation of MasR could be used as a diagnostic marker of NPC and Ang-(1-7) may be a novel therapeutic agent for nasopharyngeal cancer therapy because it exerts significant antiangiogenic activity.

  17. Central angiotensin II stimulates cutaneous water intake behavior via an angiotensin II type-1 receptor pathway in the Japanese tree frog Hyla japonica.

    PubMed

    Maejima, Sho; Konno, Norifumi; Matsuda, Kouhei; Uchiyama, Minoru

    2010-08-01

    Angiotensin II (Ang II) stimulates oral water intake by causing thirst in all terrestrial vertebrates except anurans. Anuran amphibians do not drink orally but absorb water osmotically through ventral skin. In this study, we examined the role of Ang II on the regulation of water-absorption behavior in the Japanese tree frog (Hyla japonica). In fully hydrated frogs, intracerebroventricular (ICV) and intralymphatic sac (ILS) injection of Ang II significantly extended the residence time of water in a dose-dependent manner. Ang II-dependent water uptake was inhibited by ICV pretreatment with an angiotensin II type-1 (AT(1)) receptor antagonist but not a type-2 (AT(2)) receptor antagonist. These results suggest that Ang II stimulates water-absorption behavior in the tree frog via an AT(1)-like but not AT(2)-like receptor. We then cloned and characterized cDNA of the tree frog AT(1) receptor from the brain. The tree frog AT(1) receptor cDNA encodes a 361 amino acid residue protein, which is 87% identical to the toad (Bufo marinus) AT(1) receptor and exhibits the functional characteristics of an Ang II receptor. AT(1) receptor mRNAs were found to be present in a number of tissues including brain (especially in the diencephalon), lung, large intestine, kidney and ventral pelvic skin. When tree frogs were exposed to dehydrating conditions, AT(1) receptor mRNA significantly increased in the diencephalon and the rhombencephalon. These data suggest that central Ang II may control water intake behavior via an AT(1) receptor on the diencephalon and rhombencephalon in anuran amphibians and may have implications for water consumption in vertebrates.

  18. Angiotensin II impairs endothelial progenitor cell number and function in vitro and in vivo: implications for vascular regeneration.

    PubMed

    Endtmann, Cathleen; Ebrahimian, Talin; Czech, Thomas; Arfa, Omar; Laufs, Ulrich; Fritz, Mathias; Wassmann, Kerstin; Werner, Nikos; Petoumenos, Vasileios; Nickenig, Georg; Wassmann, Sven

    2011-09-01

    Endothelial progenitor cells (EPCs) contribute to endothelial regeneration. Angiotensin II (Ang II) through Ang II type 1 receptor (AT(1)-R) activation plays an important role in vascular damage. The effect of Ang II on EPCs and the involved molecular mechanisms are incompletely understood. Stimulation with Ang II decreased the number of cultured human early outgrowth EPCs, which express both AT(1)-R and Ang II type 2 receptor, mediated through AT(1)-R activation and induction of oxidative stress. Ang II redox-dependently induced EPC apoptosis through increased apoptosis signal-regulating kinase 1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase phosphorylation; decreased Bcl-2 and increased Bax expression; and activation of caspase 3 but had no effect on the low cell proliferation. In addition, Ang II impaired colony-forming and migratory capacities of early outgrowth EPCs. Ang II infusion diminished numbers and functional capacities of EPCs in wild-type (WT) but not AT(1)a-R knockout mice (AT(1)a(-/-)). Reendothelialization after focal carotid endothelial injury was decreased during Ang II infusion. Salvage of reendothelialization by intravenous application of spleen-derived progenitor cells into Ang II-treated WT mice was pronounced with AT(1)a(-/-) cells compared with WT cells, and transfusion of Ang II-pretreated WT cells into WT mice without Ang II infusion was associated with less reendothelialization. Transplantation of AT(1)a(-/-) bone marrow reduced atherosclerosis development in cholesterol-fed apolipoprotein E-deficient mice compared with transplantation of apolipoprotein E-deficient or WT bone marrow. Randomized treatment of patients with stable coronary artery disease with the AT(1)-R blocker telmisartan significantly increased the number of circulating CD34/KDR-positive EPCs. Ang II through AT(1)-R activation, oxidative stress, and redox-sensitive apoptosis signal-regulating kinase 1-dependent proapoptotic pathways impairs EPCs in

  19. Angiotensin II activates the proinflammatory transcription factor nuclear factor-kappaB in human monocytes.

    PubMed

    Kranzhöfer, R; Browatzki, M; Schmidt, J; Kübler, W

    1999-04-21

    The renin-angiotensin system may contribute to the pathogenesis of atherosclerosis. A common feature of all stages of atherosclerosis is inflammation of the vessel wall. The transcription factor nuclear factor-kappaB (NF-kappaB) participates in most signaling pathways involved in inflammation. This study therefore examined the effect of angiotensin (ANG) II on NF-kappaB activation in monocytic cells, a major cellular component of human atheroma, by electrophoretic mobility shift assay. ANG II, like TNFalpha, caused rapid activation of NF-kappaB in human mononuclear cells isolated from peripheral blood by Ficoll density gradient. This ANG II effect was blocked by the angiotensin AT1 receptor antagonist losartan. Specificity of ANG II-induced NF-kappaB activation was ascertained by supershift and competition experiments. Moreover, ANG II stimulated NF-kappaB activation in human monocytes, but not in lymphocytes from the same preparation. Together, the data demonstrate the ability of the vasoactive peptide ANG II to activate inflammatory pathways in human monocytes.

  20. A Fluorometric Method of Measuring Carboxypeptidase Activities for Angiotensin II and Apelin-13

    PubMed Central

    Liu, Pan; Wysocki, Jan; Serfozo, Peter; Ye, Minghao; Souma, Tomokazu; Batlle, Daniel; Jin, Jing

    2017-01-01

    Degradation of the biologically potent octapeptide angiotensin Ang II-(1-8) is mediated by the activities of several peptidases. The conversion of Ang II to the septapeptide Ang-(1-7) is of particular interest as the latter also confers organ protection. The conversion is catalyzed by angiotensin-converting enzyme 2 and other enzymes that selectively cleave the peptide bond between the proline and the phenylalanine at the carboxyl terminus of Ang II. The contribution of various enzyme activities that collectively lead to the formation of Ang-(1-7) from Ang II, in both normal conditions and in disease states, remains only partially understood. This is largely due to the lack of a reliable and sensitive method to detect these converting activities in complex samples, such as blood and tissues. Here, we report a fluorometric method to measure carboxypeptidase activities that cleave the proline-phenylalanine dipeptide bond in Ang II. This method is also suitable for measuring the conversion of apelin-13. The assay detects the release of phenylalanine amino acid in a reaction with the yeast enzyme of phenylalanine ammonia lyase (PAL). When used in cell and mouse organs, the assay can robustly measure endogenous Ang II and apelin-13-converting activities involved in the renin-angiotensin and the apelinergic systems, respectively. PMID:28378780

  1. Preparation and one-step purification of mono-125I-angiotensin II for radioligand binding assays

    SciTech Connect

    Speth, R.C.; Husain, A.

    1984-04-01

    A one-step purification of mono-/sup 125/I-angiotensin II prepared by the chloramine T procedure is described. The purification is effected on a cellulose cation exchange column with isocratic elution by 50 mM sodium acetate, pH 5.0. The purity of the mono-/sup 125/I-angiotensin II was determined by thin layer chromatography, high pressure liquid chromatography, enzymatic digestion, radioreceptor assay, and radioimmunoassay. Preparation and purification of mono-/sup 125/I-angiotensin II by this procedure offers significant advantages over existing methods for its preparation in terms of purity, simplicity, efficiency, and cost.

  2. Angiopoietin-2 attenuates angiotensin II-induced aortic aneurysm and atherosclerosis in apolipoprotein E-deficient mice

    PubMed Central

    Yu, Hongyou; Moran, Corey S.; Trollope, Alexandra F.; Woodward, Lynn; Kinobe, Robert; Rush, Catherine M.; Golledge, Jonathan

    2016-01-01

    Angiogenesis and inflammation are implicated in aortic aneurysm and atherosclerosis and regulated by angiopoietin-2 (Angpt2). The effect of Angpt2 administration on experimental aortic aneurysm and atherosclerosis was examined. Six-month-old male apolipoprotein E deficient (ApoE−/−) mice were infused with angiotensin II (AngII) and administered subcutaneous human Fc-protein (control) or recombinant Angpt2 (rAngpt2) over 14 days. Administration of rAngpt2 significantly inhibited AngII-induced aortic dilatation and rupture of the suprarenal aorta (SRA), and development of atherosclerosis within the aortic arch. These effects were blood pressure and plasma lipoprotein independent and associated with Tie2 activation and down-regulation of monocyte chemotactic protein-1 (MCP-1) within the SRA. Plasma concentrations of MCP-1 and interleukin-6 were significantly lower in mice receiving rAngpt2. Immunostaining for the monocyte/macrophage marker MOMA-2 and the angiogenesis marker CD31 within the SRA were less in mice receiving rAngpt2 than controls. The percentage of inflammatory (Ly6Chi) monocytes within the bone marrow was increased while that in peripheral blood was decreased by rAngpt2 administration. In conclusion, administration of rAngpt2 attenuated angiotensin II-induced aortic aneurysm and atherosclerosis in ApoE−/− mice associated with reduced aortic inflammation and angiogenesis. Up-regulation of Angpt2 may have potential therapeutic value in patients with aortic aneurysm and atherosclerosis. PMID:27767064

  3. Enhancement of Adipocyte Browning by Angiotensin II Type 1 Receptor Blockade

    PubMed Central

    Tsukuda, Kana; Mogi, Masaki; Iwanami, Jun; Kanno, Harumi; Nakaoka, Hirotomo; Wang, Xiao-Li; Bai, Hui-Yu; Shan, Bao-Shuai; Kukida, Masayoshi; Higaki, Akinori; Yamauchi, Toshifumi; Min, Li-Juan; Horiuchi, Masatsugu

    2016-01-01

    Browning of white adipose tissue (WAT) has been highlighted as a new possible therapeutic target for obesity, diabetes and lipid metabolic disorders, because WAT browning could increase energy expenditure and reduce adiposity. The new clusters of adipocytes that emerge with WAT browning have been named ‘beige’ or ‘brite’ adipocytes. Recent reports have indicated that the renin-angiotensin system (RAS) plays a role in various aspects of adipose tissue physiology and dysfunction. The biological effects of angiotensin II, a major component of RAS, are mediated by two receptor subtypes, angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R). However, the functional roles of angiotensin II receptor subtypes in WAT browning have not been defined. Therefore, we examined whether deletion of angiotensin II receptor subtypes (AT1aR and AT2R) may affect white-to-beige fat conversion in vivo. AT1a receptor knockout (AT1aKO) mice exhibited increased appearance of multilocular lipid droplets and upregulation of thermogenic gene expression in inguinal white adipose tissue (iWAT) compared to wild-type (WT) mice. AT2 receptor-deleted mice did not show miniaturization of lipid droplets or alteration of thermogenic gene expression levels in iWAT. An in vitro experiment using adipose tissue-derived stem cells showed that deletion of the AT1a receptor resulted in suppression of adipocyte differentiation, with reduction in expression of thermogenic genes. These results indicate that deletion of the AT1a receptor might have some effects on the process of browning of WAT and that blockade of the AT1 receptor could be a therapeutic target for the treatment of metabolic disorders. PMID:27992452

  4. Tumor necrosis factor-α produced in the kidney contributes to angiotensin II-dependent hypertension.

    PubMed

    Zhang, Jiandong; Patel, Mehul B; Griffiths, Robert; Mao, Alice; Song, Young-soo; Karlovich, Norah S; Sparks, Matthew A; Jin, Huixia; Wu, Min; Lin, Eugene E; Crowley, Steven D

    2014-12-01

    Immune system activation contributes to the pathogenesis of hypertension and the resulting progression of chronic kidney disease. In this regard, we recently identified a role for proinflammatory Th1 T-lymphocyte responses in hypertensive kidney injury. Because Th1 cells generate interferon-γ and tumor necrosis factor-α (TNF-α), we hypothesized that interferon-γ and TNF-α propagate renal damage during hypertension induced by activation of the renin-angiotensin system. Therefore, after confirming that mice genetically deficient of Th1 immunity were protected from kidney glomerular injury despite a preserved hypertensive response, we subjected mice lacking interferon-γ or TNF-α to our model of hypertensive chronic kidney disease. Interferon deficiency had no impact on blood pressure elevation or urinary albumin excretion during chronic angiotensin II infusion. By contrast, TNF-deficient (knockout) mice had blunted hypertensive responses and reduced end-organ damage in our model. As angiotensin II-infused TNF knockout mice had exaggerated endothelial nitric oxide synthase expression in the kidney and enhanced nitric oxide bioavailability, we examined the actions of TNF-α generated from renal parenchymal cells in hypertension by transplanting wild-type or TNF knockout kidneys into wild-type recipients before the induction of hypertension. Transplant recipients lacking TNF solely in the kidney had blunted hypertensive responses to angiotensin II and augmented renal endothelial nitric oxide synthase expression, confirming a role for kidney-derived TNF-α to promote angiotensin II-induced blood pressure elevation by limiting renal nitric oxide generation.

  5. A low salt diet and circadian dysfunction synergize to induce angiotensin II-dependent hypertension in mice

    PubMed Central

    Pati, Paramita; Fulton, David J.R.; Bagi, Zsolt; Chen, Feng; Wang, Yusi; Kitchens, Julia; Cassis, Lisa A.; Stepp, David W.; Rudic, R. Daniel

    2015-01-01

    Blood pressure exhibits a robust circadian rhythm in health. In hypertension, sleep apnea, and even shift work, this balanced rhythm is perturbed via elevations in nighttime blood pressure, inflicting silent damage to the vasculature and body organs. Herein, we examined the influence of circadian dysfunction during experimental hypertension in mice. Using radiotelemetry to measure ambulatory blood pressure and activity, the effects of angiotensin II administration were studied in wild-type (WT) and Period isoform knockout mice (Per2-KO, Per2,3-KO and Per1,2,3-KO/PerTKO mice). On a normal diet, administration of Ang II caused caused non-dipping blood pressure and exacerbated vascular hypertrophy in the Period isoform knockout mice. To study the endogenous effects of Ang II stimulation, we then administered a low salt diet to the mice, which does stimulate endogenous Ang II in addition to lowering blood pressure. A low salt diet decreased blood pressure in WT mice. In contrast, Period isoform knockout mice lost their circadian rhythm in blood pressure on a low salt diet, due to an increase in resting blood pressure, which was restorable to rhythmicity by the angiotensin receptor blocker losartan. Chronic low salt caused vascular hypertrophy in Period isoform knockout mice which also exhibited increased renin levels and altered AT1 receptor expression. These data suggest that circadian clock genes may act to inhibit or control renin/angiotensin signaling. Moreover, circadian disorders such as sleep apnea and shift work may alter the homeostatic responses to sodium restriction to potentially influence nocturnal hypertension. PMID:26781276

  6. Molecular basis and functional significance of Angiotensin II-induced increase in Discoidin Domain Receptor 2 gene expression in cardiac fibroblasts.

    PubMed

    George, Mereena; Vijayakumar, Anupama; Dhanesh, Sivadasan Bindu; James, Jackson; Shivakumar, K

    2016-01-01

    Delineation of mechanisms underlying the regulation of fibrosis-related genes in the heart is an important clinical goal as cardiac fibrosis is a major cause of myocardial dysfunction. This study probed the regulation of Discoidin Domain Receptor 2 (DDR2) gene expression and the regulatory links between Angiotensin II, DDR2 and collagen in Angiotensin II-stimulated cardiac fibroblasts. Real-time PCR and western blot analyses showed that Angiotensin II enhances DDR2 mRNA and protein expression in rat cardiac fibroblasts via NADPH oxidase-dependent reactive oxygen species induction. NF-κB activation, demonstrated by gel shift assay, abolition of DDR2 expression upon NF-κB inhibition, and luciferase and chromatin immunoprecipitation assays confirmed transcriptional control of DDR2 by NF-κB in Angiotensin II-treated cells. Inhibitors of Phospholipase C and Protein kinase C prevented Angiotensin II-dependent p38 MAPK phosphorylation that in turn blocked NF-κB activation. Angiotensin II also enhanced collagen gene expression. Importantly, the stimulatory effects of Angiotensin II on DDR2 and collagen were inter-dependent as siRNA-mediated silencing of one abolished the other. Angiotensin II promoted ERK1/2 phosphorylation whose inhibition attenuated Angiotensin II-stimulation of collagen but not DDR2. Furthermore, DDR2 knockdown prevented Angiotensin II-induced ERK1/2 phosphorylation, indicating that DDR2-dependent ERK1/2 activation enhances collagen expression in cells exposed to Angiotensin II. DDR2 knockdown was also associated with compromised wound healing response to Angiotensin II. To conclude, Angiotensin II promotes NF-κB activation that up-regulates DDR2 transcription. A reciprocal regulatory relationship between DDR2 and collagen, involving cross-talk between the GPCR and RTK pathways, is central to Angiotensin II-induced increase in collagen expression in cardiac fibroblasts.

  7. Gamma Delta T Cells Mediate Angiotensin II-Induced Hypertension and Vascular Injury.

    PubMed

    Caillon, Antoine; Mian, Muhammad Oneeb Rehman; Fraulob-Aquino, Julio C; Huo, Ku-Geng; Barhoumi, Tlili; Ouerd, Sofiane; Sinnaeve, Peter R; Paradis, Pierre; Schiffrin, Ernesto L

    2017-03-22

    Background -Innate antigen-presenting cells and adaptive immune T cells have been implicated in the development of hypertension. However, the T-lymphocyte subsets involved in the pathophysiology of hypertension remain unclear. A small subset of "innate-like" T cells expressing the γδ T cell receptor (TCR) rather than the αβ TCR could play a role in the initiation of the immune response in hypertension. We aimed to determine whether angiotensin (Ang) II caused kinetic changes in γδ T cells, whether deficiency in γδ T cells blunted Ang II-induced hypertension, vascular injury and T-cell activation, and whether γδ T cells are associated with human hypertension. Methods -Male C57BL/6 wild-type (WT) and Tcrδ(-/-) mice, which are devoid of γδ T cells, or WT mice injected IP with control isotype IgG or γδ T cell-depleting antibodies, were infused or not with Ang II for 3, 7 or 14 days. T cell profiling was determined by flow cytometry, systolic blood pressure (SBP) by telemetry and mesentery artery endothelial function by pressurized myography. TCR γ constant region gene expression levels and clinical data of a whole blood gene expression microarray study including normotensive and hypertensive subjects were used to demonstrate an association between γδ T cells and SBP. Results -Seven- and 14-day Ang II infusion increased γδ T cell numbers and activation in the spleen of WT mice (P<0.05). Fourteen days of Ang II infusion increased SBP (P<0.01) and decreased mesenteric artery endothelial function (P<0.01) in WT mice, both of which were abrogated in Tcrδ(-/-) mice (P<0.01). Anti-TCR γδ antibody-induced γδ T cell depletion blunted Ang II-induced SBP rise and endothelial dysfunction (P<0.05), compared to isotype antibody-treated Ang II-infused mice. Ang II-induced T cell activation in the spleen and perivascular adipose tissue was blunted in Tcrδ(-/-) mice (P<0.01). In humans, the association between SBP and γδ T cells was demonstrated by a

  8. Long-Term Reduction of High Blood Pressure by Angiotensin II DNA Vaccine in Spontaneously Hypertensive Rats.

    PubMed

    Koriyama, Hiroshi; Nakagami, Hironori; Nakagami, Futoshi; Osako, Mariana Kiomy; Kyutoku, Mariko; Shimamura, Munehisa; Kurinami, Hitomi; Katsuya, Tomohiro; Rakugi, Hiromi; Morishita, Ryuichi

    2015-07-01

    Recent research on vaccination has extended its scope from infectious diseases to chronic diseases, including Alzheimer disease, dyslipidemia, and hypertension. The aim of this study was to design DNA vaccines for high blood pressure and eventually develop human vaccine therapy to treat hypertension. Plasmid vector encoding hepatitis B core-angiotensin II (Ang II) fusion protein was injected into spontaneously hypertensive rats using needleless injection system. Anti-Ang II antibody was successfully produced in hepatitis B core-Ang II group, and antibody response against Ang II was sustained for at least 6 months. Systolic blood pressure was consistently lower in hepatitis B core-Ang II group after immunization, whereas blood pressure reduction was continued for at least 6 months. Perivascular fibrosis in heart tissue was also significantly decreased in hepatitis B core-Ang II group. Survival rate was significantly improved in hepatitis B core-Ang II group. This study demonstrated that Ang II DNA vaccine to spontaneously hypertensive rats significantly lowered high blood pressure for at least 6 months. In addition, Ang II DNA vaccines induced an adequate humoral immune response while avoiding the activation of self-reactive T cells, assessed by ELISPOT assay. Future development of DNA vaccine to treat hypertension may provide a new therapeutic option to treat hypertension.

  9. Simultaneous determination of hydrochlorothiazide and several angiotensin-II-receptor antagonists by capillary electrophoresis.

    PubMed

    Hillaert, S; Van den Bossche, W

    2003-02-26

    We have investigated the capability of the capillary zone electrophoretic (CZE) and micellar electrokinetic capillary chromatographic (MEKC) methods to simultaneously separate hydrochlorothiazide and six angiotensin-II-receptor antagonists (ARA-IIs): candesartan, eprosartan mesylate, irbesartan, losartan potassium, telmisartan, and valsartan. The CZE and MEKC methods are suitable for the qualitative and quantitative determination of combined HCT/ARA-IIs in pharmaceutical formulations. Depending on the ARA-II, at least one of the two methods can be used for each combination. The two methods have been validated in terms of their linearity of response, reproducibility, and accuracy.

  10. [Ca{sup 2+}]{sub i} and PKC-{alpha} are involved in the inhibitory effects of Ib, a novel nonpeptide AngiotensinII subtype AT{sub 1} receptor antagonist, on AngiotensinII-induced vascular contraction in vitro

    SciTech Connect

    Wang Yu; Wang Wei; Wang Qiujuan Wu Jinhui; Xu Jinyi; Wu Xiaoming

    2007-12-07

    The vasoactive peptide AngiotensinII (AngII) is an important factor in the cardiovascular system, exerting most of its effects through AngII receptor type 1 (AT{sub 1}). Ib, a new nonpeptide AT{sub 1} receptor antagonist, has been observed to play a positive role in the treatment of hypertension in preclinical tests. In this study, the inhibitory effects of Ib on AngII-induced vascular contraction in vitro were investigated, and its molecular mechanisms were further explored. In endothelium-denuded aortic rings from rabbits, Ib produced a rightward shift in the concentration-response curve for AngII with a decrease in the maximal contractile response and the pD{sub 2}{sup '} was 7.29. In vascular smooth muscle cells (VSMCs), the specific binding of [{sup 125}I]AngII to AT{sub 1} receptors was inhibited by Ib in a concentration-dependent manner with IC{sub 50} value of 0.96 nM. Ib could inhibit both AngII-induced Ca{sup 2+} mobilization from internal stores and Ca{sup 2+} influx. Moreover, the translocation of PKC-{alpha} stimulated by AngII was inhibited by Ib. Thus, the inhibitory effects of Ib might be related with the depression on AngII-induced increase in [Ca{sup 2+}]{sub i} and translocation of PKC-{alpha} through blocking AT{sub 1} receptors.

  11. Central actions of angiotensin II on spontaneous baroreflex sensitivity in the trout Onc orhynchus mykiss.

    PubMed

    Lancien, Frédéric; Le Mével, Jean-Claude

    2007-02-01

    The goal of the present study was to investigate the central action of native angiotensin II (ANG II) on the spontaneous baroreflex sensitivity (BRS) in unanesthetized trout. The animals were equipped with two subcutaneous electrocardiographic (ECG) electrodes, a dorsal aorta catheter and an intracerebroventricular (ICV) cannula which was inserted within the third ventricle of the brain. The ECG and the systolic blood pressure (SBP) signals were recorded during a pre-injection period of 5 min and during five post-injection periods of 5 min. All injections were made at the fifth minute of the test. The time-series were processed with a sequence technique in order to detect the sequences of three or more consecutive increases in the SBP pulse, or three or more decreases in the SBP pulse correlated respectively with one delay beat increase of the RR interval of the ECG signal or shortening of this interval. The slope of the average regression line between the SBP and the RR intervals for each type of sequence was taken as a measure of the spontaneous BRS. Compared with pre-injection values, the ICV injection of vehicle (0.5 microl) had no effect on heart rate (HR), SBP, the total number of positive or negative sequences or on the spontaneous BRS during the post-injection periods. By contrast, ANG II at doses of 5 and 50 pmol increased HR but only 50 pmol ANG II elevated SBP. For all doses, ANG II depressed the spontaneous BRS, but the peptide had no effect upon the number of each baroreflex sequences. Intra-arterial injections of atropine dramatically reduced the number of positive and negative baroreflex sequences and decreased the sensitivity of the few remaining sequences, suggesting that the autonomic control of the cardiac BRS was solely due to vagal parasympathetic control. In atropinized trout the ICV injection of 5 pmol ANG II had no effect upon HR, SBP and the baroreflex parameters. This study determines for the first time the spontaneous BRS in a non

  12. The renal and vascular effects of central angiotensin II and atrial natriuretic factor in the anaesthetized rat.

    PubMed Central

    Al-Barazanji, K A; Balment, R J

    1990-01-01

    1. The interaction between atrial natriuretic factor (ANF) and angiotensin II (Ang II) within the brain to influence renal function and blood pressure was studied in Inactin-anaesthetized male Sprague-Dawley rats. 2. Central infusion of ANF produced a diuresis which was associated with a significant decrease in plasma arginine vasopressin (AVP) level. There was no change in sodium excretion rate over the 80 min of intracerebroventricular ANF infusion and ANF produced no detectable change in mean arterial blood pressure. 3. Central Ang II administration produced a significant decrease in urine flow, which was associated with elevated plasma AVP, an increase in sodium excretion and a rise in mean arterial blood pressure. 4. Combined ANF and Ang II infusion produced an antidiuresis, which was associated with increased plasma AVP concentration. Both the natriuretic and vasopressor actions of central Ang II were abolished when ANF was co-administered. 5. It is concluded that ANF and Ang II interact centrally; ANF antagonizes the pressor and natriuretic effects but not the antidiuretic effects of central Ang II. These data suggest the possibility of distinct and separate sites within the brain through which Ang II influences vasopressin release and renal sodium handling and elevates blood pressure. PMID:2143782

  13. Potential effect of angiotensin II receptor blockade in adipose tissue and bone.

    PubMed

    Nakagami, Hironori; Osako, Mariana Kiomy; Morishita, Ryuichi

    2013-01-01

    Recent evidence demonstrated that dysregulation of adipocytokine functions seen in abdominal obesity may be involved in the pathogenesis of the metabolic syndrome. Angiotensinogen, the precursor of angiotensin (Ang) II, is produced primarily in the liver, and also in adipose tissue, where it is up-regulated during the development of obesity and involved in blood pressure regulation and adipose tissue growth. Blockade of renin-angiotensin system (RAS) attenuates weight gain and adiposity by enhanced energy expenditure, and the favorable metabolic effects of telmisartan have been related to its Ang II receptor blockade and action as a partial agonist of peroxisome proliferators activated receptor (PPAR)-γ. PPARγ plays an important role in regulating carbohydrate and lipid metabolism, and ligands for PPARγ can improve insulin sensitivity and reduce triglyceride levels. Similarly, bone metabolism is closely regulated by hormones and cytokines, which have effects on both bone resorption and deposition. It is known that the receptors of Ang II are expressed in culture osteoclasts and osteoblasts, and Ang II is postulated to be able to act upon the cells involved in bone metabolism. In in vitro system, Ang II induced the differentiation and activation of osteoclasts responsible for bone resorption. Importantly, it was demonstrated by the sub-analysis of a recent clinical study that the fracture risk was significantly reduced by the usage of angiotensin-converting enzyme inhibitors. To treat the subgroups of hypertensive patients with osteoporosis RAS can be considered a novel target.

  14. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system.

    PubMed

    Mehta, Puja K; Griendling, Kathy K

    2007-01-01

    The renin-angiotensin system is a central component of the physiological and pathological responses of cardiovascular system. Its primary effector hormone, angiotensin II (ANG II), not only mediates immediate physiological effects of vasoconstriction and blood pressure regulation, but is also implicated in inflammation, endothelial dysfunction, atherosclerosis, hypertension, and congestive heart failure. The myriad effects of ANG II depend on time (acute vs. chronic) and on the cells/tissues upon which it acts. In addition to inducing G protein- and non-G protein-related signaling pathways, ANG II, via AT(1) receptors, carries out its functions via MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases [PDGF, EGFR, insulin receptor], and nonreceptor tyrosine kinases [Src, JAK/STAT, focal adhesion kinase (FAK)]. AT(1)R-mediated NAD(P)H oxidase activation leads to generation of reactive oxygen species, widely implicated in vascular inflammation and fibrosis. ANG II also promotes the association of scaffolding proteins, such as paxillin, talin, and p130Cas, leading to focal adhesion and extracellular matrix formation. These signaling cascades lead to contraction, smooth muscle cell growth, hypertrophy, and cell migration, events that contribute to normal vascular function, and to disease progression. This review focuses on the structure and function of AT(1) receptors and the major signaling mechanisms by which angiotensin influences cardiovascular physiology and pathology.

  15. Angiotensin II up-regulates CX3CR1 expression in THP-1 monocytes: impact on vascular inflammation and atherogenesis.

    PubMed

    Apostolakis, Stavros; Vlata, Zacharenia; Vogiatzi, Konstantina; Krambovitis, Elias; Spandidos, Demetrios A

    2010-05-01

    The potential regulatory effect of angiotensins on circulating mononuclear cell activation and migration has not yet been thoroughly evaluated. Using flow cytometry we assessed the possible effect of angiotensin I and II on the expression of CX3CR1 and a single representative of each major chemokine family (CCR5 and CXCR4) in THP-1 monocytes, Jurcat T lymphocytes and primary monocytes-isolated from healthy donors. Fluorescence intensity and the rate of chemokine-positive cells was measured in naïve cells and cells treated with angiotensin I and II. Neither angiotensin I nor angiotensin II exhibited any effect on fluorescence intensity and the rate of CX3CR1-, CCR5- and CXCR4-positive cells in primary peripheral blood mononuclear cells and Jurkat T cells. However, angiotensin II significantly increased the rate of CX3CR1-positive THP-1 cells. This effect was not attenuated by the pre-incubation of THP-1 cells with the AT-1 receptor blocker losartan, suggesting that this was not an AT-1-mediated effect. Angiotensin I and II had no effect on fluorescence intensity and the rate of CCR5- and CXCR4-positive THP-1 cells. In conclusion, angiotensin II increases the rate of CX3CR1-positive THP-1 cells. By extrapolating this in vitro observation to disease mechanisms, we speculate that angiotensin II induces up-regulation of CX3CR1 and promotes firm adhesion of circulation CX3CR1-positive monocytes on CX3CL1 expressing endothelial cells inducing vascular inflammation and atherogenesis.

  16. Hypoxia-induced angiotensin II by the lactate-chymase-dependent mechanism mediates radioresistance of hypoxic tumor cells

    PubMed Central

    Xie, Guozhu; Liu, Ying; Yao, Qiwei; Zheng, Rong; Zhang, Lanfang; Lin, Jie; Guo, Zhaoze; Du, Shasha; Ren, Chen; Yuan, Quan; Yuan, Yawei

    2017-01-01

    The renin-angiotensin system (RAS) is a principal determinant of arterial blood pressure and fluid and electrolyte balance. RAS component dysregulation was recently found in some malignancies and correlated with poor patient outcomes. However, the exact mechanism of local RAS activation in tumors is still unclear. Here, we find that the local angiotensin II predominantly exists in the hypoxic regions of tumor formed by nasopharyngeal carcinoma CNE2 cells and breast cancer MDA-MB-231 cells, where these tumor cells autocrinely produce angiotensin II by a chymase-dependent rather than an angiotensin converting enzyme-dependent mechanism. We further demonstrate in nasopharyngeal carcinoma CNE2 and 5–8F cells that this chymase-dependent effect is mediated by increased levels of lactate, a by-product of glycolytic metabolism. Finally, we show that the enhanced angiotensin II plays an important role in the intracellular accumulation of HIF-1α of hypoxic nasopharyngeal carcinoma cells and mediates the radiation-resistant phenotype of these nasopharyngeal carcinoma cells. Thus, our findings reveal the critical role of hypoxia in producing local angiotensin II by a lactate-chymase-dependent mechanism and highlight the importance of local angiotensin II in regulating radioresistance of hypoxic tumor cells. PMID:28205588

  17. Valsartan Attenuates Atherosclerosis via Upregulating the Th2 Immune Response in Prolonged Angiotensin II-Treated ApoE(-/-) Mice.

    PubMed

    Meng, Kai; Zeng, Qiutang; Lu, Qinghua; Lin, Yingzhong; Wu, Bangwei; Yu, Kunwu; Dong, Zhaoqiang; Zhang, Jianwei; Chai, Meng; Liu, Yuyang; Ji, Qingwei; Zhou, Yujie

    2015-02-09

    Valsartan has a protective effect against hypertension and atherosclerosis in humans and experimental animal models. This study aimed to determine the effect of prolonged treatment with angiotensin II (Ang II) on atherosclerosis and the effect of valsartan on the activity of CD4(+) T lymphocyte subsets. The results showed that prolonged treatment (8 wks) with exogenous Ang II resulted in an increased atherosclerotic plaque size and a switch of stable-to-unstable plaque via modulating on CD4(+) T lymphocyte activity, including an increase in the T helper cell type 1 (Th1) and Th17 cells and a decrease in Th2 and regulatory T (Treg) cells. In contrast, valsartan treatment efficiently reversed the imbalance in CD4(+) T lymphocyte activity, ameliorated atherosclerosis and elicited a stable plaque phenotype in addition to controlling blood pressure. In addition, treatment with anti-interleukin (IL)-5 monoclonal antibodies weakened the antiatherosclerotic effects of valsartan without affecting blood pressure.

  18. Local generation of angiotensin II as a mechanism of regulation of peripheral vascular tone in the rat.

    PubMed Central

    Oliver, J A; Sciacca, R R

    1984-01-01

    Renin is present in vascular smooth muscle cells and has been shown to coexist with angiotensins I (AI) and II (AII) in many cell types. Accordingly, we postulated that the renin-angiotensin system controls vascular tone, not by the action of circulating renal renin but rather, by the local generation of angiotensin by vascular renin. Isolated rat hindquarters were perfused in vitro with Krebs-Henseleit buffer containing 7% albumin, and flow-adjusted to obtain a perfusion pressure of approximately 90 mmHg. Infusion of 4.8 nmol X min-1 for 5 min of AII or AI markedly increased perfusion pressure. An identical dose of the synthetic tetradecaptide of renin substrate (TDCP-RS) increased pressure similarly to AI. The pressure increase evoked by TDCP-RS was markedly decreased by captopril and by two different peptides that inhibit renin. Renin activity in the perfusate, incubated with semipurified rat renin substrate, was 21 +/- 3 pg AI X ml-1 X h-1 (mean +/- SEM) at 15 min of perfusion and 47 +/- 4 pg AI X ml-1 X h-1 at 45 min (n = 9; P less than 0.01). When TDCP-RS was infused at 4.8 nmol X min-1 for 5 min in the presence of captopril, AI in the perfusate increased linearly at a rate of 16.5 pmol X min-1 for 10 min (n = 5). The results indicate that TDCP-RS constricted the vasculature by its conversion to AII and suggest that AII was generated from a two-step hydrolysis of TDCP-RS by renin and converting enzyme. The data thus suggest that the renin-angiotensin system controls vascular tone by the local generation of AII by renin and converting enzyme in the vasculature. PMID:6384268

  19. Angiotensin II type 1 (AT1) receptor-mediated accumulation of angiotensin II in tissues and its intracellular half-life in vivo.

    PubMed

    van Kats, J P; de Lannoy, L M; Jan Danser, A H; van Meegen, J R; Verdouw, P D; Schalekamp, M A

    1997-07-01

    Angiotensin II (Ang II) is internalized by various cell types via receptor-mediated endocytosis. Little is known about the kinetics of this process in the whole animal and about the half-life of intact Ang II after its internalization. We measured the levels of 125I-Ang II and 125I-Ang I that were reached in various tissues and blood plasma during infusions of these peptides into the left cardiac ventricle of pigs. Steady-state concentrations of 125I-Ang II in skeletal muscle, heart, kidney, and adrenal were 8% to 41%, 64% to 150%, 340% to 550%, and 680% to 2100%, respectively, of the 125I-Ang II concentration in arterial blood plasma (ranges of six experiments). The tissue concentrations of 125I-Ang I were less than 5% of the arterial plasma concentrations. 125I-Ang II accumulation seen in heart, kidney, and adrenal was almost completely blocked by a specific Ang II type 1 (AT1) receptor antagonist. Steady-state concentrations of 125I-Ang II were reached within 30 to 60 minutes in the tissues and within 5 minutes in blood plasma. The in vivo half-life of intact 125I-Ang II in heart, kidney, and adrenal was approximately 15 minutes, compared with 0.5 minute in the circulation. Thus, Ang II, but not Ang I, from the circulation is accumulated by some tissues, and this is mediated by AT1 receptors. The time course of this process and the long half-life of the accumulated Ang II support the contention that this Ang II has been internalized after its binding to the AT1 receptor, so that it is protected from rapid degradation by endothelial peptidases. The results of this study are in agreement with growing evidence of an important physiological role for internalized Ang II.

  20. Prolonged Subcutaneous Administration of Oxytocin Accelerates Angiotensin II-Induced Hypertension and Renal Damage in Male Rats.

    PubMed

    Phie, James; Haleagrahara, Nagaraja; Newton, Patricia; Constantinoiu, Constantin; Sarnyai, Zoltan; Chilton, Lisa; Kinobe, Robert

    2015-01-01

    Oxytocin and its receptor are synthesised in the heart and blood vessels but effects of chronic activation of this peripheral oxytocinergic system on cardiovascular function are not known. In acute studies, systemic administration of low dose oxytocin exerted a protective, preconditioning effect in experimental models of myocardial ischemia and infarction. In this study, we investigated the effects of chronic administration of low dose oxytocin following angiotensin II-induced hypertension, cardiac hypertrophy and renal damage. Angiotensin II (40 μg/Kg/h) only, oxytocin only (20 or 100 ng/Kg/h), or angiotensin II combined with oxytocin (20 or 100 ng/Kg/h) were infused subcutaneously in adult male Sprague-Dawley rats for 28 days. At day 7, oxytocin or angiotensin-II only did not change hemodynamic parameters, but animals that received a combination of oxytocin and angiotensin-II had significantly elevated systolic, diastolic and mean arterial pressure compared to controls (P < 0.01). Hemodynamic changes were accompanied by significant left ventricular cardiac hypertrophy and renal damage at day 28 in animals treated with angiotensin II (P < 0.05) or both oxytocin and angiotensin II, compared to controls (P < 0.01). Prolonged oxytocin administration did not affect plasma concentrations of renin and atrial natriuretic peptide, but was associated with the activation of calcium-dependent protein phosphatase calcineurin, a canonical signalling mechanism in pressure overload-induced cardiovascular disease. These data demonstrate that oxytocin accelerated angiotensin-II induced hypertension and end-organ renal damage, suggesting caution should be exercised in the chronic use of oxytocin in individuals with hypertension.

  1. Angiotensin II induces phosphatidic acid formation in neonatal rat cardiac fibroblasts: evaluation of the roles of phospholipases C and D.

    PubMed

    Booz, G W; Taher, M M; Baker, K M; Singer, H A

    1994-12-21

    Phosphatidic acid has been proposed to contribute to the mitogenic actions of various growth factors. In 32P-labeled neonatal rat cardiac fibroblasts, 100 nM [Sar1]angiotensin II was shown to rapidly induce formation of 32P-phosphatidic acid. Levels peaked at 5 min (1.5-fold above control), but were partially sustained over 2 h. Phospholipase D contributed in part to phosphatidic acid formation, as 32P- or 3H-phosphatidylethanol was produced when cells labeled with [32P]H3PO4 or 1-O-[1,2- 3H]hexadecyl-2-lyso-sn-glycero-3-phosphocholine were stimulated in the presence of 1% ethanol. [Sar1]angiotensin II-induced phospholipase D activity was transient and mainly mediated through protein kinase C (PKC), since PKC downregulation reduced phosphatidylethanol formation by 68%. Residual activity may have been due to increased intracellular Ca2+, as ionomycin also activated phospholipase D in PKC-depleted cells. Phospholipase D did not fully account for [Sar1]angiotensin II-induced phosphatidic acid: 1) compared to PMA, a potent activator of phospholipase D, [Sar1]angiotensin II produced more phosphatidic acid relative to phosphatidylethanol, and 2) PKC downregulation did not affect [Sar1]angiotensin II-induced phosphatidic acid formation. The diacylglycerol kinase inhibitor R59949 depressed [Sar1]angiotensin II-induced phosphatidic acid formation by only 21%, indicating that activation of a phospholipase C and diacylglycerol kinase also can not account for the bulk of phosphatidic acid. Thus, additional pathways not involving phospholipases C and D, such as de novo synthesis, may contribute to [Sar1]angiotensin II-induced phosphatidic acid in these cells. Finally, as previously shown for [Sar1]angiotensin II, phosphatidic acid stimulated mitogen activated protein (MAP) kinase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders.

    PubMed

    Saavedra, Juan M

    2012-11-01

    The effects of brain AngII (angiotensin II) depend on AT(1) receptor (AngII type 1 receptor) stimulation and include regulation of cerebrovascular flow, autonomic and hormonal systems, stress, innate immune response and behaviour. Excessive brain AT(1) receptor activity associates with hypertension and heart failure, brain ischaemia, abnormal stress responses, blood-brain barrier breakdown and inflammation. These are risk factors leading to neuronal injury, the incidence and progression of neurodegerative, mood and traumatic brain disorders, and cognitive decline. In rodents, ARBs (AT(1) receptor blockers) ameliorate stress-induced disorders, anxiety and depression, protect cerebral blood flow during stroke, decrease brain inflammation and amyloid-β neurotoxicity and reduce traumatic brain injury. Direct anti-inflammatory protective effects, demonstrated in cultured microglia, cerebrovascular endothelial cells, neurons and human circulating monocytes, may result not only in AT(1) receptor blockade, but also from PPARγ (peroxisome-proliferator-activated receptor γ) stimulation. Controlled clinical studies indicate that ARBs protect cognition after stroke and during aging, and cohort analyses reveal that these compounds significantly reduce the incidence and progression of Alzheimer's disease. ARBs are commonly used for the therapy of hypertension, diabetes and stroke, but have not been studied in the context of neurodegenerative, mood or traumatic brain disorders, conditions lacking effective therapy. These compounds are well-tolerated pleiotropic neuroprotective agents with additional beneficial cardiovascular and metabolic profiles, and their use in central nervous system disorders offers a novel therapeutic approach of immediate translational value. ARBs should be tested for the prevention and therapy of neurodegenerative disorders, in particular Alzheimer's disease, affective disorders, such as co-morbid cardiovascular disease and depression, and traumatic

  3. Angiotensin II Type 1 Receptor-Dependent GLP-1 and PYY Secretion in Mice and Humans

    PubMed Central

    Pais, Ramona; Rievaj, Juraj; Larraufie, Pierre

    2016-01-01

    Angiotensin II (Ang II) is the key hormone mediator of the renin angiotensin system, which regulates blood pressure and fluid and electrolyte balance in the body. Here we report that in the colonic epithelium, the Ang II type 1 receptor is highly and exclusively expressed in enteroendocrine L cells, which produce the gut hormones glucagon-like peptide-1 and peptide YY (PYY). Ang II stimulated glucagon-like peptide-1 and PYY release from primary cultures of mouse and human colon, which was antagonized by the specific Ang II type 1 receptor blocker candesartan. Ang II raised intracellular calcium levels in L cells in primary cultures, recorded by live-cell imaging of L cells specifically expressing the fluorescent calcium sensor GCaMP3. In Ussing chamber recordings, Ang II reduced short circuit currents in mouse distal colon preparations, which was antagonized by candesartan or a specific neuropeptide Y1 receptor inhibitor but insensitive to amiloride. We conclude that Ang II stimulates PYY secretion, in turn inhibiting epithelial anion fluxes, thereby reducing net fluid secretion into the colonic lumen. Our findings highlight an important role of colonic L cells in whole-body fluid homeostasis by controlling water loss through the intestine. PMID:27447725

  4. Peach (Prunus persica) extract inhibits angiotensin II-induced signal transduction in vascular smooth muscle cells.

    PubMed

    Kono, Ryohei; Okuno, Yoshiharu; Nakamura, Misa; Inada, Ken-ichi; Tokuda, Akihiko; Yamashita, Miki; Hidaka, Ryu; Utsunomiya, Hirotoshi

    2013-08-15

    Angiotensin II (Ang II) is a vasoactive hormone that has been implicated in cardiovascular diseases. Here, the effect of peach, Prunus persica L. Batsch, pulp extract on Ang II-induced intracellular Ca(2+) mobilization, reactive oxygen species (ROS) production and signal transduction events in cultured vascular smooth muscle cells (VSMCs) was investigated. Pretreatment of peach ethyl acetate extract inhibited Ang II-induced intracellular Ca(2+) elevation in VSMCs. Furthermore, Ang II-induced ROS generation, essential for signal transduction events, was diminished by the peach ethyl acetate extract. The peach ethyl acetate extract also attenuated the Ang II-induced phosphorylation of epidermal growth factor receptor and myosin phosphatase target subunit 1, both of which are associated with atherosclerosis and hypertension. These results suggest that peach ethyl acetate extract may have clinical potential for preventing cardiovascular diseases by interfering with Ang II-induced intracellular Ca(2+) elevation, the generation of ROS, and then blocking signal transduction events.

  5. Effects of a lipoxygenase inhibitor, panaxynol, on vascular contraction induced by angiotensin II.

    PubMed

    Takai, S; Jin, D; Kirimura, K; Ikeda, J; Sakaguchi, M; Baba, K; Fujita, T; Miyazaki, M

    1999-05-01

    We investigated whether a lipoxygenase inhibitor, panaxynol, affected the vascular contraction induced by angiotensin (Ang) II and the mean arterial pressure in spontaneously hypertensive rats (SHR). Panaxynol suppressed dose-dependently the contractile responses induced by 30 nM Ang II in isolated intact and endothelial cell-denuded aorta in the hamster. IC50 values in the intact and endothelial cell-denuded aorta were 23 and 20 microM, respectively. In SHR, the mean arterial pressure after injection of 30 and 60 mg/kg panaxynol was reduced, and the maximum hypotensive values were 23 and 48 mmHg, respectively. Thus, lipoxygenase products may affect the renin-angiotensin system.

  6. Angiotensin II natriuresis and antinatriuresis: role of renal artery pressure, renal hemodynamics, and tubular reabsorption.

    PubMed

    Olsen, M E; Hall, J E; Montani, J P; Guyton, A C

    1985-01-01

    The aim of this study was to determine the role of changes in renal artery pressure (RAP), renal hemodynamics, and tubular reabsorption in mediating the natriuretic and antinatriuretic actions of angiotensin II (AII). In anesthetized dogs, endogenous AII formation was blocked with SQ-14225 and AII was infused i.v. at rates of 5-1215 ng/kg/min while RAP was either servo-controlled at the normal level or permitted to increase. When RAP was servo-controlled to prevent a rise i RAP, AII infusion at all rates from 5-1215 ng/kg/min decreased urinary sodium excretion (UNaV) and fractional sodium excretion (FENa), while increasing fractional reabsorption of lithium (FRLi), an index of proximal tubule fractional sodium reabsorption and distal fractional sodium reabsorption (FRDNa): When RAP was permitted to increase, AII infusion rates up to 45 ng/kg/min decreased UNaV, and FENa, while increasing FRLi and FRDNa. However, at 135 ng/kg/min and above, UNaV and FENa increased while FRLi and FRDNa decreased when RAP was allowed to rise, even though RBF and FF were not substantially different from the values observed when RAP was servo-controlled. Filtered sodium load was slightly higher when RAP was permitted to increase during AII infusion, compared to the dogs in which RAP was servo-controlled, although the differences were not statistically significant. Thus, even very large doses of AII cause antinatriuresis when RAP was prevented from increasing. The natriuretic effect of high dose of AII is caused by increased RAP which decreases fractional sodium reabsorption in proximal and distal tubules and causes slight increases in sodium delivery to the tubules.

  7. Structure of the human angiotensin II type 1 (AT1) receptor bound to angiotensin II from multiple chemoselective photoprobe contacts reveals a unique peptide binding mode.

    PubMed

    Fillion, Dany; Cabana, Jérôme; Guillemette, Gaétan; Leduc, Richard; Lavigne, Pierre; Escher, Emanuel

    2013-03-22

    Breakthroughs in G protein-coupled receptor structure determination based on crystallography have been mainly obtained from receptors occupied in their transmembrane domain core by low molecular weight ligands, and we have only recently begun to elucidate how the extracellular surface of G protein-coupled receptors (GPCRs) allows for the binding of larger peptide molecules. In the present study, we used a unique chemoselective photoaffinity labeling strategy, the methionine proximity assay, to directly identify at physiological conditions a total of 38 discrete ligand/receptor contact residues that form the extracellular peptide-binding site of an activated GPCR, the angiotensin II type 1 receptor. This experimental data set was used in homology modeling to guide the positioning of the angiotensin II (AngII) peptide within several GPCR crystal structure templates. We found that the CXC chemokine receptor type 4 accommodated the results better than the other templates evaluated; ligand/receptor contact residues were spatially grouped into defined interaction clusters with AngII. In the resulting receptor structure, a β-hairpin fold in extracellular loop 2 in conjunction with two extracellular disulfide bridges appeared to open and shape the entrance of the ligand-binding site. The bound AngII adopted a somewhat vertical binding mode, allowing concomitant contacts across the extracellular surface and deep within the transmembrane domain core of the receptor. We propose that such a dualistic nature of GPCR interaction could be well suited for diffusible linear peptide ligands and a common feature of other peptidergic class A GPCRs.

  8. Cellular FLICE-inhibitory protein protects against cardiac remodeling induced by angiotensin II in mice.

    PubMed

    Li, Hongliang; Tang, Qi-Zhu; Liu, Chen; Moon, Mark; Chen, Manyin; Yan, Ling; Bian, Zhou-Yan; Zhang, Yan; Wang, Ai-Bing; Nghiem, Mai P; Liu, Peter P

    2010-12-01

    The development of cardiac hypertrophy in response to increased hemodynamic load and neurohormonal stress is initially a compensatory response that may eventually lead to ventricular dilatation and heart failure. Cellular FLICE-inhibitory protein (cFLIP) is a homologue of caspase 8 without caspase activity that inhibits apoptosis initiated by death receptor signaling. Previous studies showed that cFLIP expression was markedly decreased in the ventricular myocardium of patients with end-stage heart failure. However, the critical role of cFLIP on cardiac remodeling remains unclear. To specifically determine the role of cFLIP in pathological cardiac remodeling, we used heterozygote cFLIP(+/-) mice and transgenic mice with cardiac-specific overexpression of the human cFLIP(L) gene. Our results demonstrated that the cFLIP(+/-) mice were susceptible to cardiac hypertrophy and fibrosis through inhibition of mitogen-activated protein kinase kinase-extracellular signal-regulated kinase 1/2 signaling, whereas the transgenic mice displayed the opposite phenotype in response to angiotensin II stimulation. These studies indicate that cFLIP protein is a crucial component of the signaling pathway involved in cardiac remodeling and heart failure.

  9. Angiotensin II type 1 receptor blockers increase tolerance of cells to copper and cisplatin

    PubMed Central

    Spincemaille, Pieter; Chandhok, Gursimran; Zibert, Andree; Schmidt, Hartmut; Verbeek, Jef; Chaltin, Patrick; Cammue, Bruno P.; Cassiman, David; Thevissen, Karin

    2014-01-01

    The human pathology Wilson disease (WD) is characterized by toxic copper (Cu) accumulation in brain and liver, resulting in, among other indications, mitochondrial dysfunction and apoptosis of hepatocytes. In an effort to identify novel compounds that can alleviate Cu-induced toxicity, we screened the Pharmakon 1600 repositioning library using a Cu-toxicity yeast screen. We identified 2 members of the drug class of Angiotensin II Type 1 receptor blockers (ARBs) that could increase yeast tolerance to Cu, namely Candesartan and Losartan. Subsequently, we show that specific ARBs can increase yeast tolerance to Cu and/or the chemotherapeutic agent cisplatin (Cp). The latter also induces mitochondrial dysfunction and apoptosis in mammalian cells. We further demonstrate that specific ARBs can prevent the prevalence of Cu-induced apoptotic markers in yeast, with Candesartan Cilexetil being the ARB which demonstrated most pronounced reduction of apoptosis-related markers. Next, we tested the sensitivity of a selection of yeast knockout mutants affected in detoxification of reactive oxygen species (ROS) and Cu for Candesartan Cilexetil rescue in presence of Cu. These data indicate that Candesartan Cilexetil increases yeast tolerance to Cu irrespectively of major ROS-detoxifying proteins. Finally, we show that specific ARBs can increase mammalian cell tolerance to Cu, as well as decrease the prevalence of Cu-induced apoptotic markers. All the above point to the potential of ARBs in preventing Cu-induced toxicity in yeast and mammalian cells. PMID:28357214

  10. Chronic kidney disease accelerates cognitive impairment in a mouse model of Alzheimer's disease, through angiotensin II.

    PubMed

    Nakagawa, Takashi; Hasegawa, Yu; Uekawa, Ken; Kim-Mitsuyama, Shokei

    2017-01-01

    Epidemiological studies suggest that chronic kidney disease (CKD) is a significant risk factor in the development of cognitive decline. However, the exact role of CKD in cognitive impairment or dementia is unclear. This work was performed to examine the potential impact of CKD on cognitive impairment in Alzheimer's disease (AD), focusing on angiotensin II. (1) CKD was induced in 5XFAD mice, an AD model mouse, and wild-type mice by feeding an adenine-containing diet and the effect on cognitive function was compared between both strains. There was no significant difference regarding the severity of CKD induced by adenine between the strains. In 5XFAD mice, the CKD group exhibited significant cognitive impairment while the control group (control diet-fed group) did not, as evidenced by a passive avoidance test. On the other hand, in wild-type mice, neither the CKD group nor the control group showed cognitive impairment. Thus, CKD itself appears to accelerate cognitive impairment in AD mice. (2) We also examined the effect of olmesartan, an angiotensin II receptor blocker, on 5XFAD mice with CKD to elucidate the potential involvement of angiotensin II. As evidenced by the findings of the water maze test, olmesartan treatment significantly ameliorated the impairment of spatial learning and memory function induced by CKD in 5XFAD mice. Olmesartan treatment significantly ameliorated blood-brain barrier (BBB) disruption induced by CKD in 5XFAD mice. Furthermore, olmesartan reduced hippocampal oxidative stress in 5XFAD with CKD to similar levels to the control group of 5XFAD fed standard diet. Hence, the amelioration of CKD-induced cognitive impairment in 5XFAD mice by olmesartan appears to be mediated by the suppression of BBB disruption or oxidative stress. In conclusion, we obtained the evidence suggesting that CKD itself accelerates cognitive impairment in AD mice, through angiotensin II. Thus, our work provides a novel insight into the underlying mechanism of the link

  11. Angiotensin II type 1a receptor signalling directly contributes to the increased arrhythmogenicity in cardiac hypertrophy

    PubMed Central

    Yasuno, Shinji; Kuwahara, Koichiro; Kinoshita, Hideyuki; Yamada, Chinatsu; Nakagawa, Yasuaki; Usami, Satoru; Kuwabara, Yoshihiro; Ueshima, Kenji; Harada, Masaki; Nishikimi, Toshio; Nakao, Kazuwa

    2013-01-01

    BACKGROUND AND PURPOSE Angiotensin II has been implicated in the development of various cardiovascular ailments, including cardiac hypertrophy and heart failure. The fact that inhibiting its signalling reduced the incidences of both sudden cardiac death and heart failure in several large-scale clinical trials suggests that angiotensin II is involved in increased cardiac arrhythmogenicity during the development of heart failure. However, because angiotensin II also promotes structural remodelling, including cardiomyocyte hypertrophy and cardiac fibrosis, it has been difficult to assess its direct contribution to cardiac arrhythmogenicity independently of the structural effects. EXPERIMENTAL APPROACH We induced cardiac hypertrophy in wild-type (WT) and angiotensin II type 1a receptor knockout (AT1aR-KO) mice by transverse aortic constriction (TAC). The susceptibility to ventricular tachycardia (VT) assessed in an in vivo electrophysiological study was compared in the two genotypes. The effect of acute pharmacological blockade of AT1R on the incidences of arrhythmias was also assessed. KEY RESULTS As described previously, WT and AT1aR-KO mice with TAC developed cardiac hypertrophy to the same degree, but the incidence of VT was much lower in the latter. Moreover, although TAC induced an increase in tyrosine phosphorylation of connexin 43, a critical component of gap junctional channels, and a reduction in ventricular levels of connexin 43 protein in both genotypes, the effect was significantly ameliorated in AT1aR-KO mice. Acute pharmacological blockade of AT1R also reduced the incidence of arrhythmias. CONCLUSIONS AND IMPLICATIONS Our findings demonstrate that AT1aR-mediated signalling makes a direct contribution to the increase in arrhythmogenicity in hypertrophied hearts independently of structural remodelling. PMID:23937445

  12. Effect of angiotensin II, ATP, and ionophore A23187 on potassium efflux in adrenal glomerulosa cells

    SciTech Connect

    Lobo, M.V.; Marusic, E.T.

    1986-02-01

    Angiotensin II stimulus on perifused bovine adrenal glomerulosa cells elicited an increase in 86Rb efflux from cells previously equilibrated with the radioisotope. When 45Ca fluxes were measured under similar conditions, it was observed that Ca and Rb effluxes occurred within the first 30 s of the addition of the hormone and were independent of the presence of external Ca. The 86Rb efflux due to angiotensin II was inhibited by quinine and apamin. The hypothesis that the angiotensin II response is a consequence of an increase in the K permeability of the glomerulosa cell membrane triggered by an increase in cytosolic Ca is supported by the finding that the divalent cation ionophore A23187 also initiated 86Rb or K loss (as measured by an external K electrode). This increased K conductance was also seen with 10(-4) M ATP. Quinine and apamin greatly reduced the effect of ATP or A23187 on 86Rb or K release in adrenal glomerulosa cells. The results suggest that Ca-dependent K channels or carriers are present in the membranes of bovine adrenal glomerulosa cells and are sensitive to hormonal stimulus.

  13. The Angiotensin II Type 2 Receptor in Brain Functions: An Update

    PubMed Central

    Guimond, Marie-Odile; Gallo-Payet, Nicole

    2012-01-01

    Angiotensin II (Ang II) is the main active product of the renin-angiotensin system (RAS), mediating its action via two major receptors, namely, the Ang II type 1 (AT1) receptor and the type 2 (AT2) receptor. Recent results also implicate several other members of the renin-angiotensin system in various aspects of brain functions. The first aim of this paper is to summarize the current state of knowledge regarding the properties and signaling of the AT2 receptor, its expression in the brain, and its well-established effects. Secondly, we will highlight the potential role of the AT2 receptor in cognitive function, neurological disorders and in the regulation of appetite and the possible link with development of metabolic disorders. The potential utility of novel nonpeptide selective AT2 receptor ligands in clarifying potential roles of this receptor in physiology will also be discussed. If confirmed, these new pharmacological tools should help to improve impaired cognitive performance, not only through its action on brain microcirculation and inflammation, but also through more specific effects on neurons. However, the overall physiological relevance of the AT2 receptor in the brain must also consider the Ang IV/AT4 receptor. PMID:23320146

  14. Salvianolic Acid B Attenuates Rat Hepatic Fibrosis via Downregulating Angiotensin II Signaling

    PubMed Central

    Li, Shu; Wang, Lina; Yan, Xiuchuan; Wang, Qinglan; Tao, Yanyan; Li, Junxia; Peng, Yuan; Liu, Ping; Liu, Chenghai

    2012-01-01

    The renin-angiotensin system (RAS) plays an important role in hepatic fibrosis. Salvianolic acid B (Sal B), one of the water-soluble components from Radix Salviae miltiorrhizae, has been used to treat hepatic fibrosis, but it is still not clear whether the effect of Sal B is related to angiotensin II (Ang II) signaling pathway. In the present study, we studied Sal B effect on rat liver fibrosis and Ang-II related signaling mediators in dimethylnitrosamine-(DMN-) induced rat fibrotic model in vivo and Ang-II stimulated hepatic stellate cells (HSCs) in vitro, with perindopril or losartan as control drug, respectively. The results showed that Sal B and perindopril inhibited rat hepatic fibrosis and reduced expression of Ang II receptor type 1 (AT1R) and ERK activation in fibrotic liver. Sal B and losartan also inhibited Ang II-stimulated HSC activation including cell proliferation and expression of type I collagen I (Col-I) and α-smooth muscle actin (α-SMA) production in vitro, reduced the gene expression of transforming growth factor beta (TGF-β), and downregulated AT1R expression and ERK and c-Jun phosphorylation. In conclusion, our results indicate that Sal B may exert an antihepatic fibrosis effect via downregulating Ang II signaling in HSC activation. PMID:23243430

  15. Angiotensin II (de)sensitization: Fluid intake studies with implications for cardiovascular control.

    PubMed

    Daniels, Derek

    2016-08-01

    Cardiovascular disease is the leading cause of death worldwide and hypertension is the most common risk factor for death. Although many anti-hypertensive pharmacotherapies are approved for use in the United States, rates of hypertension have increased over the past decade. This review article summarizes a presentation given at the 2015 meeting of the Society for the Study of Ingestive Behavior. The presentation described work performed in our laboratory that uses angiotensin II-induced drinking as a model system to study behavioral and cardiovascular effects of the renin-angiotensin system, a key component of blood pressure regulation, and a common target of anti-hypertensives. Angiotensin II (AngII) is a potent dipsogen, but the drinking response shows a rapid desensitization after repeated injections of AngII. This desensitization appears to be dependent upon the timing of the injections, requires activation of the AngII type 1 (AT1) receptor, requires activation of mitogen-activated protein (MAP) kinase family members, and involves the anteroventral third ventricle (AV3V) region as a critical site of action. Moreover, the response does not appear to be the result of a more general suppression of behavior, a sensitized pressor response to AngII, or an aversive state generated by the treatment. More recent studies suggest that the treatment regimen used to produce desensitization in our laboratory also prevents the sensitization that occurs after daily bolus injections of AngII. Our hope is that these findings can be used to support future basic research on the topic that could lead to new developments in treatments for hypertension.

  16. Angiotensin II increases CTGF expression via MAPKs/TGF-{beta}1/TRAF6 pathway in atrial fibroblasts

    SciTech Connect

    Gu, Jun; Liu, Xu; Wang, Quan-xing; Tan, Hong-wei; Guo, Meng; Jiang, Wei-feng; Zhou, Li

    2012-10-01

    The activation of transforming growth factor-{beta}1(TGF-{beta}1)/Smad signaling pathway and increased expression of connective tissue growth factor (CTGF) induced by angiotensin II (AngII) have been proposed as a mechanism for atrial fibrosis. However, whether TGF{beta}1/non-Smad signaling pathways involved in AngII-induced fibrogenetic factor expression remained unknown. Recently tumor necrosis factor receptor associated factor 6 (TRAF6)/TGF{beta}-associated kinase 1 (TAK1) has been shown to be crucial for the activation of TGF-{beta}1/non-Smad signaling pathways. In the present study, we explored the role of TGF-{beta}1/TRAF6 pathway in AngII-induced CTGF expression in cultured adult atrial fibroblasts. AngII (1 {mu}M) provoked the activation of P38 mitogen activated protein kinase (P38 MAPK), extracellular signal-regulated kinase 1/2(ERK1/2) and c-Jun NH(2)-terminal kinase (JNK). AngII (1 {mu}M) also promoted TGF{beta}1, TRAF6, CTGF expression and TAK1 phosphorylation, which were suppressed by angiotensin type I receptor antagonist (Losartan) as well as p38 MAPK inhibitor (SB202190), ERK1/2 inhibitor (PD98059) and JNK inhibitor (SP600125). Meanwhile, both TGF{beta}1 antibody and TRAF6 siRNA decreased the stimulatory effect of AngII on TRAF6, CTGF expression and TAK1 phosphorylation, which also attenuated AngII-induced atrial fibroblasts proliferation. In summary, the MAPKs/TGF{beta}1/TRAF6 pathway is an important signaling pathway in AngII-induced CTGF expression, and inhibition of TRAF6 may therefore represent a new target for reversing Ang II-induced atrial fibrosis. -- Highlights: Black-Right-Pointing-Pointer MAPKs/TGF{beta}1/TRAF6 participates in AngII-induced CTGF expression in atrial fibroblasts. Black-Right-Pointing-Pointer TGF{beta}1/TRAF6 participates in AngII-induced atrial fibroblasts proliferation. Black-Right-Pointing-Pointer TRAF6 may represent a new target for reversing Ang II-induced atrial fibrosis.

  17. Angiotensin II induces the expression of c-reactive protein via MAPK-dependent signal pathway in U937 macrophages.

    PubMed

    Li, Ming; Liu, Juntian; Han, Chunjie; Wang, Bin; Pang, Xiaoming; Mao, Junjun

    2011-01-01

    Atherosclerosis is an inflammatory disease in the vessel wall. As an inflammatory molecule, C-reactive protein (CRP) participates in all stages of atherosclerotic process. Although angiotensin II (Ang II) can stimulate the vascular cells to produce CRP, it is unknown whether Ang II induces CRP expression in macrophages. The present study was to observe effect of Ang II on CRP production and the related signal pathway in U937 macrophages so as to provide more evidence for the proinflammatory action of Ang II. The results showed that Ang II significantly increased mRNA and protein expression of CRP in U937 macrophages in time- and concentration-dependent manners. AT(1) receptor blocker losartan blocked Ang II -induced CRP expression in mRNA and protein levels in U937 macrophages. Losartan and complex II inhibitor TIFA decreased Ang II -stimulated reactive oxygen species (ROS) generation, and antioxidant NAC completely abolished Ang II -induced CRP expression in U937 macrophages. The further study indicated that losartan, NAC, MEK1/2 inhibitor PD98059, p38MAPK inhibitor SB203580 obviously inhibited ERK1/2 and p38MAPK phosphorylation, and PD98059, SB203580 and NF-κB inhibitor PDTC reduced Ang II -induced mRNA and protein expression of CRP in U937 macrophages. These demonstrate that Ang II is capable of inducing CRP generation in macrophages via AT(1)-ROS-ERK1/2/p38MAPK-NF-κB signal pathway, which contributes to better understanding of the proinflammatory and proatherosclerotic actions of Ang II.

  18. Angiotensin II counteracts the effects of cAMP/PKA on NHE3 activity and phosphorylation in proximal tubule cells.

    PubMed

    Crajoinas, Renato O; Polidoro, Juliano Z; Carneiro de Morais, Carla P A; Castelo-Branco, Regiane C; Girardi, Adriana C C

    2016-11-01

    Binding of angiotensin II (ANG II) to the AT1 receptor (AT1R) in the proximal tubule stimulates Na(+)/H(+) exchanger isoform 3 (NHE3) activity through multiple signaling pathways. However, the effects of ANG II/AT1R-induced inihibitory G protein (Gi) activation and subsequent decrease in cAMP accumulation on NHE3 regulation are not well established. We therefore tested the hypothesis that ANG II reduces cAMP/PKA-mediated phosphorylation of NHE3 on serine 552 and, in doing so, stimulates NHE3 activity. Under basal conditions, ANG II stimulated NHE3 activity but did not affect PKA-mediated NHE3 phosphorylation at serine 552 in opossum kidney (OKP) cells. However, in the presence of the cAMP-elevating agent forskolin (FSK), ANG II blocked FSK-induced NHE3 inhibition, reduced intracellular cAMP concentrations, lowered PKA activity, and prevented the FSK-mediated increase in NHE3 serine 552 phosphorylation. All effects of ANG II were blocked by pretreating OKP cells with the AT1R antagonist losartan, highlighting the contribution of the AT1R/Gi pathway in ANG II-mediated NHE3 upregulation under cAMP-elevating conditions. Accordingly, Gi inhibition by pertussis toxin treatment decreased NHE3 activity both in vitro and in vivo and, more importantly, prevented the stimulatory effect of ANG II on NHE3 activity in rat proximal tubules. Collectively, our results suggest that ANG II counteracts the effects of cAMP/PKA on NHE3 phosphorylation and inhibition by activating the AT1R/Gi pathway. Moreover, these findings support the notion that NHE3 dephosphorylation at serine 552 may represent a key event in the regulation of renal proximal tubule sodium handling by ANG II in the presence of natriuretic hormones that promote cAMP accumulation and transporter phosphorylation.

  19. Ghrelin Protects against Renal Damages Induced by Angiotensin-II via an Antioxidative Stress Mechanism in Mice

    PubMed Central

    Fujimura, Keiko; Wakino, Shu; Minakuchi, Hitoshi; Hasegawa, Kazuhiro; Hosoya, Koji; Komatsu, Motoaki; Kaneko, Yuka; Shinozuka, Keisuke; Washida, Naoki; Kanda, Takeshi; Tokuyama, Hirobumi; Hayashi, Koichi; Itoh, Hiroshi

    2014-01-01

    We explored the renal protective effects by a gut peptide, Ghrelin. Daily peritoneal injection with Ghrelin ameliorated renal damages in continuously angiotensin II (AngII)-infused C57BL/6 mice as assessed by urinary excretion of protein and renal tubular markers. AngII-induced increase in reactive oxygen species (ROS) levels and senescent changes were attenuated by Ghrelin. Ghrelin also inhibited AngII-induced upregulations of transforming growth factor-β (TGF-β) and plasminogen activator inhibitor-1 (PAI-1), ameliorating renal fibrotic changes. These effects were accompanied by concomitant increase in mitochondria uncoupling protein, UCP2 as well as in a key regulator of mitochondria biosynthesis, PGC1α. In renal proximal cell line, HK-2 cells, Ghrelin reduced mitochondria membrane potential and mitochondria-derived ROS. The transfection of UCP2 siRNA abolished the decrease in mitochondria-derived ROS by Ghrelin. Ghrelin ameliorated AngII-induced renal tubular cell senescent changes and AngII-induced TGF-β and PAI-1 expressions. Finally, Ghrelin receptor, growth hormone secretagogue receptor (GHSR)-null mice exhibited an increase in tubular damages, renal ROS levels, renal senescent changes and fibrosis complicated with renal dysfunction. GHSR-null mice harbored elongated mitochondria in the proximal tubules. In conclusion, Ghrelin suppressed AngII-induced renal damages through its UCP2 dependent anti-oxidative stress effect and mitochondria maintenance. Ghrelin/GHSR pathway played an important role in the maintenance of ROS levels in the kidney. PMID:24747517

  20. Selectively engaging β-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance.

    PubMed

    Violin, Jonathan D; DeWire, Scott M; Yamashita, Dennis; Rominger, David H; Nguyen, Lisa; Schiller, Kevin; Whalen, Erin J; Gowen, Maxine; Lark, Michael W

    2010-12-01

    Biased G protein-coupled receptor ligands engage subsets of the receptor signals normally stimulated by unbiased agonists. However, it is unclear whether ligand bias can elicit differentiated pharmacology in vivo. Here, we describe the discovery of a potent, selective β-arrestin biased ligand of the angiotensin II type 1 receptor. TRV120027 (Sar-Arg-Val-Tyr-Ile-His-Pro-D-Ala-OH) competitively antagonizes angiotensin II-stimulated G protein signaling, but stimulates β-arrestin recruitment and activates several kinase pathways, including p42/44 mitogen-activated protein kinase, Src, and endothelial nitric-oxide synthase phosphorylation via β-arrestin coupling. Consistent with β-arrestin efficacy, and unlike unbiased antagonists, TRV120027 increased cardiomyocyte contractility in vitro. In rats, TRV120027 reduced mean arterial pressure, as did the unbiased antagonists losartan and telmisartan. However, unlike the unbiased antagonists, which decreased cardiac performance, TRV120027 increased cardiac performance and preserved cardiac stroke volume. These striking differences in vivo between unbiased and β-arrestin biased ligands validate the use of biased ligands to selectively target specific receptor functions in drug discovery.

  1. Excessive zinc intake increases systemic blood pressure and reduces renal blood flow via kidney angiotensin II in rats.

    PubMed

    Kasai, Miyoko; Miyazaki, Takashi; Takenaka, Tsuneo; Yanagisawa, Hiroyuki; Suzuki, Hiromichi

    2012-12-01

    This study investigated the effects of excess zinc intake on the mean arterial pressure (MAP), renal blood flow (RBF), inulin clearance (IC), serum zinc level, serum angiotensin-converting enzyme (ACE) activity, and kidney angiotensin II (AT II) levels in rats. Experiments were performed on male Sprague-Dawley rats maintained for 4 weeks on a diet containing either 5 mg/100 g (control group), 50 mg/100 g (Zn50 group), or 200 mg/100 g (Zn200 group) zinc carbonate. Serum zinc levels significantly increased to 126.5 % in the Zn50 group and 198.1 % in the Zn200 group compared with controls. MAP significantly increased to 107.8 % in the Zn50 group and 114.5 % in the Zn200 group again compared with controls. Although the difference in serum ACE activity was independent of the serum zinc levels, the kidney AT II levels increased significantly to 137.2 % in the Zn50 group and 174.4 % in the Zn200 group compared with the controls. RBF was decreased significantly to 74.4 % in the Zn50 group and 69.7 % in the Zn200 group compared with the controls. IC values were significantly decreased to 69.6 % in the Zn50 group and 52.7 % in the Zn200 group as compared with control levels. Combined together, these results show that excessive Zn intake reduced IC and RBF and increased MAP and kidney AT II levels, suggesting that excessive Zn intake reduces renal function.

  2. Preventive effect of gomisin J from Schisandra chinensis on angiotensin II-induced hypertension via an increased nitric oxide bioavailability.

    PubMed

    Ye, Byeong Hyeok; Lee, Seung Jin; Choi, Young Whan; Park, So Youn; Kim, Chi Dae

    2015-03-01

    Gomisin J (GJ) is a small molecular weight lignan found in Schisandra chinensis and has been demonstrated to have vasodilatory activity. In this study, the authors investigated the effect of GJ on blood pressure (BP) in angiotensin II (Ang II)-induced hypertensive mice. In addition, we determined the relative potencies of gomisin A (GA) and GJ with respect to vasodilatory activity and antihypertensive effects. C57/BL6 mice infused s.c. with Ang II (2 μg kg(-1) min(-1) for 2 weeks) showed an increase in BP and a decrease in plasma nitric oxide (NO) metabolites. In the thoracic aortas of Ang II-induced hypertensive mice, a decrease in vascular NO was accompanied by an increase in reactive oxygen species (ROS) production. Furthermore, these alterations in BP, plasma concentrations of NO metabolites and in the vascular productions of NO and ROS in Ang II-treated mice were reversed by the co-administration of GJ (1 and 3 μg kg(-1) min(-1)). In in vitro studies, Ang II decreased the cellular concentration of NO, which was accompanied by a reduction in phosphorylated endothelial nitric oxide synthase (eNOS) and an increase in ROS production. These eNOS phosphorylation and ROS production changes in Ang II-treated cells were also reversed by GJ pretreatment (0-3 μg ml(-1)). Interestingly, the vasodilatory and antihypertensive effects of GJ were more prominent than those of GA. Collectively, an increase in BP in mice treated with Ang II was markedly attenuated by GJ, which was attributed to the preservations of vascular NO bioavailability and eNOS function, and to the inhibition of ROS production in Ang II-induced hypertensive mice.

  3. Add-on angiotensin II receptor blockade lowers urinary transforming growth factor-beta levels.

    PubMed

    Agarwal, Rajiv; Siva, Senthuran; Dunn, Stephen R; Sharma, Kumar

    2002-03-01

    Progression of renal failure, despite renoprotection with angiotensin-converting enzyme (ACE) inhibitors in patients with proteinuric nephropathies, may be caused by persistent renal production of transforming growth factor-beta1 (TGF-beta1) through the angiotensin II subtype 1 (AT1) receptors. We tested the hypothesis that AT1-receptor blocker therapy added to a background of chronic maximal ACE inhibitor therapy will result in a reduction in urinary TGF-beta1 levels in such patients. Sixteen patients completed a two-period, crossover, randomized, controlled trial, details of which have been previously reported. All patients were administered lisinopril, 40 mg/d, with either losartan, 50 mg/d, or placebo. Blood pressure (BP) was measured using a 24-hour ambulatory BP monitor. Overnight specimens of urine were analyzed for urine TGF-beta1, protein, and creatinine concentrations. Mean age of the study population was 53 +/- 9 (SD) years; body mass index, 38 +/- 5.7 kg/m2; seated BP, 156 +/- 18/88 +/- 12 mm Hg; and urine protein excretion, 3.6 +/- 0.71 g/g of creatinine. Twelve patients had diabetic nephropathy, and the remainder had chronic glomerulonephritis. At baseline, urinary TGF-beta1 levels were significantly increased in the study population compared with healthy controls (13.2 +/- 1.2 versus 1.7 +/- 1.1 ng/g creatinine; P < 0.001). There was a strong correlation between baseline urine protein excretion and urinary TGF-beta1 level (r2 = 0.53; P = 0.001), as well as systolic BP and urinary TGF-beta1 level (r2 = 0.57; P < 0.001). After 4 weeks of add-on losartan therapy, there was a 38% (95% confidence interval [CI], 16% to 55%) decline in urinary TGF-beta1 levels (13.3 [95% CI, 11.4 to 15.5] to 8.2 pg/mg creatinine [95% CI, 6.2 to 10.7]). The reduction in urinary TGF-beta1 levels occurred independent of changes in mean urinary protein excretion or BP. Thus, proteinuric patients with renal failure, despite maximal ACE inhibition, had increased urinary levels of

  4. Angiotensin II stimulates basolateral 50-pS K channels in the thick ascending limb.

    PubMed

    Wang, Mingxiao; Luan, Haiyan; Wu, Peng; Fan, Lili; Wang, Lijun; Duan, Xinpeng; Zhang, Dandan; Wang, Wen-Hui; Gu, Ruimin

    2014-03-01

    We used the patch-clamp technique to examine the effect of angiotensin II (ANG II) on the basolateral K channels in the thick ascending limb (TAL) of the rat kidney. Application of ANG II increased the channel activity and the current amplitude of the basolateral 50-pS K channel. The stimulatory effect of ANG II on the K channels was completely abolished by losartan, an inhibitor of type 1 angiotensin receptor (AT1R), but not by PD123319, an AT2R antagonist. Moreover, inhibition of phospholipase C (PLC) and protein kinase C (PKC) also abrogated the stimulatory effect of ANG II on the basolateral K channels in the TAL. This suggests that the stimulatory effect of ANG II on the K channels was induced by activating PLC and PKC pathways. Western blotting demonstrated that ANG II increased the phosphorylation of c-Src at tyrosine residue 416, an indication of c-Src activation. This effect was mimicked by PKC stimulator but abolished by calphostin C. Moreover, inhibition of NADPH oxidase (NOX) also blocked the effect of ANG II on c-Src tyrosine phosphorylation. The role of Src-family protein tyrosine kinase (SFK) in mediating the effect of ANG II on the basolateral K channel was further suggested by the experiments in which inhibition of SFK abrogated the stimulatory effect of ANG II on the basolateral 50-pS K channel. We conclude that ANG II increases basolateral 50-pS K channel activity via AT1R and that activation of AT1R stimulates SFK by a PLC-PKC-NOX-dependent mechanism.

  5. ACE inhibitors and angiotensin II receptor blockers in IgA nephropathy with mild proteinuria: the ACEARB study.

    PubMed

    Pozzi, Claudio; Del Vecchio, Lucia; Casartelli, Donatella; Pozzoni, Pietro; Andrulli, Simeone; Amore, Alessandro; Peruzzi, Licia; Coppo, Rosanna; Locatelli, Francesco

    2006-01-01

    Few studies have investigated IgA nephropathy patients presenting with 'favorable' clinical features at onset, such as normal renal function, proteinuria<1 g/24 hours and the absence of hypertension, and no controlled clinical trials have tested the effects of treatment in such patients who may nevertheless develop end-stage renal disease. It is therefore important to find a well-tolerated and economic therapy capable of decreasing their risk of high proteinuria and blood pressure levels. The aim of this multicenter open-label randomized clinical trial is to test whether blocking the renin-angiotensin system (RAS) decreases the risk of progression in patients aged 3-60 years with biopsy-proven benign IgA glomerulonephritis, proteinuria levels of 0.3-0.9 g/24 hours, and normal renal function and blood pressure. The RAS is blocked by first using a single drug class (angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker), and then combining the 2 classes as soon as the 1-drug blockade has become ineffective. We plan to enroll 378 patients over the next 3 years and randomize them to receive ramipril 5 mg/day (3 mg/m2 in children) (group A), irbesartan 300 mg/day (175 mg/m 2 in children) (group B) or supportive therapy (group C); if an increase in proteinuria of at least 50% from baseline is detected after 6 months of treatment, the other RAS inhibitor will be added. The observation period will be at least 5 years (except in the case of the development of the primary end point).

  6. Antidiuretic action of angiotensin II in the river lamprey Lampetra fluviatilis: evidence for endocrine control of kidney function in cyclostomes.

    PubMed

    Cobb, C S; Brown, J A; Rankin, J C

    2010-10-01

    Intravenous infusion of angiotensin II ([Asn¹ Val⁵]-Ang II) at 10⁻⁹ mol min⁻¹ kg⁻¹ body mass produced a significant antidiuresis in river lamprey Lampetra fluviatilis, captured during upstream migration and maintained in fresh water. Although the renin-angiotensin hormonal system (RAS) is now recognized in jawless fishes, until this study, the role of homologous Ang II in L. fluviatilis kidney function had not been examined. This study provides the first evidence for an antidiuretic action of Ang II in cyclostomes and, in evolutionary terms, suggests a renal function for the RAS in early vertebrates.

  7. Metabolism of vasoactive peptides by human endothelial cells in culture. Angiotensin I converting enzyme (kininase II) and angiotensinase.

    PubMed

    Johnson, A R; Erdös, E G

    1977-04-01

    Cultured endothelial cells provide a model for the study of interactions of vasoactive peptides with endothelium. Endothelial cell cultured from veins of human umbilical cords contain both angiotensin I converting enzyme (kininase II) and angiotensinase activities. Intact monolayers of cells can both activate angiotensin I and inactivate bradykinin when the peptides are added to culture flasks in protein-free medium. Intact suspended cells or lysed cells convert angiotensin I to angiotensin II, inactivate bradykinin, and hydrolyze hippuryldiglycine to hippuric acid and diglycine. These actions are inhibited by SQ 20881, the specific inhibitor of converting enzyme. The kininase activity of endothelial cells was partially inhibited by antibody to human lung converting enzyme. Endothelial cells also inactivate longer analogs of bradykinin, such as kallidin, methionyl-lysyl bradykinin, and bradykinin coupled covalently to 500,000 mol wt dextran. The endothelial cells retained converting enzyme activity through four successive subcultures, indicating that the enzyme is synthesized by the cells surface, and it is apparently a marker for endothelial cells, since cultured human fibroblasts, smooth muscle cells, and baby hamster kidney cells do not have it. Endothelial cells also contain an aminopheptidase which hydrolyzes both angiotensin II and the synthetic substrate, alpha-L-aspartyl beta-naphthylamide. The angiotensinase activity increased when the cells were lysed, which suggests that the enzyme is localized within the cells, Hydrolysis of both alpha-L-aspartyl beta-naphthylamide and angiotensin II was inhibited by omicron-phenanthroline, indicating that the enzyme is an A-tipe anigotensinase.

  8. Angiotensin II, Aldosterone, and Anti-Inflammatory Lymphocytes: Interplay and Therapeutic Opportunities

    PubMed Central

    Kasal, Daniel Arthur B.; Schiffrin, Ernesto L.

    2012-01-01

    Inflammation is recognized as an important factor in the pathophysiology of hypertension, with the renin-angiotensin-aldosterone system (RAAS) playing a key role in the disease. Initially described because of its contribution to extracellular fluid and electrolyte homeostasis, the RAAS has been implicated in endothelial dysfunction, vascular remodeling, oxidative stress, proinflammatory cytokine production, and adhesion molecule synthesis by the vascular wall. Both angiotensin II and aldosterone are involved in these systemic effects, activating innate and adaptive immune responses. This paper highlights some aspects connecting RAAS to the hypertensive phenotype, based on experimental and clinical studies, with emphasis on new findings regarding the contribution of an increasingly studied population of T lymphocytes: the T-regulatory lymphocytes. These cells can suppress inflammation and may exert beneficial vascular effects in animal models of hypertension. PMID:22685633

  9. Increased angiotensin II contraction of the uterine artery at early gestation in a transgenic model of hypertensive pregnancy is reduced by inhibition of endocannabinoid hydrolysis.

    PubMed

    Pulgar, Victor M; Yamaleyeva, Liliya M; Varagic, Jasmina; McGee, Carolynne M; Bader, Michael; Dechend, Ralf; Howlett, Allyn C; Brosnihan, K Bridget

    2014-09-01

    Increased vascular sensitivity to angiotensin II (Ang II) is a marker of a hypertensive human pregnancy. Recent evidence of interactions between the renin-angiotensin system and the endocannabinoid system suggests that anandamide and 2-arachidonoylglycerol may modulate Ang II contraction. We hypothesized that these interactions may contribute to the enhanced vascular responses in hypertensive pregnancy. We studied Ang II contraction in isolated uterine artery (UA) at early gestation in a rat model that mimics many features of preeclampsia, the transgenic human angiotensinogen×human renin (TgA), and control Sprague-Dawley rats. We determined the role of the cannabinoid receptor 1 by blockade with SR171416A, and the contribution of anandamide and 2-arachidonoylglycerol degradation to Ang II contraction by inhibiting their hydrolyzing enzyme fatty acid amide hydrolase (with URB597) or monoacylglycerol lipase (with JZL184), respectively. TgA UA showed increased maximal contraction and sensitivity to Ang II that was inhibited by indomethacin. Fatty acid amide hydrolase blockade decreased Ang IIMAX in Sprague-Dawley UA, and decreased both Ang IIMAX and sensitivity in TgA UA. Monoacylglycerol lipase blockade had no effect on Sprague-Dawley UA and decreased Ang IIMAX and sensitivity in TgA UA. Blockade of the cannabinoid receptor 1 in TgA UA had no effect. Immunolocalization of fatty acid amide hydrolase and monoacylglycerol lipase showed a similar pattern between groups; fatty acid amide hydrolase predominantly localized in endothelium and monoacylglycerol lipase in smooth muscle cells. We demonstrated an increased Ang II contraction in TgA UA before initiation of the hypertensive phenotype. Anandamide and 2-arachidonoylglycerol reduced Ang II contraction in a cannabinoid receptor 1-independent manner. These renin-angiotensin system-endocannabinoid system interactions may contribute to the enhanced vascular reactivity in early stages of hypertensive pregnancy.

  10. Changes in glomerular hemodynamic response to angiotensin II after subacute renal denervation in rats.

    PubMed Central

    Tucker, B J; Mundy, C A; Maciejewski, A R; Printz, M P; Ziegler, M G; Pelayo, J C; Blantz, R C

    1986-01-01

    We examined the changes in glomerular hemodynamics produced by angiotensin II (AII) in both normal Munich-Wistar rats and rats which were unilaterally renal denervated (measured kidney) 4-6 d prior to the measurement periods. Measurements of glomerular dynamics were performed in a control period after plasma volume expansion and during infusion of 11 ng X 100 g body wt-1 X min-1 of AII. The glomerular hydrostatic pressure gradient increased from 38 +/- 1 to 49 +/- 1 mmHg in denervated rats compared with a lesser response in controls (from 39 +/- 1 to 45 +/- 1 mmHg, P less than 0.05). Single nephron plasma flow decreased from 213 +/- 17 to 87 +/- 4 nl X min-1 X g kidney wt (KW)-1 in denervated kidneys versus a more modest decrease in control kidneys (from 161 +/- 9 to 102 +/- 5 nl X min X gKW-1). These changes were due to a greater increase in both afferent and efferent arteriolar resistance after AII infusion in denervated compared with control kidneys. Glomerular AII receptor maximum binding was 1,196 +/- 267 fmol/mg protein in denervated kidneys compared with 612 +/- 89 fmol/mg protein (P less than 0.01) in controls with no change in receptor affinity. We conclude the subacute unilateral renal denervation results in renal vasodilation, denervation magnifies the vasoconstrictive effect of AII infusion on glomerular hemodynamics, and the observed increased response to AII after denervation is associated with increases in glomerular AII receptors. PMID:3745432

  11. Paradoxical role of angiotensin II type 2 receptors in resistance arteries of old rats

    PubMed Central

    Pinaud, Frédéric; Bocquet, Arnaud; Dumont, Odile; Retailleau, Kevin; Baufreton, Christophe; Andriantsitohaina, Ramaroson; Loufrani, Laurent; Henrion, Daniel

    2007-01-01

    The role of angiotensin II type 2 receptors (AT2R) remains a matter of controversy. Its vasodilatory and antitrophic properties are well accepted. Nevertheless, in hypertensive rats AT2R stimulation induces a vasoconstriction counteracting flow-mediated dilation (FMD). This contraction is reversed by hydralazine. As FMD is also decreased in aging, another risk factor for cardiovascular diseases, we hypothesized that AT2R function might be altered in old rats resistance arteries. Mesenteric resistance arteries (250 μm diameter) were isolated from old (24 months) and control (4 months) rats receiving hydralazine (16 mg/kg/day, 2 weeks) or water. FMD, NO-mediated dilation and eNOS expression were lower in old than in control rats. AT2R blockade improved FMD in old rats, suggesting that AT2R stimulation produced vasoconstriction. AT2R expression was higher in old rats and mainly located in the smooth muscle layer. In old rats AT2R stimulation induced endothelium-independent contraction, which was suppressed by the antioxydant Tempol. Reactive oxygen species (ROS) level was higher in old rats arteries than in controls. Hydralazine improved FMD and NO-dependent dilation in old rats without change in AT2R expression and location. In old rats treated with hydralazine ROS level was reduced in endothelial and smooth muscle cells and AT2R-dependent contraction was abolished. Thus, AT2R stimulation induced vasoconstriction through activation of ROS production, contributing to decrease FMD in old rats resistance arteries. Hydralazine suppressed AT2R-dependent ROS production and AT2R-dependent contraction, improving FMD. Importantly, endothelial alterations in aging were reversible. These findings are important to consider in the choice of vasoactive drugs in aging. PMID:17485601

  12. Physiological regulation of extracellular matrix collagen and elastin in the arterial wall of rats by noradrenergic tone and angiotensin II.

    PubMed

    Dab, Houcine; Kacem, Kamel; Hachani, Rafik; Dhaouadi, Nadra; Hodroj, Wassim; Sakly, Mohsen; Randon, Jacques; Bricca, Giampiero

    2012-03-01

    The interactions between the effects of the sympathetic nervous system (SNS) and angiotensin II (ANG II) on vascular extracellular matrix (ECM) synthesis were determined in rats. The mRNA and protein content of collagen I, collagen III and elastin in the abdominal aorta (AA) and femoral artery (FA) was investigated in Wistar-Kyoto rats treated for 5 weeks with guanethidine, a sympathoplegic, losartan, an ANG II AT1 receptor (AT1R) blocker, or both. The effects of noradrenaline (NE) and ANG II on collagen III and elastin mRNA, and the receptor involved, were tested in cultured vascular smooth muscle cells (VSMCs) in vitro. Guanethidine increased collagen types I and III and decreased elastin, while losartan had an opposite effect, although without effect on collagen III. The combination of treatments abrogated changes induced by simple treatment with collagen I and elastin, but increased collagen III mRNA in AA and not in FA. NE stimulated collagen III mRNA via β receptors and elastin via α1 and α2 receptors. ANG II stimulated collagen III but inhibited elastin mRNA via AT1R. Overall, SNS and ANG II exert opposite and antagonistic effects on major components of ECM in the vascular wall. This may be of relevance for the choice of a therapeutic strategy in vascular diseases.

  13. Luminal angiotensin II stimulates rat medullary thick ascending limb chloride transport in the presence of basolateral norepinephrine.

    PubMed

    Baum, Michel

    2016-02-15

    Angiotensin II (ANG II) is secreted by the proximal tubule resulting in a luminal concentration that is 100- to 1,000-fold greater than that in the blood. Luminal ANG II has been shown to stimulate sodium transport in the proximal tubule and distal nephron. Surprisingly, luminal ANG II inhibits NaCl transport in the medullary thick ascending limb (mTAL), a nephron segment responsible for a significant amount of NaCl absorption from the glomerular ultrafiltrate. We confirmed that addition of 10(-8) M ANG II to the lumen inhibited mTAL chloride transport (220 ± 19 to 165 ± 25 pmol·mm(-1)·min(-1), P < 0.01) and examined whether an interaction with basolateral norepinephrine existed to simulate the in vivo condition of an innervated tubule. We found that in the presence of a 10(-6) M norepinephrine bath, luminal ANG II stimulated mTAL chloride transport from 298 ± 18 to 364 ± 42 pmol·mm(-1)·min(-1) (P < 0.05). Stimulation of chloride transport by luminal ANG II was also observed with 10(-3) M bath dibutyryl cAMP in the bathing solution and bath isoproterenol. A bath of 10(-5) H-89 blocked the stimulation of chloride transport by norepinephrine and prevented the effect of luminal ANG II to either stimulate or inhibit chloride transport. Bath phentolamine, an α-adrenergic agonist, also prevented the decrease in mTAL chloride transport by luminal ANG II. Thus luminal ANG II increases chloride transport with basolateral norepinephrine; an effect likely mediated by stimulation of cAMP. Alpha-1 adrenergic stimulation prevents the inhibition of chloride transport by luminal ANG II.

  14. Effect of angiotensin II on proliferation and differentiation of mouse induced pluripotent stem cells into mesodermal progenitor cells

    SciTech Connect

    Ishizuka, Toshiaki; Goshima, Hazuki; Ozawa, Ayako; Watanabe, Yasuhiro

    2012-03-30

    Highlights: Black-Right-Pointing-Pointer Treatment with angiotensin II enhanced LIF-induced DNA synthesis of mouse iPS cells. Black-Right-Pointing-Pointer Angiotensin II may enhance the DNA synthesis via induction of superoxide. Black-Right-Pointing-Pointer Treatment with angiotensin II significantly increased JAK/STAT3 phosphorylation. Black-Right-Pointing-Pointer Angiotensin II enhanced differentiation into mesodermal progenitor cells. Black-Right-Pointing-Pointer Angiotensin II may enhance the differentiation via activation of p38 MAPK. -- Abstract: Previous studies suggest that angiotensin receptor stimulation may enhance not only proliferation but also differentiation of undifferentiated stem/progenitor cells. Therefore, in the present study, we determined the involvement of the angiotensin receptor in the proliferation and differentiation of mouse induced pluripotent stem (iPS) cells. Stimulation with angiotensin II (Ang II) significantly increased DNA synthesis in mouse iPS cells cultured in a medium with leukemia inhibitory factor (LIF). Pretreatment of the cells with either candesartan (a selective Ang II type 1 receptor [AT{sub 1}R] antagonist) or Tempol (a cell-permeable superoxide scavenger) significantly inhibited Ang II-induced DNA synthesis. Treatment with Ang II significantly increased JAK/STAT3 phosphorylation. Pretreatment with candesartan significantly inhibited Ang II- induced JAK/STAT3 phosphorylation. In contrast, induction of mouse iPS cell differentiation into Flk-1-positive mesodermal progenitor cells was performed in type IV collagen (Col IV)- coated dishes in a differentiation medium without LIF. When Col IV-exposed iPS cells were treated with Ang II for 5 days, the expression of Flk-1 was significantly increased compared with that in the cells treated with the vehicle alone. Pretreatment of the cells with both candesartan and SB203580 (a p38 MAPK inhibitor) significantly inhibited the Ang II- induced increase in Flk-1 expression

  15. Evidence for modulation of pericryptal sheath myofibroblasts in rat descending colon by Transforming Growth Factor β and Angiotensin II.

    PubMed Central

    Thiagarajah, Jay R; Griffiths, Nina M; Pedley, Kevin C; Naftalin, Richard J

    2002-01-01

    Background Absorption of water and Na+ in descending colonic crypts is dependent on the barrier function of the surrounding myofibroblastic pericryptal sheath. Here the effects of high and low Na+ diets and exposure to whole body ionising radiation on the growth and activation of the descending colonic pericryptal myofibroblasts are evaluated. In addition the effect of a post-irradiation treatment with the angiotensin converting enzyme inhibitor Captopril was investigated. Methods The levels of Angiotensin II type 1 receptor (AT1), ACE, collagen type IV, transforming growth factor-β type 1 receptor (TGF-βR1), OB cadherin and α-smooth muscle actin in both descending colon and caecum were evaluated, using immunocytochemistry and confocal microscopy, in rats fed on high and low Na+ diets (LS). These parameters were also determined during 3 months post-irradiation with 8Gy from a 60Co source in the presence and absence of the angiotensin converting enzyme inhibitor, Captopril. Results Increases in AT1 receptor (135.6% ± 18.3, P < 0.001); ACE (70.1% ± 13.1, P < 0.001); collagen type IV (49.6% ± 15.3, P < 0.001); TGF-β1 receptors (291.0% ± 26.5, P < 0.001); OB-cadherin (26.3% ± 13.8, P < 0.05) and α-smooth muscle actin (82.5% ± 12.4, P < 0.001) were observed in the pericryptal myofibroblasts of the descending colon after LS diet. There are also increases in AT1 receptor and TGF-β1 receptor, smooth muscle actin and collagen type IV after irradiation. Captopril reduced all these effects of irradiation on the pericryptal sheath and also decreased the amount of collagen and smooth muscle actin in control rats (P < 0.001). Conclusions These results demonstrate an activation of descending colonic myofibroblasts to trophic stimuli, or irradiation, which can be attenuated by Captopril, indicative of local trophic control by angiotensin II and TGF-β release. PMID:11872151

  16. Angiotensin II and FCCP mobilizes calcium from different intracellular pools in adrenal glomerulosa cells; analysis of calcium fluxes.

    PubMed

    Balla, T; Szebeny, M; Kanyar, B; Spät, A

    1985-08-01

    The aim of the present study was to examine the effect of angiotensin II on the different pools of exchangeable Ca2+ in isolated rat adrenal glomerulosa cells. On the basis of steady state analysis of 45Ca exchange curves at least three kinetically distinct Ca2+ compartments are present in these cells. The most rapidly exchangeable compartment was regarded as Ca2+ loosely bound to the glycocalyx and the other compartments were considered to be intracellular Ca2+ pools. The effect of angiotensin II on different intracellular compartments was examined by adding the hormone at different phases of Ca2+ washout. Angiotensin increased the rate of 45Ca efflux within 1.5 min when added at the beginning of the washout. This effect, however, could not be detected when the hormone was added at the 30th min of washout, indicating that at least one hormone sensitive pool had lost most of its radioactivity by this time. In contrast to angiotensin II, the mitochondrial uncoupler FCCP mobilized almost the same quantity of 45Ca irrespective of the time of its addition during the washout. This latter finding suggests that this presumably mitochondrial Ca2+ pool has a slow rate of exchange and thus differs from the pool initially mobilized by angiotensin II. The initial Ca2+ mobilizing effect of angiotensin II was also observed in a Ca2+-free media which contained EGTA, indicating that this effect is not triggered by increased Ca2+ influx. In the present study we demonstrate in the intact glomerulosa cell that angiotensin II mobilizes Ca2+ from an intracellular Ca2+ store which appears to be distinct from the FCCP-sensitive store.

  17. The effect of resveratrol on angiotensin II levels and the rate of transcription of its receptors in the rat cardiac hypertrophy model.

    PubMed

    Dorri Mashhadi, Fahimeh; Zavvar Reza, Javad; Jamhiri, Mohabbat; Hafizi, Zeinab; Zare Mehrjardi, Fatemeh; Safari, Fatemeh

    2017-03-01

    This study investigated the effect of resveratrol on serum and cardiac levels of angiotensin II and transcription of its main receptors following pressure overload induced-hypertrophy. Rats were divided into untreated (Hyp) and resveratrol treated hypertrophied groups (H + R). Intact animals served as the control (Ctl). Cardiac hypertrophy was induced by abdominal aortic banding. Blood pressure (BP) was recorded via left carotid artery cannula. Fibrosis was confirmed by Masson trichrome staining. Angiotensin II level was measured using an ELIZA test. Gene expression was assessed by a real time PCR (RT-PCR) technique. We observed that in the H + R group BP and heart weight/body weight were decreased significantly (p < 0.001, p < 0.05, respectively vs Hyp). The cardiac levels of angiotensin II and AT1a mRNA were increased in the Hyp group (p < 0.01 vs Ctl). In the H + R group the AT1a mRNA level was decreased significantly (p < 0.05 vs Hyp). It could be concluded that resveratrol protects the heart against hypertrophy progression in part by affecting cardiac AT1a transcription.

  18. Solving the cardiac hypertrophy riddle: The angiotensin II-mechanical stress connection.

    PubMed

    Zablocki, Daniela; Sadoshima, Junichi

    2013-11-08

    A series of studies conducted 20 years ago, documenting the cardiac hypertrophy phenotype and its underlying signaling mechanism induced by angiotensin II (Ang II) and mechanical stress, showed a remarkable similarity between the effect of the Gαq agonist and that of mechanical forces on cardiac hypertrophy. Subsequent studies confirmed the involvement of autocrine/paracrine mechanisms, including stretch-induced release of Ang II in load-induced cardiac hypertrophy. Recent studies showed that the Ang II type 1 (AT1) receptor is also directly activated by mechanical forces, suggesting that AT1 receptors play an important role in mediating load-induced cardiac hypertrophy through both ligand- and mechanical stress-dependent mechanisms.

  19. Pitting type of pretibial edema in a patient with silent thyroiditis successfully treated by angiotensin ii receptor blockade

    PubMed Central

    Kazama, Itsuro; Mori, Yoko; Baba, Asuka; Nakajima, Toshiyuki

    2014-01-01

    Patient: Female, 56 Final Diagnosis: Thyroiditis – silent Symptoms: Palpitations • pretibial pitting edema • short of breath • sweating Medication: — Clinical Procedure: — Specialty: Endocrinology and Metabolic Objective: Unknown etiology Background: Hyper- or hypothyroidism sometimes causes pretibial myxedema characterized by non-pitting infiltration of a proteinaceous ground substance. However, in those patients, the “pitting” type of pretibial edema as a result of increased sodium and fluid retention or vascular hyper-permeability rarely occurs, except in cases complicated by heart failures due to severe cardiomyopathy or pulmonary hypertension. Case Report: A 56-year-old woman developed bilateral pretibial pitting edema, followed by occasional sweating, palpitations, and shortness of breath, which persisted for more than 2 months. The diagnosis of hyperthyroidism due to silent thyroiditis was supported by elevated levels of free thyroxine (T4) and triiodothyronine (T3), with a marked decrease in thyroid-stimulating hormone (TSH), and the negative results for TSH receptor antibodies with typical findings of destructive thyrotoxicosis. Despite her “pitting” type of pretibial edema, a chest radio-graph demonstrated the absence of cardiomyopathy or congestive heart failure. Oral administration of angiotensin II receptor blocker (ARB) was initiated for her systolic hypertension, with a relatively higher elevation of plasma renin activity compared to that of the aldosterone level. Although the symptoms characteristic to hyperthyroidism, such as increased sweating, palpitations and shortness of breath, slowly improved with a spontaneous resolution of the disease, ARB quickly resolved the pretibial pitting edema shortly after the administration.. Conclusions: In this case, increased activity of the renin-angiotensin-aldosterone system stimulated by thyroid hormone was likely responsible for the patient’s pitting type of edema. The pharmacological

  20. Angiotensin II and renal prostaglandin release in the dog. Interactions in controlling renal blood flow and glomerular filtration rate.

    PubMed

    Bugge, J F; Stokke, E S

    1994-04-01

    The relationship between angiotensin II and renal prostaglandins, and their interactions in controlling renal blood flow (RBF) and glomerular filtration rate (GFR) were investigated in 18 anaesthetized dogs with acutely denervated kidneys. Intrarenal angiotensin II infusion increased renal PGE2 release (veno-arterial concentration difference times renal plasma flow) from 1.7 +/- 0.9 to 9.1 +/- 0.4 and 6-keto-PGF1 alpha release from 0.1 +/- 0.1 to 5.3 +/- 2.1 pmol min-1. An angiotensin II induced reduction in RBF of 20% did not measurably change GFR whereas a 30% reduction reduced GFR by 18 +/- 8%. Blockade of prostaglandin synthesis approximately doubled the vasoconstrictory action of angiotensin II, and all reductions in RBF were accompanied by parallel reductions in GFR. When prostaglandin release was stimulated by infusion of arachidonic acid (46.8 +/- 13.3 and 15.9 +/- 5.4 pmol min-1 for PGE2, and 6-keto-PGF1 alpha, respectively), angiotensin II did not change prostaglandin release, but had similar effects on the relationship between RBF and GFR as during control. In an ureteral occlusion model with stopped glomerular filtration measurements of ureteral pressure and intrarenal venous pressure permitted calculations of afferent and efferent vascular resistances. Until RBF was reduced by 25-30% angiotensin II increased both afferent and efferent resistances almost equally, keeping the ureteral pressure constant. At greater reductions in RBF, afferent resistance increased more than the efferent leading to reductions in ureteral pressure. This pattern was not changed by blockade of prostaglandin synthesis indicating no influence of prostaglandins on the distribution of afferent and efferent vascular resistances during angiotensin II infusion. In this ureteral occlusion model glomerular effects of angiotensin II will not be detected, and it might well be that the shift from an effect predominantly on RBF to a combined effect on both RBF and GFR induced by inhibition

  1. Treatment with Salvianolic Acid B restores endothelial function in angiotensin II-induced hypertensive mice.

    PubMed

    Ling, Wei Chih; Liu, Jian; Lau, Chi Wai; Murugan, Dharmani Devi; Mustafa, Mohd Rais; Huang, Yu

    2017-04-07

    Salvianolic acid B (Sal B) is one of the most abundant phenolic acids derived from the root of Danshen with potent anti-oxidative properties. The present study examined the vasoprotective effect of Sal B in hypertensive mice induced by angiotensin II (Ang II). Sal B (25 mg/kg/day) was administered via oral gavage for 11 days to Ang II (1.2 mg/kg/day)-infused C57BL/6J mice (8-10 weeks old). The vascular reactivity (both endothelium-dependent relaxations and contractions) in mouse arteries was examined by wire myography. The production of reactive oxygen species (ROS), protein level and localization of angiotensin AT1 receptors and the proteins involved in ROS formation were evaluated using dihydroethidium (DHE) fluorescence, lucigenin-enhanced chemiluminescence, immunohistochemistry and Western blotting, respectively. The changes of ROS generating proteins were also assessed in vitro in human umbilical vein endothelial cells (HUVECs) exposed to Ang II with and without co-treatment with Sal B (0.1 - 10 nM). Oral administration of Sal B reversed the Ang II-induced elevation of arterial systolic blood pressure in mice, augmented the impaired endothelium-dependent relaxations and attenuated the exaggerated endothelium-dependent contractions in both aortas and renal arteries of Ang II-infused mice. In addition, Sal B treatment normalized the elevated levels of AT1 receptors, NADPH oxidase subunits (NOx-2 and NOx-4) and nitrotyrosine in arteries of Ang II-infused mice or in Ang II-treated HUVECs. In summary, the present study provided additional evidence demonstrating that Sal B treatment for 11 days reverses the impaired endothelial function and with a marked inhibition of AT1 receptor-dependent vascular oxidative stress. This vasoprotective and anti-oxidative action of Sal B most likely contributes to the anti-hypertensive action of the plant-derived compound.

  2. Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

    SciTech Connect

    Kang, Yu-Ming; Zhang, Dong-Mei; Yu, Xiao-Jing; Yang, Qing; Qi, Jie; Su, Qing; Suo, Yu-Ping; Yue, Li-Ying; Zhu, Guo-Qing; Qin, Da-Nian

    2014-02-01

    The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy. - Highlights: • Chronic ANG II infusion results in sympathetic hyperactivity and cardiac hypertrophy. • PVN inhibition of ACE

  3. Effect of hepatocyte growth factor and angiotensin II on rat cardiomyocyte hypertrophy

    PubMed Central

    Chen, Ai-Lan; Ou, Cai-Wen; He, Zhao-Chu; Liu, Qi-Cai; Dong, Qi; Chen, Min-Sheng

    2012-01-01

    Angiotensin II (Ang II) plays an important role in cardiomyocyte hypertrophy. The combined effect of hepatocyte growth factor (HGF) and Ang II on cardiomyocytes is unknown. The present study was designed to determine the effect of HGF on cardiomyocyte hypertrophy and to explore the combined effect of HGF and Ang II on cardiomyocyte hypertrophy. Primary cardiomyocytes were isolated from neonatal rat hearts and cultured in vitro. Cells were treated with Ang II (1 µM) alone, HGF (10 ng/mL) alone, and Ang II (1 µM) plus HGF (10 ng/mL) for 24, 48, and 72 h. The amount of [3H]-leucine incorporation was then measured to evaluate protein synthesis. The mRNA levels of β-myosin heavy chain and atrial natriuretic factor were determined by real-time PCR to evaluate the presence of fetal phenotypes of gene expression. The cell size of cardiomyocytes was also studied. Ang II (1 µM) increased cardiomyocyte hypertrophy. Similar to Ang II, treatment with 1 µM HGF promoted cardiomyocyte hypertrophy. Moreover, the combination of 1 µM Ang II and 10 ng/mL HGF clearly induced a combined pro-hypertrophy effect on cardiomyocytes. The present study demonstrates for the first time a novel, combined effect of HGF and Ang II in promoting cardiomyocyte hypertrophy. PMID:23044624

  4. A peptide vaccine targeting angiotensin II attenuates the cardiac dysfunction induced by myocardial infarction

    PubMed Central

    Watanabe, Ryo; Suzuki, Jun-ichi; Wakayama, Kouji; Maejima, Yasuhiro; Shimamura, Munehisa; Koriyama, Hiroshi; Nakagami, Hironori; Kumagai, Hidetoshi; Ikeda, Yuichi; Akazawa, Hiroshi; Morishita, Ryuichi; Komuro, Issei; Isobe, Mitsuaki

    2017-01-01

    A peptide vaccine targeting angiotensin II (Ang II) was recently developed as a novel treatment for hypertension to resolve the problem of noncompliance with pharmacotherapy. Ang II plays a crucial role in the pathogenesis of cardiac remodeling after myocardial infarction (MI), which causes heart failure. In the present study, we examined whether the Ang II vaccine is effective in preventing heart failure. The injection of the Ang II vaccine in a rat model of MI attenuated cardiac dysfunction in association with an elevation in the serum anti-Ang II antibody titer. Furthermore, any detrimental effects of the Ang II vaccine were not observed in the rats that underwent sham operations. Treatment with immunized serum from Ang II vaccine-injected rats significantly suppressed post-MI cardiac dysfunction in MI rats and Ang II-induced remodeling-associated signaling in cardiac fibroblasts. Thus, our present study demonstrates that the Ang II vaccine may provide a promising novel therapeutic strategy for preventing heart failure. PMID:28266578

  5. Sex differences in angiotensin II responses contribute to a differential regulation of cox-mediated vascular dysfunction during aging.

    PubMed

    Costa, Gustavo; Garabito, Manel; Jiménez-Altayó, Francesc; Onetti, Yara; Sabate, Manel; Vila, Elisabet; Dantas, Ana Paula

    2016-12-01

    Aging is a cardiovascular risk factor partially related to activation of the Renin-Angiotensin System (RAS). RAS activation is also influenced by sex. In this regard, our study aims to determine whether sex-associated differences in RAS contribute to a differential regulation of vascular aging and associated dysfunction. Male and female outbreed CD-1 mice were studied at 3 and 12months of age (M). Contribution of RAS was determined by treating mice from 3M to 12M with the AngII type 1 receptor blocker losartan (0.6g/L in the drinking water). At 12M, contractions to AngII were higher in males compared to females (P<0.05). This effect was paralleled by a decrease in AngII type 2 receptors in 12M males. Aging also diminished ACh relaxation in males, but did not modify female responses. Treatment of aortas with indomethacin (10μM) restored the impaired endothelium-dependent relaxation in 12M males, suggesting an increase of cyclooxygenase (COX)-derived vasoconstrictors in aged males. Chronic treatment of mice with losartan also improved endothelium-dependent relaxation. Besides, losartan significantly decreased COX-2 expression and activity in 12M male, with a minor effect in aged females. Aging increases AngII contraction and induces endothelial dysfunction differently in males and females. In aged males, RAS contributed to increased COX-2 expression and activity, which in turn may lead to vascular dysfunction.

  6. Role of connective tissue growth factor in vascular and renal damage associated with hypertension in rats. Interactions with angiotensin II.

    PubMed

    de las Heras, Natalia; Ruiz-Ortega, Marta; Rupérez, Mónica; Sanz-Rosa, David; Miana, María; Aragoncillo, Paloma; Mezzano, Sergio; Lahera, Vicente; Egido, Jesus; Cachofeiro, Victoria

    2006-12-01

    We have evaluated the role of connective tissue growth factor (CTGF) in vascular and renal damage associated with hypertension and possible interactions with angiotensin II (Ang II). Spontaneously hypertensive rats (SHR) were treated with either the Ang II receptor antagonist candesartan (C;2 mg/Kg(-1)/day(-1)) or antihypertensive triple therapy (TT; in mg/Kg(-1)/day(-1);20 hydralazine +7 hydrochlorothiazide +0.15 reserpine) for 10 weeks. Wistar Kyoto rats were used as a normotensive control group. Hypertension was associated with an increase in aortic media area, media-to-lumen ratio and collagen density. Kidneys from SHR showed minimum renal alterations. Aorta and renal gene expression and immunostaining of CTGF were higher in SHR. Candesartan decreased arterial pressure, aortic media area, media-to-lumen ratio and collagen density. However, although arterial pressure decrease was comparable for both treatments, TT partially reduced these parameters. Candesartan-treated rats showed lower levels of vascular CTGF expression, aortic media area, media-to-lumen ratio and collagen density than TT-treated animals. Treatments improve renal damage and reduce renal gene expression and CTGF immunostaining in SHR in a similar manner. The results show that vascular and renal damage is associated with stimulation of CTGF gene and protein content. These results also might suggest that CTGF could be one downstream mediator of Ang II in hypertension-associated organ damage in SHR.

  7. Cross-talk related to insulin and angiotensin II binding on myocardial remodelling in diabetic rat hearts.

    PubMed

    Maharsy, Wael M; Kadi, Lina N; Issa, Nahla G; Bitar, Khalil M; Der-Boghossian, Asdghig H; Abrahamian, Roy; Bikhazi, Anwar B

    2007-06-01

    This study focused on the regulation and affinity modulation of angiotensin II (Ang II) binding to its receptor subtypes (AT(1)- and AT(2)-receptor) in the coronary endothelium (CE) and cardiomyocytes (CM) of Sprague-Dawley male rats in normal (N), normal treated with losartan (NL), streptozotocin-induced diabetic (D), insulin-treated diabetic (DI), losartan-treated diabetic (DL), and diabetic co-treated with insulin and losartan (DIL). Heart perfusion was used to estimate Ang II binding affinity (tau=1/k-(n)) to its receptor subtypes on CE and CM. Diabetes decreased tau value on CE and increased it on CM as compared to normal. In DL group, the tau value decreased on CE but was normalised on CM. Insulin treatment alone (DI) or with losartan (DIL) restored t to normal on both CE and CM. Western blot results for AT(1)-receptor density showed an increase in diabetics compared to normal with no normalising effect with insulin treatment. The AT(1)-receptor density was normalised in the diabetic groups treated with losartan +/- insulin. Results for AT(2)-receptor regulation revealed a significant difference between untreated (D) and losartan-treated (DL, DIL) diabetic groups. All of these data show the interrelated pathway and cross-talk between insulin and Ang II system indicating potentially negative effects on the diabetic heart.

  8. Effect of angiotensin II on some behavioral and neurochemical measures of the central serotonine system.

    PubMed

    Braszko, J J; Majewski, K; Maciejewski, A; Wisniewski, K

    1985-01-01

    The effects of angiotensin II (AII) given intracerebroventricularly (icv.) on behaviors controlled by central serotonine (5-HT) and on some neurochemical measures of central 5-HT function have been investigated in rats. AII (0.1 and 0.5 micrograms) increased the 5-HT (20 micrograms, icv.) and L-tryptophan (200 mg/kg, ip.) induced hyposensitivity to painful electric stimuli delivered to the animals feet. Also AII (0.5 micrograms) intensified yawning, a 5-HT dependent behavior. This effect was decreased or abolished, respectively, by mianserin (3 mg/kg, i.p.) or cyproheptadine (1 mg/kg, i.p.), the 5-HT receptors blockers. AII, however, influenced neither the slight hyposensitivity of rats to electric current caused by 5-hydroxytryptophane (5-HTP, 12.5 and 25 mg/kg, ip.) nor the number of 'Wet-Dog' shakes evoked by 5-HTP (100 mg/kg, i.p.). Also, the peptide did change the rate of 5-HTP accumulation in brain measured after pretreatment of the animals with L-tryptophan (200 and 500 mg/kg, i.p.) preceded by the inhibition of central aromatic amino acid decarboxylase. In vitro AII (10(-5) - 10(-9) mol/l) did not affect release and only slightly increased uptake of 3H-5-HT by blood platelets. The data indicate that AII stimulates central 5-HT neurotransmission and that this action does not result from the peptide interference with the synthesis, release and uptake of 5-HT.

  9. Evidence to Consider Angiotensin II Receptor Blockers for the Treatment of Early Alzheimer's Disease.

    PubMed

    Saavedra, Juan M

    2016-03-01

    Alzheimer's disease is the most frequent type of dementia and diagnosed late in the progression of the illness when irreversible brain tissue loss has already occurred. For this reason, treatments have been ineffective. It is imperative to find novel therapies ameliorating modifiable risk factors (hypertension, stroke, diabetes, chronic kidney disease, and traumatic brain injury) and effective against early pathogenic mechanisms including alterations in cerebral blood flow leading to poor oxygenation and decreased access to nutrients, impaired glucose metabolism, chronic inflammation, and glutamate excitotoxicity. Angiotensin II receptor blockers (ARBs) fulfill these requirements. ARBs are directly neuroprotective against early injury factors in neuronal, astrocyte, microglia, and cerebrovascular endothelial cell cultures. ARBs protect cerebral blood flow and reduce injury to the blood brain barrier and neurological and cognitive loss in animal models of brain ischemia, traumatic brain injury, and Alzheimer's disease. These compounds are clinically effective against major risk factors for Alzheimer's disease: hypertension, stroke, chronic kidney disease, diabetes and metabolic syndrome, and ameliorate age-dependent cognitive loss. Controlled studies on hypertensive patients, open trials, case reports, and database meta-analysis indicate significant therapeutic effects of ARBs in Alzheimer's disease. ARBs are safe compounds, widely used to treat cardiovascular and metabolic disorders in humans, and although they reduce hypertension, they do not affect blood pressure in normotensive individuals. Overall, there is sufficient evidence to consider long-term controlled clinical studies with ARBs in patients suffering from established risk factors, in patients with early cognitive loss, or in normal individuals when reliable biomarkers of Alzheimer's disease risk are identified.

  10. Concentration-dependent mode of interaction of angiotensin II receptor blockers with uric acid transporter.

    PubMed

    Iwanaga, Takashi; Sato, Masanobu; Maeda, Tomoji; Ogihara, Toshio; Tamai, Ikumi

    2007-01-01

    Serum uric acid (SUA) is currently recognized as a risk factor for cardiovascular disease. It has been reported that an angiotensin II receptor blocker (ARB), losartan, decreases SUA level, whereas other ARBs, such as candesartan, have no lowering effect. Because the renal uric acid transporter (URAT1) is an important factor controlling the SUA level, we examined the involvement of URAT1 in those differential effects of various ARBs on SUA level at clinically relevant concentrations. This study was done by using URAT1-expressing Xenopus oocytes. Losartan, pratosartan, and telmisartan exhibited cis-inhibitory effects on the uptake of uric acid by URAT1, whereas at higher concentrations, only telmisartan did, and these ARBs reduced the uptake in competitive inhibition kinetics. On the other hand, candesartan, EXP3174 [2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yI)methyl]imidazole-5-carboxylic acid] (a major metabolite of losartan), olmesartan, and valsartan were not inhibitory. Preloading of those ARBs in the oocytes enhanced the URAT1-mediated uric acid uptake, showing a trans-stimulatory effect. The present study is a first demonstration of the differential effects of ARBs on URAT1 that some ARBs are both cis-inhibitory and trans-stimulatory, depending on concentration, whereas others exhibit either a trans-stimulatory or cis-inhibitory effect alone, which could explain the clinically observed differential effects of ARBs on SUA level. Furthermore, it was found that such differential effects of ARBs on URAT1 could be predicted from the partial chemical structures of ARBs, which will be useful information for the appropriate use and development of ARBs without an increase of SUA.

  11. Imbalance of angiotensin type 1 receptor and angiotensin II type 2 receptor in the rostral ventrolateral medulla: potential mechanism for sympathetic overactivity in heart failure.

    PubMed

    Gao, Lie; Wang, Wei-Zhong; Wang, Wei; Zucker, Irving H

    2008-10-01

    Upregulation of angiotensin II type 1 receptors (AT(1)R) in the rostral ventrolateral medulla (RVLM) contributes to the sympathoexcitation in the chronic heart failure (CHF). However, the role of angiotensin II type 2 receptor (AT(2)R) is not clear. In this study, we measured AT(1)R and AT(2)R protein expression in the RVLM and determined their effects on renal sympathetic nerve activity, blood pressure, and heart rate in anesthetized sham and CHF rats. We found that (1) although AT(1)R expression in the RVLM was upregulated, the AT(2)R was significantly downregulated (CHF: 0.06+/-0.02 versus sham: 0.15+/-0.02, P<0.05); (2) simultaneously stimulating RVLM AT(1)R and AT(2)R by angiotensin II evoked sympathoexcitation, hypertension, and tachycardia in both sham and CHF rats with greater responses in CHF; (3) stimulating RVLM AT1R with angiotensin II plus the specific AT(2)R antagonist PD123319 induced a larger sympathoexcitatory response than simultaneously stimulating AT(1)R and AT(2)R in sham rats, but not in CHF; (4) activating RVLM AT(2)R with CGP42112 induced a sympathoinhibition, hypotension, and bradycardia only in sham rats (renal sympathetic nerve activity: 36.4+/-5.1% of baseline versus 102+/-3.9% of baseline in artificial cerebrospinal fluid, P<0.05); (5) pretreatment with 5,8,11,14-eicosatetraynoic acid, a general inhibitor of arachidonic acid metabolism, into the RVLM attenuates the CGP42112-induced sympathoinhibition. These results suggest that AT(2)R in the RVLM exhibits an inhibitory effect on sympathetic outflow, which is, at least partially, mediated by an arachidonic acid metabolic pathway. These data implicate a downregulation in the AT(2)R as a contributory factor in the sympathoexcitation in CHF.

  12. Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy

    PubMed Central

    Yoon, Hye Eun; Ghee, Jung Yeon; Piao, ShangGuo; Song, Ji-Hyun; Han, Dong He; Kim, Sol; Ohashi, Naro; Kobori, Hiroyuki; Kuro-o, Makoto; Yang, Chul Woo

    2011-01-01

    Background. The Klotho gene plays a role in suppressing ageing-related disorders. It is suggested that activation of renin–angiotensin system (RAS) or oxidative stress suppresses Klotho in the kidney. This study evaluated the association between Klotho expression and RAS in cyclosporine (CsA)-induced renal injury. Methods. Chronic CsA nephropathy was induced by administering CsA (30 mg/kg) to mice on a low-salt diet (LSD) for 4 weeks. A normal-salt diet (NSD) was used as the control. Reverse transcription–polymerase chain reaction, western blot and immunohistochemistry were performed for Klotho and intrarenal RAS activity was measured using immunohistochemistry for angiotensinogen and renin. Oxidative stress was measured with urinary excretion of 8-hydroxy-2′-deoxyguanosine (8-OHdG). Results. CsA treatment decreased Klotho mRNA and protein in mouse kidney in a dose-dependent and time-dependent manner, but a concurrent treatment with losartan, an angiotensin II type 1 (AT1) receptor blocker, reversed the decrease in Klotho expression with histological improvement. This finding was more marked in the LSD than the NSD. Klotho expression was correlated with angiotensinogen and renin expression, tubulointerstitial fibrosis score and urinary 8-OHdG excretion. Conclusions. Angiotensin II may play a pivotal role in regulating Klotho expression in CsA-induced renal injury. AT1 receptor blocker may inhibit the ageing process by decreasing oxidative stress caused by CsA. PMID:20813770

  13. Sulforaphane Prevents Angiotensin II-Induced Testicular Cell Death via Activation of NRF2

    PubMed Central

    Wang, Yonggang; Xin, Ying; Tan, Yi

    2017-01-01

    Although angiotensin II (Ang II) was reported to facilitate sperm motility and intratesticular sperm transport, recent findings shed light on the efficacy of Ang II in stimulating inflammatory events in testicular peritubular cells, effect of which may play a role in male infertility. It is still unknown whether Ang II can induce testicular apoptotic cell death, which may be a more direct action of Ang II in male infertility. Therefore, the present study aims to determine whether Ang II can induce testicular apoptotic cell death and whether this action can be prevented by sulforaphane (SFN) via activating nuclear factor (erythroid-derived 2)-like 2 (NRF2), the governor of antioxidant-redox signalling. Eight-week-old male C57BL/6J wild type (WT) and Nrf2 gene knockout mice were treated with Ang II, in the presence or absence of SFN. In WT mice, SFN activated testicular NRF2 expression and function, along with a marked attenuation in Ang II-induced testicular oxidative stress, inflammation, endoplasmic reticulum stress, and apoptotic cell death. Deletion of the Nrf2 gene led to a complete abolishment of these efficacies of SFN. The present study indicated that Ang II may result in testicular apoptotic cell death, which can be prevented by SFN via the activation of NRF2. PMID:28191275

  14. Regulation of ERK5 by insulin and angiotensin-II in vascular smooth muscle cells

    SciTech Connect

    Sharma, Girish; Goalstone, Marc Lee; E-mail: Marc.Goalstone@uchsc.edu

    2007-03-23

    ERK5 is involved in proliferation of vascular smooth muscle cells (VSMC). The proliferative actions of insulin and angiotensin-II (A-II) in VSMC are mediated in part by ERK1/2. We hypothesized that insulin and A-II also regulate ERK5 activity in VSMC. Acute treatment (<60 min) with insulin or A-II increased phosphorylation of ERK1/2 at 15 min and ERK5 at 5 min. Chronic treatment ({<=}8 h) with insulin increased ERK1/2 phosphorylation by 4 h and ERK5 by 8 h. A-II-stimulated phosphorylation of ERK1/2 by 8 h and ERK5 by 4 h. The EC{sub 50} for insulin treatment effecting ERK1/2 and ERK5 phosphorylation was 1.5 and 0.1 nM, whereas the EC{sub 50} for A-II was 2 nM, each. Insulin plus A-II induced an additive effect only on ERK5 phosphorylation. Inhibition of insulin- and A-II-stimulated phosphorylation of ERK5 and ERK1/2 by PD98059 and Wortmannin exhibited differential and time-dependent effects. Taken together, these data indicate that insulin and A-II regulate the activity of ERK5, but different from that seen for ERK1/2.

  15. Effect of angiotensin II on rhythmic per2 expression in the suprachiasmatic nucleus and heart and daily rhythm of activity in Wistar rats.

    PubMed

    Herichová, Iveta; Šoltésová, Dorota; Szántóová, Kristína; Mravec, Boris; Neupauerová, Denisa; Veselá, Anna; Zeman, Michal

    2013-09-10

    Endogenous daily rhythms are generated by the hierarchically organized circadian system predominantly synchronized by the external light (L): dark (D) cycle. During recent years several humoral signals have been found to influence the generation and manifestation of daily rhythm. Since most studies have been performed under in vitro conditions, the mechanisms employed under in vivo conditions need to be investigated. Our study focused on angiotensin II (angII)-mediated regulation of Per2 expression in the suprachiasmatic nuclei (SCN) and heart and spontaneous locomotor activity in Wistar rats under synchronized conditions. Angiotensin II was infused (100ng/kg/min) via subcutaneously implanted osmotic minipumps for 7 or 28days. Samples were taken in 4-h intervals during a 24hcycle and after a light pulse applied in the first and second part of the dark phase. Gene expression was measured using real time PCR. Locomotor activity was monitored using an infrared camera with a remote control installed in the animal facility. Seven days of angII infusion caused an increase in blood pressure and heart/body weight index and 28days of angII infusion also increased water intake in comparison with controls. We observed a distinct daily rhythm in Per2 expression in the SCN and heart of control rats and infused rats. Seven days of angII infusion did not influence Per2 expression in the heart. 28days of angII treatment caused significant phase advance and a decrease in nighttime expression of Per2 and influenced expression of clock controlled genes Rev-erb alpha and Dbp in the heart compared to the control. Four weeks of angII infusion decreased the responsiveness of Per2 expression in the SCN to a light pulse at the end of the dark phase of the 24hcycle. Expression of mRNA coding angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) showed a daily rhythm in the heart of control rats. Four weeks of angII infusion caused a decrease in amplitude of rhythmic

  16. Angiotensin II: a candidate for an aldosterone-independent mediator of potassium preservation during volume depletion.

    PubMed

    Hoover, Robert S

    2011-02-01

    Two different stimulators of aldosterone secretion, high-potassium diet and low-sodium diet, have disparate effects on potassium secretion in the distal nephron. The mechanism by which the kidney preserves potassium in the face of a high-aldosterone, volume-depleted state has engendered much thought. Yue et al. now propose that angiotensin II inhibits the renal outer medullary potassium channel (ROMK1) through stimulation of the protein tyrosine kinase c-Src, perhaps acting as a signal to differentiate volume depletion from a high-potassium diet.

  17. Reflex limb dilatation following norepinephrine and angiotensin II in conscious dogs

    NASA Technical Reports Server (NTRS)

    Vatner, S. F.; Mcritchie, R. J.

    1976-01-01

    The extent to which norepinephrine (NE) and angiotensin II (AN) constrict the mesenteric, renal, and iliac beds in conscious dogs is evaluated with a view to elicit opposing reflex actions tempering the vasoconstriction in the limb of the animals tested. The afferent and efferent mechanisms mediating this reflex are analyzed. It is shown that intravenous NE and AN cause striking reflex iliac dilatation in the limb of the conscious dog. The afferent arc of this reflex involves both arterial baroreceptor and vagal path-ways, whereas the efferent mechanism involves an interaction of alpha-adrenergic and histaminergic receptors.

  18. Tea polyphenols regulate nicotinamide adenine dinucleotide phosphate oxidase subunit expression and ameliorate angiotensin II-induced hyperpermeability in endothelial cells.

    PubMed

    Ying, Chen-Jiang; Xu, Jin-Wen; Ikeda, Katsumi; Takahashi, Kyoko; Nara, Yasuo; Yamori, Yukio

    2003-10-01

    Out-of-control reactive oxygen species (ROS) signaling is one of the key events in the pathogenesis of endothelial dysfunction and essential hypertension. We observed that tea polyphenols decreased the production of ROS via regulation of the protein expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in bovine carotid artery endothelial cells (BCAECs). Both green tea polyphenols (GTP) and black tea polyphenols (BTP) down-regulated the expression of NADPH oxidase subunits p22phox and p67phox while up-regulating catalase expression (p < 0.05, respectively). Pre-treatment with GTP or BTP for 24 h significantly decreased the superoxide anion level (p < 0.05) and permeable fluorescence intensities in Ang II-stimulated BCAECs. A decrease in cell permeability was also observed by pre-treatment with diphenylene iodonium chloride (DPI) or vitamin E (p < 0.05, respectively). The result demonstrates that tea polyphenols alleviate angiotensin (Ang) II-induced hyperpermeability mainly by decreasing ROS production. Our results suggest that tea polyphenols regulate ROS-related protein expression and may be beneficial in preventing endothelial cell dysfunction and development of cardiovascular diseases, including hypertension.

  19. 3,3',4',5,7-Pentamethylquercetin reduces angiotensin II-induced cardiac hypertrophy and apoptosis in rats.

    PubMed

    Mao, Zhangfan; Liang, Yuanxin; Du, Xinling; Sun, Zongquan

    2009-09-01

    Quercetin has been shown to possess beneficial pharmacological properties in treatment of heart disease, but lack of stability and bioavailability limits its clinical use. In this study, we investigated for the first time the effect of a methylated form of quercetin, 3,3',4',5,7-pentamethylquercetin (PMQ), on myocardial protection in rats. Angiotensin II was delivered to Sprague-Dawley rats subcutaneously, while PMQ (5 mg/kg) was administered by oral gavage; blood pressure was monitored daily. The production of NADPH oxidase was measured, and cardiac hypertrophy and apoptosis were detected. The results revealed that PMQ could downregulate the expression of the NADPH oxidase gene and reduce angiotensin II- induced cardiac hypertrophy and apoptosis in rats. Therefore, we believe that PMQ showed beneficial effects on myocardium in angiotensin II-administered rats, and its potential to be used for treatment of cardiovascular disease deserves further attention.

  20. The role of mAKAPβ in the process of cardiomyocyte hypertrophy induced by angiotensin II.

    PubMed

    Guo, Huixin; Liu, Baoxin; Hou, Lei; The, Erlinda; Li, Gang; Wang, Dongzhi; Jie, Qiqiang; Che, Wenliang; Wei, Yidong

    2015-05-01

    Angiotensin II (AngII) is the central product of the renin-angiotensin system (RAS) and this octapeptide contributes to the pathophysiology of cardiac hypertrophy and remodeling. mAKAPβ is an A-kinase anchoring protein (AKAP) that has the function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. In this study, we aimed to investigate the role of mAKAPβ in AngII‑induced cardiomyocyte hypertrophy and the possible mechanisms involved. Cultured cardiomyocytes from neonatal rats were treated with AngII. Subsequently, the morphology of the cardiomyocytes was observed and the expression of mAKAPβ and cardiomyocyte hypertrophic markers was measured. mAKAPβ‑shRNA was constructed for RNA interference; the expression of mAKAPβ and hypertrophic markers, the cell surface area and the [3H]Leucine incorporation rate in the AngII‑treated rat cardiomyocytes were detected following RNA interference. Simultaneously, changes in the expression levels of phosphorylated extracellular signal-regulated kinase (p-ERK)2 in the cardiomyocytes were assessed. The cell size of the AngII-treated cardiaomyocytes was significantly larger than that of the untreated cardiomyocytes. The expression of hypertrophic markers and p-ERK2, the cell surface area and the [3H]Leucine incorporation rate were all significantly increased in the AngII‑treated cells. However, the expression of mAKAPβ remained unaltered in this process. RNA interference simultaneously inhibited the protein expression of mAKAPβ and p‑ERK2, and the hypertrophy of the cardiomyocytes induced by AngII was attenuated. These results demonstrate that AngII induces hypertrophy in cardiomyocytes, and mAKAPβ is possibly involved in this process. The effects of mAKAPβ on AngII‑induced cardiomyocyte hypertrophy may be associated with p-ERK2 expression.

  1. The restoration of kidney mitochondria function by inhibition of angiotensin-II production in rats with acute adriamycin-induced nephrotoxicity.

    PubMed

    Taskin, Eylem; Ozdogan, Kalender; Kunduz Kindap, Elvan; Dursun, Nurcan

    2014-05-01

    Adriamycin (ADR) is commonly used for many solid tumor treatments. Its clinical utility is, however, largely limited by the adverse reactions, are known to be nephrotoxic. The mechanism by which it induces kidney damage is still not completely understood, but its nephrotoxicity might relate to increase reactive oxidant status (ROS), mitochondrial dysfunction. Until now, neurohormonal activation of it is unclear. ADR might activate the renin angiotensin system. Angiotensin-II also induced ROS and mitochondrial dysfunction. The aim of this study was to investigate whether angiotensin-II production inhibition has the protective effect on attenuation of mitochondrial function in rats with acute ADR-nephrotoxicity or not. Rats were divided into five groups as a control, ADR, co-treated ADR with captopril (CAP), co-treated ADR with Aliskren, co-treated ADR with both CAP and Aliskren groups. Creatinine kinase (CK) levels were measured at the end of treatment period. The kidneys were homogenized and biochemical measurements were made in mitochondria, cytosol. Mitochondria membrane potential (MMP) and ATP levels were determined. ADR increased CK levels and oxidative stress in mitochondria too (p<0.05). ADR significantly decreased MMP and ATP level in kidney mitochondria (p<0.05). Co-administration with ADR and Aliskren and CAP improved the dissipation of MMP (p<0.05). The decrease in ATP level was restored by treatment with inhibitors of ACE and renin. We concluded that inhibitors of angiotensin-II are effective against acute ADR induced nephrotoxicity via the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo.

  2. Autoradiographic localization of (/sup 125/I)-angiotensin II binding sites in the rat adrenal gland

    SciTech Connect

    Healy, D.P.; Maciejewski, A.R.; Printz, M.P.

    1985-03-01

    To gain greater insight into sites of action of circulating angiotensin II (Ang II) within the adrenal, we have localized the (/sup 125/I)-Ang II binding site using in vitro autoradiography. Autoradiograms were generated either by apposition of isotope-sensitive film or with emulsion-coated coverslips to slide-mounted adrenal sections labeled in vitro with 1.0 nM (/sup 125/I)-Ang II. Analysis of the autoradiograms showed that Ang II binding sites were concentrated in a thin band in the outer cortex (over the cells of the zona glomerulosa) and in the adrenal medulla, which at higher power was seen as dense patches. Few sites were evident in the inner cortex. The existence of Ang II binding sites in the adrenal medulla was confirmed by conventional homogenate binding techniques which revealed a single class of high affinity Ang II binding site (K/sub d/ . 0.7nM, B/sub max/ . 168.7 fmol/mg). These results suggest that the adrenal medulla may be a target for direct receptor-mediated actions of Ang II.

  3. Role of protein kinase C delta in angiotensin II induced cardiac fibrosis

    PubMed Central

    Chintalgattu, Vishnu; Katwa, Laxmansa C

    2009-01-01

    Previous studies have demonstrated a role for angiotensin II (AngII) and myofibroblasts (myoFb) in cardiac fibrosis. However, the role of PKC-δ in AngII mediated cardiac fibrosis is unclear. Therefore, the present study was designed to investigate the role of PKC-δ in AngII induced cardiac collagen expression and fibrosis. AngII treatment significantly (p<0.05) increased myoFb collagen expression, whereas PKC-δ siRNA treatment or rottlerin, a PKC-δ inhibitor abrogated (p<0.05) AngII induced collagen expression. MyoFb transfected with PKC-δ over expression vector showed significant increase (p<0.05) in the collagen expression as compared to control. Two-weeks of chronic AngII infused rats showed significant (p<0.05) increase in collagen expression compared to sham operated rats. This increase in cardiac collagen expression was abrogated by rottlerin treatment. In conclusion, both in vitro and in vivo data strongly suggest a role for PKC-δ in AngII induced cardiac fibrosis. PMID:19540196

  4. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis

    PubMed Central

    Bataller, Ramón; Schwabe, Robert F.; Choi, Youkyung H.; Yang, Liu; Paik, Yong Han; Lindquist, Jeffrey; Qian, Ting; Schoonhoven, Robert; Hagedorn, Curt H.; Lemasters, John J.; Brenner, David A.

    2003-01-01

    Angiotensin II (Ang II) is a pro-oxidant and fibrogenic cytokine. We investigated the role of NADPH oxidase in Ang II–induced effects in hepatic stellate cells (HSCs), a fibrogenic cell type. Human HSCs express mRNAs of key components of nonphagocytic NADPH oxidase. Ang II phosphorylated p47phox, a regulatory subunit of NADPH oxidase, and induced reactive oxygen species formation via NADPH oxidase activity. Ang II phosphorylated AKT and MAPKs and increased AP-1 DNA binding in a redox-sensitive manner. Ang II stimulated DNA synthesis, cell migration, procollagen α1(I) mRNA expression, and secretion of TGF-β1 and inflammatory cytokines. These effects were attenuated by N-acetylcysteine and diphenylene iodonium, an NADPH oxidase inhibitor. Moreover, Ang II induced upregulation of genes potentially involved in hepatic wound-healing response in a redox-sensitive manner, as assessed by microarray analysis. HSCs isolated from p47phox–/– mice displayed a blunted response to Ang II compared with WT cells. We also assessed the role of NADPH oxidase in experimental liver fibrosis. After bile duct ligation, p47phox–/– mice showed attenuated liver injury and fibrosis compared with WT counterparts. Moreover, expression of smooth muscle α-actin and expression of TGF-β1 were reduced in p47phox–/– mice. Thus, NADPH oxidase mediates the actions of Ang II on HSCs and plays a critical role in liver fibrogenesis. PMID:14597764

  5. DIFFERENTIAL EFFECTS OF MINERALOCORTICOID AND ANGIOTENSIN II ON INCENTIVE AND MESOLIMBIC ACTIVITY

    PubMed Central

    Grafe, Laura A.; Flanagan-Cato, Loretta M.

    2016-01-01

    The controls of thirst and sodium appetite are mediated in part by the hormones aldosterone and angiotensin II (AngII). The present study examined the behavioral and neural mechanisms of altered effort-value in animals treated with systemic mineralocorticoids, intracerebroventricular AngII, or both. First, rats treated with mineralocorticoid and AngII were tested in the progressive ratio operant task. The willingness to work for sodium versus water depended on hormonal treatment. In particular, rats treated with both mineralocorticoid and AngII preferentially worked for access to sodium versus water compared with rats given only one of these hormones. Second, components of the mesolimbic dopamine pathway were examined for modulation by mineralocorticoids and AngII. Based on cFos immunohistochemistry, AngII treatment activated neurons in the ventral tegmental area and nucleus accumbens, with no enhancement by mineralocorticoid pretreatment. In contrast, western blot analysis revealed that combined hormone treatment increased levels of phospho-tyrosine hydroxylase in the ventral tegmental area. Thus, mineralocorticoid and AngII treatments differentially engaged the mesolimbic pathway based on tyrosine hydroxylase levels versus cFos activation. PMID:26730722

  6. Angiotensin II regulates collagen metabolism through modulating tissue inhibitor of metalloproteinase-1 in diabetic skin tissues.

    PubMed

    Ren, Meng; Hao, Shaoyun; Yang, Chuan; Zhu, Ping; Chen, Lihong; Lin, Diaozhu; Li, Na; Yan, Li

    2013-09-01

    We investigated the effect of angiotensin II (Ang II) on matrix metalloproteinase-1 (MMP-1)/tissue inhibitor of metalloproteinase-1 (TIMP-1) balance in regulating collagen metabolism of diabetic skin. Skin tissues from diabetic model were collected, and the primary cultured fibroblasts were treated with Ang II receptor inhibitors before Ang II treatment. The collagen type I (Coll I) and collagen type III (Coll III) were measured by histochemistry. The expressions of transforming growth factor-β (TGF-β), MMP-1, TIMP-1 and propeptides of types I and III procollagens in skin tissues and fibroblasts were quantified using polymerase chain reaction (PCR), Western blot or enzyme-linked immunosorbent assay (ELISA). Collagen dysfunction was documented by changed collagen I/III ratio in streptozotocin (STZ)-injected mice compared with controls. This was accompanied by increased expression of TGF-β, TIMP-1 and propeptides of types I and III procollagens in diabetic skin tissues. In primary cultured fibroblasts, Ang II prompted collagen synthesis accompanied by increases in the expressions of TGF-β, TIMP-1 and types I and III procollagens, and these increases were inhibited by losartan, an Ang II type 1 (AT1) receptor blocker, but not affected by PD123319, an Ang II type 2 (AT2) receptor antagonist. These findings present evidence that Ang-II-mediated changes in the productions of MMP-1 and TIMP-1 occur via AT1 receptors and a TGF-β-dependent mechanism.

  7. TRIF promotes angiotensin II-induced cross-talk between fibroblasts and macrophages in atrial fibrosis

    SciTech Connect

    Chen, Xiao-Qing; Zhang, Dao-Liang; Zhang, Ming-Jian; Guo, Meng; Zhan, Yang-Yang; Liu, Fang; Jiang, Wei-Feng; Zhou, Li; Zhao, Liang; Wang, Quan-Xing; Liu, Xu

    2015-08-14

    Aims: Atrial fibroblasts and macrophages have long been thought to participate in atrial fibrillation (AF). However, which specific mediator may regulate the interaction between them remains unclear. Methods and results: We provided the evidence for the involvement of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF), an important inflammation-related molecule, in the pathophysiology of AF. Patients with AF showed higher levels of angiotensin II (AngII) and TRIF expression and larger number of macrophages infiltration in left atria appendage than individuals with sinus rhythm (SR). In the cell study, AngII induced chemokines expressions in mouse atrial fibroblasts and AngII-stimulated atrial fibroblasts induced the chemotaxis of macrophages, which were reduced by losartan and TRIF siRNA. Meanwhile, AngII-stimulated atrial fibroblasts proliferation was enhanced by macrophages. Conclusions: Our data demonstrated that TRIF may be a crucial factor promoting the interaction between atrial fibroblasts and macrophages, leading to atrial fibrosis. - Highlights: • Compared with SR, AF showed higher TRIF expression in left atrial appendage. • TRIF siRNA reversed macrophage chemotaxis induced by AngII-treated fibroblast. • TRIF siRNA reversed chemokines expressions induced by AngII in fibroblast. • AngII-stimulated atrial fibroblast proliferation was enhanced by macrophage.

  8. Long-term intracerebroventricular infusion of angiotensin II after kainate-induced status epilepticus: Effects on epileptogenesis, brain damage, and diurnal behavioral changes.

    PubMed

    Ivanova, Natasha M; Atanasova, Dimitrina; Pechlivanova, Daniela M; Mitreva, Rumyana; Lazarov, Nikolai; Stoynev, Alexander G; Tchekalarova, Jana D

    2015-10-01

    Our previous studies revealed that Angiotensin (Ang) II has anticonvulsant effects in acute seizure models. However, data on its role in experimental models of epilepsy are missing. In the present study, we tested whether posttreatment with Ang II after kainate (KA)-induced status epilepticus (SE) can affect epileptogenesis, concomitant behavioral changes, and brain damage. The Wistar rats were intracerebroventricularly infused via osmotic mini-pumps with Ang II (1.52μg/μl/day for 28days) after SE. Spontaneous motor seizures (SMS) were video-recorded for up to three months. Locomotor activity, anxiety, and depression-like behavior were evaluated during the last week of drug infusion, while spatial memory was assessed during the 3rd month after SE. Angiotensin II decreased the latency for onset of the first SMS and increased the frequency of SMS two months after SE. The continuous peptide infusion exacerbated the KA-induced hyperactivity and caused depression-like behavior. The reduced anxiety of KA-treated rats was alleviated by Ang II exposure. The KA-induced deficit in the hippocampal-dependent spatial memory was not influenced by Ang II. However, Ang II partially prevented the neuronal damage in the hippocampus, specifically in the CA1 area. The role of AT1 and AT2 receptor activation in the effects of the octapeptide is discussed.

  9. Angiotensin II Contributes to Renal Fibrosis Independently of Notch Pathway Activation

    PubMed Central

    Lavoz, Carolina; Rodrigues-Diez, Raquel; Benito-Martin, Alberto; Rayego-Mateos, Sandra; Rodrigues-Diez, Raúl R.; Alique, Matilde; Ortiz, Alberto; Mezzano, Sergio; Egido, Jesús; Ruiz-Ortega, Marta

    2012-01-01

    Recent studies have described that the Notch signaling pathway is activated in a wide range of renal diseases. Angiotensin II (AngII) plays a key role in the progression of kidney diseases. AngII contributes to renal fibrosis by upregulation of profibrotic factors, induction of epithelial mesenchymal transition and accumulation of extracellular matrix proteins. In cultured human tubular epithelial cells the Notch activation by transforming growth factor-β1 (TGF-β1) has been involved in epithelial mesenchymal transition. AngII mimics many profibrotic actions of TGF-β1. For these reasons, our aim was to investigate whether AngII could regulate the Notch/Jagged system in the kidney, and its potential role in AngII-induced responses. In cultured human tubular epithelial cells, TGF-β1, but not AngII, increased the Notch pathway-related gene expression, Jagged-1 synthesis, and caused nuclear translocation of the activated Notch. In podocytes and renal fibroblasts, AngII did not modulate the Notch pathway. In tubular epithelial cells, pharmacological Notch inhibition did not modify AngII-induced changes in epithelial mesenchymal markers, profibrotic factors and extracellular matrix proteins. Systemic infusion of AngII into rats for 2 weeks caused tubulointerstitial fibrosis, but did not upregulate renal expression of activated Notch-1 or Jagged-1, as observed in spontaneously hypertensive rats. Moreover, the Notch/Jagged system was not modulated by AngII type I receptor blockade in the model of unilateral ureteral obstruction in mice. These data clearly indicate that AngII does not regulate the Notch/Jagged signaling system in the kidney, in vivo and in vitro. Our findings showing that the Notch pathway is not involved in AngII-induced fibrosis could provide important information to understand the complex role of Notch system in the regulation of renal regeneration vs damage progression. PMID:22792351

  10. Effect of angiotensin II-induced arterial hypertension on the voltage-dependent contractions of mouse arteries.

    PubMed

    Fransen, Paul; Van Hove, Cor E; Leloup, Arthur J A; Schrijvers, Dorien M; De Meyer, Guido R Y; De Keulenaer, Gilles W

    2016-02-01

    Arterial hypertension (AHT) affects the voltage dependency of L-type Ca(2+) channels in cardiomyocytes. We analyzed the effect of angiotensin II (AngII)-induced AHT on L-type Ca(2+) channel-mediated isometric contractions in conduit arteries. AHT was induced in C57Bl6 mice with AngII-filled osmotic mini-pumps (4 weeks). Normotensive mice treated with saline-filled osmotic mini-pumps were used for comparison. Voltage-dependent contractions mediated by L-type Ca(2+) channels were studied in vaso-reactive studies in vitro in isolated aortic and femoral arteries by using extracellular K(+) concentration-response (KDR) experiments. In aortic segments, AngII-induced AHT significantly sensitized isometric contractions induced by elevated extracellular K(+) and depolarization. This sensitization was partly prevented by normalizing blood pressure with hydralazine, suggesting that it was caused by AHT rather than by direct AngII effects on aortic smooth muscle cells. The EC50 for extracellular K(+) obtained in vitro correlated significantly with the rise in arterial blood pressure induced by AngII in vivo. The AHT-induced sensitization persisted when aortic segments were exposed to levcromakalim or to inhibitors of basal nitric oxide release. Consistent with these observations, AngII-treatment also sensitized the vaso-relaxing effects of the L-type Ca(2+) channel blocker diltiazem during K(+)-induced contractions. Unlike aorta, AngII-treatment desensitized the isometric contractions to depolarization in femoral arteries pointing to vascular bed specific responses of arteries to hypertension. AHT affects the voltage-dependent L-type Ca(2+) channel-mediated contraction of conduit arteries. This effect may contribute to the decreased vascular compliance in AHT and explain the efficacy of Ca(2+) channel blockers to reduce vascular stiffness and central blood pressure in AHT.

  11. ClC-3 deficiency prevents apoptosis induced by angiotensin II in endothelial progenitor cells via inhibition of NADPH oxidase.

    PubMed

    Liu, Jing; Zhang, Fei-Fei; Li, Lei; Yang, Jing; Liu, Jie; Guan, Yong-Yuan; Du, Yan-Hua

    2013-10-01

    Endothelial progenitor cells (EPCs) play an important role in postnatal neovascularization and re-endothelialization in response to tissue ischemia and endothelial injury. It is reported that the circulating EPCs number is decreased during hypertension. However, the detailed mechanism is still unclear. Our previous studies have shown that ClC-3 chloride channel is up-regulated with the development of hypertension. This study aims to test whether ClC-3 participates in EPC apoptosis under the condition of increased oxidative stress in angiotensin II (Ang II)-induced hypertension. The results showed that stimulation with 10(-6)mol/L Ang II significantly up-regulated the endogenous ClC-3 expression and increased intracellular reactive oxygen species (ROS) generation in EPCs of wild type mice, accompanied by an enhanced NADPH oxidase activity and the expression of gp91(phox) (NOX-2), a key catalytic subunit of NADPH oxidase. However, these effects of Ang II were significantly reduced in EPCs of ClC-3(-/-) mice. Compared with control, treatment with Ang II induced EPCs apoptosis in wild type mice, concomitantly with declined Bcl-2/Bax ratio, depressed mitochondrial membrane potential and activation of poly(ADP-ribose) polymerase, which was remarkably prevented by both ClC-3 knockout and NADPH oxidase inhibitor apocynin. In addition, the role of ClC-3 deficiency in protecting EPCs against Ang II-induced oxidative stress and apoptosis was further confirmed in Ang II-infused hypertensive mice in vivo. In conclusion, ClC-3 deficiency inhibited Ang II-induced EPC apoptosis via suppressing ROS generation derived from NADPH oxidase.

  12. Angiotensin II limits NO production by upregulating arginase through a p38 MAPK-ATF-2 pathway.

    PubMed

    Shatanawi, Alia; Lemtalsi, Tahira; Yao, Lin; Patel, Chintan; Caldwell, Ruth B; Caldwell, R William

    2015-01-05

    Enhanced vascular arginase activity can impair endothelium-dependent vasorelaxation by decreasing l-arginine availability to endothelial nitric oxide (NO) synthase, thereby reducing NO production and uncoupling NOS function. Elevated angiotensin II (Ang II) is a key component of endothelial dysfunction in many cardiovascular diseases and has been linked to elevated arginase activity. In this study we explored the signaling pathway leading to increased arginase expression/activity in response to Ang II in bovine aortic endothelial cells (BAEC). Our previous studies indicate involvement of p38 mitogen activated protein kinase (MAPK) in Ang II-induced arginase upregulation and reduced NO production. In this study, we further investigated the Ang II-transcriptional regulation of arginase 1 in endothelial cells. Our results indicate the involvement of ATF-2 transcription factor of the AP1 family in arginase 1 upregulation and in limiting NO production. Using small interfering RNA (siRNA) targeting ATF-2, we showed that this transcription factor is required for Ang II-induced arginase 1 gene upregulation and increased arginase 1 expression and activity, leading to reduced NO production. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay further confirmed the involvement of ATF-2. Moreover, our data indicate that p38 MAPK phosphorylates ATF-2 in response to Ang II. Collectively, our results indicate that Ang II increases endothelial arginase activity/expression through a p38 MAPK/ATF-2 pathway leading to reduced endothelial NO production. These signaling steps might be therapeutic targets for preventing vascular endothelial dysfunction associated with elevated arginase activity/expression.

  13. Effects of angiotensin II (AT1) receptor blockade on cardiac vagal control in heart failure.

    PubMed

    Vaile, J C; Chowdhary, S; Osman, F; Ross, H F; Fletcher, J; Littler, W A; Coote, J H; Townend, J N

    2001-12-01

    The objective of the present study was to determine the autonomic effects of angiotensin II (AT(1)) receptor blocker therapy in heart failure. In a randomized double-blind cross-over study, we compared the effects of candesartan and placebo on baroreflex sensitivity and on heart rate variability at rest, during stress and during 24 h monitoring. Acute effects were assessed 4 h after oral candesartan (8 mg) and chronic effects after 4 weeks of treatment (dose titrated to 16 mg daily). The study group comprised 21 patients with heart failure [mean (S.E.M.) ejection fraction 33% (1%)], in the absence of angiotensin-converting enzyme (ACE) inhibitor therapy. We found that acute candesartan was not different from placebo in its effects on blood pressure or mean RR interval. Chronic candesartan significantly reduced blood pressure [placebo, 137 (3)/82 (3) mmHg; candesartan, 121 (4)/75 (2) mmHg; P<0.001; values are mean (S.E.M.)], but had no effect on mean RR interval [placebo, 857 (25) ms; candesartan, 857 (21) ms]. Compared with placebo there were no significant effects of acute or chronic candesartan on heart rate variability in the time domain and no consistent effects in the frequency domain. Baroreflex sensitivity assessed by the phenylephrine bolus method was significantly increased after chronic candesartan [placebo, 3.5 (0.5) ms/mmHg; candesartan, 4.8 (0.7) ms/mmHg; P<0.05], although there were no changes in cross-spectral baroreflex sensitivity. Thus, in contrast with previous results with ACE inhibitors, angiotensin II receptor blockade in heart failure did not increase heart rate variability, and there was no consistent effect on baroreflex sensitivity.

  14. 6β-hydroxytestosterone, a cytochrome P450 1B1 metabolite of testosterone, contributes to angiotensin II-induced hypertension and its pathogenesis in male mice.

    PubMed

    Pingili, Ajeeth K; Kara, Mehmet; Khan, Nayaab S; Estes, Anne M; Lin, Zongtao; Li, Wei; Gonzalez, Frank J; Malik, Kafait U

    2015-06-01

    Previously, we showed that Cyp1b1 gene disruption minimizes angiotensin II-induced hypertension and associated pathophysiological changes in male mice. This study was conducted to test the hypothesis that cytochrome P450 1B1-generated metabolites of testosterone, 6β-hydroxytestosterone and 16α-hydroxytestosterone, contribute to angiotensin II-induced hypertension and its pathogenesis. Angiotensin II infusion for 2 weeks increased cardiac cytochrome P450 1B1 activity and plasma levels of 6β-hydroxytestosterone, but not 16α-hydroxytestosterone, in Cyp1b1(+/+) mice without altering Cyp1b1 gene expression; these effects of angiotensin II were not observed in Cyp1b1(-/-) mice. Angiotensin II-induced increase in systolic blood pressure and associated cardiac hypertrophy, and fibrosis, measured by intracardiac accumulation of α-smooth muscle actin, collagen, and transforming growth factor-β, and increased nicotinamide adenine dinucleotide phosphate oxidase activity and production of reactive oxygen species; these changes were minimized in Cyp1b1(-/-) or castrated Cyp1b1(+/+) mice, and restored by treatment with 6β-hydroxytestoterone. In Cyp1b1(+/+) mice, 6β-hydroxytestosterone did not alter the angiotensin II-induced increase in systolic blood pressure; the basal systolic blood pressure was also not affected by this agent in either genotype. Angiotensin II or castration did not alter cardiac, angiotensin II type 1 receptor, angiotensin-converting enzyme, Mas receptor, or androgen receptor mRNA levels in Cyp1b1(+/+) or in Cyp1b1(-/-) mice. These data suggest that the testosterone metabolite, 6β-hydroxytestosterone, contributes to angiotensin II-induced hypertension and associated cardiac pathogenesis in male mice, most probably by acting as a permissive factor. Moreover, cytochrome P450 1B1 could serve as a novel target for developing agents for treating renin-angiotensin and testosterone-dependent hypertension and associated pathogenesis in males.

  15. Surgery-Induced Hippocampal Angiotensin II Elevation Causes Blood-Brain Barrier Disruption via MMP/TIMP in Aged Rats

    PubMed Central

    Li, Zhengqian; Mo, Na; Li, Lunxu; Cao, Yiyun; Wang, Wenming; Liang, Yaoxian; Deng, Hui; Xing, Rui; Yang, Lin; Ni, Cheng; Chui, Dehua; Guo, Xiangyang

    2016-01-01

    Reversible blood-brain barrier (BBB) disruption has been uniformly reported in several animal models of postoperative cognitive dysfunction (POCD). Nevertheless, the precise mechanism underlying this occurrence remains unclear. Using an aged rat model of POCD, we investigated the dynamic changes in expression of molecules involved in BBB disintegration, matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9), as well as three of their endogenous tissue inhibitors of MMP (TIMP-1, -2, -3), and tried to establish the correlation between MMP/TIMP balance and surgery-induced hippocampal BBB disruption. We validated the increased hippocampal expression of angiotensin II (Ang II) and Ang II receptor type 1 (AT1) after surgery. We also found MMP/TIMP imbalance as early as 6 h after surgery, together with increased BBB permeability and decreased expression of Occludin and zonula occludens-1 (ZO-1), as well as increased basal lamina protein laminin at 24 h postsurgery. The AT1 antagonist candesartan restored MMP/TIMP equilibrium and modulated expression of Occludin and laminin, but not ZO-1, thereby improving BBB permeability. These events were accompanied by suppression of the surgery-induced canonical nuclear factor-κB (NF-κB) activation cascade. Nevertheless, AT1 antagonism did not affect nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) expression. Collectively, these findings suggest that surgery-induced Ang II release impairs BBB integrity by activating NF-κB signaling and disrupting downstream MMP/TIMP balance via AT1 receptor. PMID:27199659

  16. Inhibition of Angiotensin-II Production Increases Susceptibility to Acute Ischemia/Reperfusion Arrhythmia

    PubMed Central

    Taskin, Eylem; Tuncer, Kadir Ali; Guven, Celal; Kaya, Salih Tunc; Dursun, Nurcan

    2016-01-01

    Background Myocardial ischemia and reperfusion lead to impairment of electrolyte balance and, eventually, lethal arrhythmias. The aim of this study was to investigate the effects of pharmacological inhibition of angiotensin-II (Ang-II) production on heart tissue with ischemia-reperfusion damage, arrhythmia, and oxidative stress. Material/Methods Rats were divided into 4 groups: only ischemia/reperfusion (MI/R), captopril (CAP), aliskiren (AL), and CAP+AL. The drugs were given by gavage 30 min before anesthesia. Blood pressure and electrocardiography (ECG) were recorded during MI/R procedures. The heart tissue and plasma was kept so as to evaluate the total oxidant (TOS), antioxidant status (TAS), and creatine kinase-MB (CK-MB). Results Creatine kinase-MB was not different among the groups. Although TAS was not affected by inhibition of Ang-II production, TOS was significantly lower in the CAP and/or AL groups than in the MI/R group. Furthermore, oxidative stress index was significantly attenuated in the CAP and/or AL groups. Captopril significantly increased the duration of VT during ischemia; however, it did not have any effect on the incidence of arrhythmias. During reperfusion periods, aliskiren and its combinations with captopril significantly reduced the incidence of other types of arrhythmias. Captopril alone had no effect on the incidence of arrhythmias, but significantly increased arrhythmias score and durations of arrhythmias during reperfusion. MAP and heart rate did not show changes in any groups during ischemic and reperfusion periods. Conclusions Angiotensin-II production appears to be associated with elevated levels of reactive oxygen species, but Ang-II inhibitions increases arrhythmia, mainly by initiating ventricular ectopic beats. PMID:27889788

  17. Angiotensin II induces MMP 2 activity via FAK/JNK pathway in human endothelial cells.

    PubMed

    Jiménez, Eugenio; Pérez de la Blanca, Enrique; Urso, Loredana; González, Irene; Salas, Julián; Montiel, Mercedes

    2009-03-20

    Matrix metalloproteinases (MMPs) play an important role in the pathogenesis of cardiovascular diseases and are modified in response to a variety of stimuli such as bioactive peptides, cytokines and/or grown factors. In this study, we demonstrated that angiotensin II (Ang II) induces a time- and dose-dependent increase in the activity of metalloproteinase 2 (MMP 2) in human umbilical vein endothelial cells (HUVEC). The effect of Ang II was markedly attenuated in cells pretreated with wortmannin and LY294002, two selective inhibitors of phosphatidylinositol-3-kinase (PI3K), indicating that PI3K plays a key role in regulating MMP 2 activity. Similar results were observed when HUVEC were pretreated with genistein, a non-selective tyrosine kinases inhibitor, or with the specific Src-family tyrosine kinase inhibitor PP2, demonstrating the involvement of protein tyrosine kinases, and particularly Src-family tyrosine kinases on the downstream signaling pathway of Ang II receptors. Furthermore, Ang II-induced MMP 2 activation was markedly blocked by SP600125, a selective c-Jun N-terminal kinase (JNK) inhibitor, or pre-treatment of cells with antisense oligonucleotide to focal adhesion kinase (FAK), indicating that both molecules were important for the activation of MMP 2 by Ang II receptor stimulation. In conclusion, these results suggest that Ang II mediates an increase in MMP 2 activity in macrovascular endothelial cells through signal transduction pathways dependent on PI3K and Src-family tyrosine kinases activation, as well as JNK and FAK phosphorylation.

  18. Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice

    PubMed Central

    Lu, Hong; Howatt, Deborah A.; Balakrishnan, Anju; Moorleghen, Jessica J.; Rateri, Debra L.; Cassis, Lisa A.; Daugherty, Alan

    2015-01-01

    Osmotic pumps continuously deliver compounds at a constant rate into small animals. This article introduces a standard protocol used to induce aortic aneurysms via subcutaneous infusion of angiotensin II (AngII) from implanted osmotic pumps. This protocol includes calculation of AngII amount and dissolution, osmotic pump filling, implantation of osmotic pumps subcutaneously, observation after pump implantation, and harvest of aortas to visualize aortic aneurysms in mice. Subcutaneous infusion of AngII through osmotic pumps following this protocol is a reliable and reproducible technique to induce both abdominal and thoracic aortic aneurysms in mice. Infusion durations range from a few days to several months based on the purpose of the study. AngII 1,000 ng/kg/min is sufficient to provide maximal effects on abdominal aortic aneurysmal formation in male hypercholesterolemic mouse models such as apolipoprotein E deficient or low-density lipoprotein receptor deficient mice. Incidence of abdominal aortic aneurysms induced by AngII infusion via osmotic pumps is 5 - 10 times lower in female hypercholesterolemic mice and also lower in both genders of normocholesterolemic mice. In contrast, AngII-induced thoracic aortic aneurysms in mice are not hypercholesterolemia or gender-dependent. Importantly, multiple features of this mouse model recapitulate those of human aortic aneurysms. PMID:26436287

  19. Angiotensin II Induces Region-Specific Medial Disruption during Evolution of Ascending Aortic Aneurysms

    PubMed Central

    Rateri, Debra L.; Davis, Frank M.; Balakrishnan, Anju; Howatt, Deborah A.; Moorleghen, Jessica J.; O’Connor, William N.; Charnigo, Richard; Cassis, Lisa A.; Daugherty, Alan

    2015-01-01

    Angiotensin II (Ang II) promotes development of ascending aortic aneurysms (AAs), but progression of this pathology is undefined. We evaluated factors potentially involved in progression, and determined the temporal sequence of tissue changes during development of Ang II–induced ascending AAs. Ang II infusion into C57BL/6J mice promoted rapid expansion of the ascending aorta, with significant increases within 5 days, as determined by both in vivo ultrasonography and ex vivo sequential acquisition of tissues. Rates of expansion were not significantly different in LDL receptor–null mice fed a saturated fat-enriched diet, demonstrating a lack of effect of hypercholesterolemia. Augmenting systolic blood pressure with norepinephrine infusion had no significant effect on ascending aortic expansion. Pathological changes observed within 5 days of Ang II infusion included increased medial thickness and intramural hemorrhage characterized by erythrocyte extravasation in outer lamellar layers of the media. Intramedial hemorrhage was not observed after prolonged Ang II infusion, although partial medial disruption was present. Elastin fragmentation and transmural medial breaks of the ascending aorta were observed with continued Ang II infusion, which were restricted to anterior aspects. CD45+ cells accumulated in adventitia but were minimal in media. Similar pathology was observed in tissues obtained from patients with ascending AAs. In conclusion, Ang II promotes ascending AAs through region-specific changes that are independent of hypercholesterolemia or systolic blood pressure. PMID:25038458

  20. Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice.

    PubMed

    Lu, Hong; Howatt, Deborah A; Balakrishnan, Anju; Moorleghen, Jessica J; Rateri, Debra L; Cassis, Lisa A; Daugherty, Alan

    2015-09-28

    Osmotic pumps continuously deliver compounds at a constant rate into small animals. This article introduces a standard protocol used to induce aortic aneurysms via subcutaneous infusion of angiotensin II (AngII) from implanted osmotic pumps. This protocol includes calculation of AngII amount and dissolution, osmotic pump filling, implantation of osmotic pumps subcutaneously, observation after pump implantation, and harvest of aortas to visualize aortic aneurysms in mice. Subcutaneous infusion of AngII through osmotic pumps following this protocol is a reliable and reproducible technique to induce both abdominal and thoracic aortic aneurysms in mice. Infusion durations range from a few days to several months based on the purpose of the study. AngII 1,000 ng/kg/min is sufficient to provide maximal effects on abdominal aortic aneurysmal formation in male hypercholesterolemic mouse models such as apolipoprotein E deficient or low-density lipoprotein receptor deficient mice. Incidence of abdominal aortic aneurysms induced by AngII infusion via osmotic pumps is 5-10 times lower in female hypercholesterolemic mice and also lower in both genders of normocholesterolemic mice. In contrast, AngII-induced thoracic aortic aneurysms in mice are not hypercholesterolemia or gender-dependent. Importantly, multiple features of this mouse model recapitulate those of human aortic aneurysms.

  1. Disparate responses of tumour vessels to angiotensin II: tumour volume-dependent effects on perfusion and oxygenation

    PubMed Central

    Thews, O; Kelleher, D K; Vaupel, P

    2000-01-01

    Perfusion and oxygenation of experimental tumours were studied during angiotensin II (AT II) administration whereby the rate of the continuous AT II infusion was chosen to increase the mean arterial blood pressure (MABP) by 50–70 mmHg. In subcutaneous DS- sarcomas the red blood cell (RBC) flux was assessed using the laser Doppler technique and the mean tumour oxygen partial pressure (p O 2) was measured polarographically using O 2-sensitive catheter and needle electrodes. Changes in RBC flux with increasing MABP depended mainly on tumour size. In small tumours, RBC flux decreased with rising MABP whereas in larger tumours RBC flux increased parallel to the MABP. As a result of these volume-dependent effects on tumour blood flow, the impact of AT II on tumour p O 2 was also mainly tumour volume-related. In small tumours oxygenation decreased with increasing MABP during AT II infusion, whereas in large tumours a positive relationship between blood pressure and O 2 status was found. This disparate behaviour might be the result of the co-existence of two functionally distinct populations of tumour vessels. In small tumours, perfusion decreases presumably due to vasoconstriction of pre-existing host vessels feeding the tumour. In larger malignancies, newly formed tumour vessels predominate and seem not to have this vasoresponsive capability (lack of smooth muscle cells and/or AT receptors), resulting in an improvement of perfusion which is not tumour-related per se, but is due to the increased perfusion pressure. © 2000 Cancer Research Campaign PMID:10901375

  2. Angiotensin II and VEGF are involved in angiogenesis induced by short-term exercise training.

    PubMed

    Amaral, S L; Papanek, P E; Greene, A S

    2001-09-01

    Results from our laboratory have suggested a pathway involving angiotensin II type 1 (AT(1)) receptors and vascular endothelial growth factor (VEGF) in angiogenesis induced by electrical stimulation. The present study investigated if similar mechanisms underlie the angiogenesis induced by short-term exercise training. Seven days before training and throughout the training period, male Sprague-Dawley rats received either captopril or losartan in their drinking water. Rats underwent a 3-day treadmill training protocol. The tibialis anterior and gastrocnemius muscles were harvested under anesthesia and lightly fixed in formalin (vessel density) or frozen in liquid nitrogen (VEGF expression). In controls, treadmill training resulted in a significant increase in vessel density in all muscles studied. However, the angiogenesis induced by exercise was completely blocked by either losartan or captopril. Western blot analysis showed that VEGF expression was increased in the exercised control group, and both losartan and captopril blocked this increase. The role of VEGF was directly confirmed using a VEGF-neutralizing antibody. These results confirm the role of angiotensin II and VEGF in angiogenesis induced by exercise.

  3. Role of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and aldosterone antagonists in the prevention of atrial and ventricular arrhythmias.

    PubMed

    Makkar, Kathy M; Sanoski, Cynthia A; Spinler, Sarah A

    2009-01-01

    Atrial arrhythmias, ventricular arrhythmias, and sudden cardiac death (SCD) are significant health problems and an economic burden to society. The renin-angiotensin-aldosterone system (RAAS) may play a key role in the occurrence of structural and electrical remodeling, potentially explaining the development of atrial and ventricular arrhythmias. Angiotensin II has been shown to regulate cardiac cell proliferation and to modulate cardiac myocyte ion channels. Results of post hoc analyses from prospective clinical trials appear to show that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are most effective in the prevention of new-onset atrial fibrillation in patients with heart failure. It is difficult to determine if these agents are useful in the prevention of new-onset atrial fibrillation after myocardial infarction, and available evidence suggests that the benefit of ACE inhibitors and ARBs for prevention of new-onset atrial fibrillation in patients with hypertension appears limited to those with left ventricular hypertrophy. Patients with structural changes in cardiac muscle, such as those with heart failure and left ventricular hypertrophy, appear to benefit the most from RAAS blockade, possibly due to the theory of reversal of cardiac remodeling. There is no evidence, to our knowledge, that either ACE inhibitors or ARBs facilitate direct electrical current cardioversion in patients with atrial fibrillation; however, it appears that RAAS blockade may be useful in the prevention of recurrent atrial fibrillation after direct electrical current cardioversion. Whether ACE inhibitors may prevent life-threatening ventricular arrhythmias or SCD is unclear. Aldosterone antagonists appear to be useful for the prevention of SCD in patients with left ventricular systolic dysfunction. Results from ongoing clinical trials are anticipated to provide further insight on the potential roles of RAAS inhibitors for the prevention of

  4. [Is there an indication for the association of betablockers and angiotensin II receptor antagonists in cardiac failure?].

    PubMed

    Jondeau, G; Milleron, O; Morisson-Castagnet, J F

    2004-06-01

    ACE inhibitors initially developed as vasodilators are effective by their anti-hormonal action. Antagonists of the receptors of angiotensin II (ARA II) should provide an equivalent or better blockade of the rennin-angiotensin system (absence of tolerance). Clinical trials have shown equivalent haemodynamic effects of the two classes, equal functional tolerance but mortality studies have shown more variable results. None have shown the superiority of ARA II over ACE inhibitors and the demonstration of their equivalence has just been reported with high doses in the post-infarction period. A deleterious effect of ARA II in association with betablockers was reported in two mortality studies but has not been confirmed in the most recent trials. The difficulty is to determine the roles of the association of ARA II-ACE inhibitors, ARA II-antialdosterones or of the association of all three classes of molecules.

  5. High affinity binding of 125I-angiotensin II to rat glomerular basement membranes.

    PubMed Central

    Sraer, J; Baud, L; Cosyns, J P; Verroust, P; Nivez, M P; Ardaillou, R

    1977-01-01

    125I-angiotensin II (AII) specifically bound to rat glomerular basement membrane (GBM). The kinetics of binding were similar to those obtained with the total glomeruli. The apparent dissociation constant was close to 50 pM with both preparations. The number of sites related to the amount of protein was two times greater with GBM than with total glomeruli. Since the amount of GBM protein extracted from a given amount of glomerular protein was about 10%, it was possible to estimate the share of the GBM binding sites for AII as representing 20% of the total number present in the entire glomerulus. Binding studies at equilibrium as a function of 125I-AII concentration and competitive binding experiments suggested either multiplicity of the binding sites or cooperativity in the binding reaction. Degradation of 125I-AII in the presence of GBM was slight and did not increase with time. The difference in the degrees of degradation of 125I-AII was too small to account for the observed difference in binding when the results obtained with GBM and isolated glomeruli preparations were compared. 125I-AII binding to GBM was increased after treatment of these membranes with collagenase, slightly diminished with neuraminidase, and almost completely abolished with trypsin suggesting the proteic nature of the receptor. 125I-AII binding to GBM was diminished after incubation of GBM with anti-GBM antibodies as a result of a decrease in the number of binding sites. 125I-AII binding was even more diminished in preparations of glomeruli isolated from rats passively immunized with anti-GBM antibodies when compared with glomeruli from control animals. This resulted from both smaller affinity for AII and decrease in the number of the binding sites. The present data provides evidence for specific binding sites for AII localized on GBM. This is noteworthy since receptors for polypeptide hormones are currently observed on the surface of cell membranes. These findings also suggest a new

  6. Vascular transcriptome profiling identifies Sphingosine kinase 1 as a modulator of angiotensin II-induced vascular dysfunction

    PubMed Central

    Siedlinski, Mateusz; Nosalski, Ryszard; Szczepaniak, Piotr; Ludwig-Gałęzowska, Agnieszka H.; Mikołajczyk, Tomasz; Filip, Magdalena; Osmenda, Grzegorz; Wilk, Grzegorz; Nowak, Michał; Wołkow, Paweł; Guzik, Tomasz J.

    2017-01-01

    Vascular dysfunction is an important phenomenon in hypertension. We hypothesized that angiotensin II (AngII) affects transcriptome in the vasculature in a region-specific manner, which may help to identify genes related to vascular dysfunction in AngII-induced hypertension. Mesenteric artery and aortic transcriptome was profiled using Illumina WG-6v2.0 chip in control and AngII infused (490 ng/kg/min) hypertensive mice. Gene set enrichment and leading edge analyses identified Sphingosine kinase 1 (Sphk1) in the highest number of pathways affected by AngII. Sphk1 mRNA, protein and activity were up-regulated in the hypertensive vasculature. Chronic sphingosine-1-phosphate (S1P) infusion resulted in a development of significantly increased vasoconstriction and endothelial dysfunction. AngII-induced hypertension was blunted in Sphk1−/− mice (systolic BP 167 ± 4.2 vs. 180 ± 3.3 mmHg, p < 0.05), which was associated with decreased aortic and mesenteric vasoconstriction in hypertensive Sphk1−/− mice. Pharmacological inhibition of S1P synthesis reduced vasoconstriction of mesenteric arteries. While Sphk1 is important in mediating vasoconstriction in hypertension, Sphk1−/− mice were characterized by enhanced endothelial dysfunction, suggesting a local protective role of Sphk1 in the endothelium. S1P serum level in humans was correlated with endothelial function (arterial tonometry). Thus, vascular transcriptome analysis shows that S1P pathway is critical in the regulation of vascular function in AngII-induced hypertension, although Sphk1 may have opposing roles in the regulation of vasoconstriction and endothelium-dependent vasorelaxation. PMID:28276483

  7. Glucose and angiotensin II-derived endothelial extracellular vesicles regulate endothelial dysfunction via ERK1/2 activation.

    PubMed

    Taguchi, Kumiko; Hida, Mari; Narimatsu, Haruka; Matsumoto, Takayuki; Kobayashi, Tsuneo

    2017-02-01

    In various diseases, including diabetes, extracellular vesicles (EVs) have been detected in circulation and tissues. EVs are small membrane vesicles released from various cell types under varying conditions. Recently, endothelial cell-derived EVs (EEVs) were identified as a marker of endothelial dysfunction in diabetes, but the ensuing mechanisms remain poorly understood. In this study, we dissected the ensuing pathways with respect to nitric oxide (NO) production under the condition of type 2 diabetes. Human umbilical vein endothelial cells (HUVECs) were stimulated with glucose alone and with glucose in combination with angiotensin II (Ang II) for 48 h. In supernatants from glucose + Ang II-stimulated HUVECs, release of EEVs was assessed using Western blotting with an anti-CD144 antibody. EEV release was significantly increased after stimulation of HUVECs, and high glucose + Ang II-derived EEVs impaired ACh-induced vascular relaxation responses and NO production in mice aortic rings. Furthermore, high glucose + Ang II-derived EEVs induced ERK1/2 signalling and decreased endothelial NO synthase (eNOS) protein expression in mice aortas. Furthermore, in the presence of the MEK/ERK1/2 inhibitor PD98059, high glucose plus Ang II treatment stimulated EEVs in HUVECs and those EEVs prevented the impairments of ACh-induced relaxation and NO production in mice aortas. These data strongly indicate that high glucose and Ang II directly affect endothelial cells and the production of EEVs; the resultant EEVs aggravate endothelial dysfunction by regulating eNOS protein levels and ERK1/2 signalling in mice aortas.

  8. Angiotensin II stimulates hyperplasia but not hypertrophy in immature ovine cardiomyocytes.

    PubMed

    Sundgren, N C; Giraud, G D; Stork, P J S; Maylie, J G; Thornburg, K L

    2003-05-01

    Rat and sheep cardiac myocytes become binucleate as they complete the 'terminal differentiation' process soon after birth and are not able to divide thereafter. Angiotensin II (Ang II) is known to stimulate hypertrophic changes in rodent cardiomyocytes under both in vivo and in vitro conditions via the AT1 receptor and intracellular extracellular regulated kinase (ERK) signalling cascade. We sought to develop culture methods for immature sheep cardiomyocytes in order to test the hypothesis that Ang II is a hypertrophic agent in the immature myocardium of the sheep. We isolated fetal sheep cardiomyocytes and cultured them for 96 h, added Ang II and phenylephrine (PE) for 48 h, and measured footprint area and proliferation (5-bromo-2'-deoxyuridine (BrdU) uptake) separately in mono- vs. binucleate myocytes. We found that neither Ang II nor PE changed the footprint area of mononucleated cells. PE stimulated an increase in footprint area of binucleate cells but Ang II did not. Ang II increased myocyte BrdU uptake compared to serum free conditions, but PE did not affect BrdU uptake. The MAP kinase kinase (MEK) inhibitor UO126 prevented BrdU uptake in Ang II-stimulated cells and prevented cell hypertrophy in PE-stimulated cells. This paper establishes culture methods for immature sheep cardiomyocytes and reports that: (1) Ang II is not a hypertrophic agent; (2) Ang II stimulates hyperplastic growth among mononucleate myocytes; (3) PE is a hypertrophic agent in binucleate myocytes; and (4) the ERK cascade is required for the proliferation effect of Ang II and the hypertrophic effect of PE.

  9. Angiotensin II stimulates hyperplasia but not hypertrophy in immature ovine cardiomyocytes

    PubMed Central

    Sundgren, N C; Giraud, G D; Stork, P J S; Maylie, J G; Thornburg, K L

    2003-01-01

    Rat and sheep cardiac myocytes become binucleate as they complete the ‘terminal differentiation’ process soon after birth and are not able to divide thereafter. Angiotensin II (Ang II) is known to stimulate hypertrophic changes in rodent cardiomyocytes under both in vivo and in vitro conditions via the AT1 receptor and intracellular extracellular regulated kinase (ERK) signalling cascade. We sought to develop culture methods for immature sheep cardiomyocytes in order to test the hypothesis that Ang II is a hypertrophic agent in the immature myocardium of the sheep. We isolated fetal sheep cardiomyocytes and cultured them for 96 h, added Ang II and phenylephrine (PE) for 48 h, and measured footprint area and proliferation (5-bromo-2′-deoxyuridine (BrdU) uptake) separately in mono- vs. binucleate myocytes. We found that neither Ang II nor PE changed the footprint area of mononucleated cells. PE stimulated an increase in footprint area of binucleate cells but Ang II did not. Ang II increased myocyte BrdU uptake compared to serum free conditions, but PE did not affect BrdU uptake. The MAP kinase kinase (MEK) inhibitor UO126 prevented BrdU uptake in Ang II-stimulated cells and prevented cell hypertrophy in PE-stimulated cells. This paper establishes culture methods for immature sheep cardiomyocytes and reports that: (1) Ang II is not a hypertrophic agent; (2) Ang II stimulates hyperplastic growth among mononucleate myocytes; (3) PE is a hypertrophic agent in binucleate myocytes; and (4) the ERK cascade is required for the proliferation effect of Ang II and the hypertrophic effect of PE. PMID:12626668

  10. The role of angiotensin II type 1 receptor antagonists in elderly patients with hypertension.

    PubMed

    Thomas, G Neil; Chan, Paul; Tomlinson, Brian

    2006-01-01

    Hypertension is a major risk factor for stroke and coronary events in elderly people and clinical trials have shown that treatment of hypertension with various drugs can result in a substantial reduction in cerebrovascular and cardiovascular events. The angiotensin II type 1 (AT1) receptor antagonists are the newest class of antihypertensive agents to be used widely in clinical practice. AT1 receptor antagonists can generally be given once-daily. They are also extremely well tolerated with minimal first-dose hypotension and an incidence of adverse effects similar to that seen with placebo. Adverse event rates are significantly lower than with other classes of antihypertensive drugs including ACE inhibitors. These factors result in improved compliance and increased rates of continuance on therapy. AT1 receptor antagonists show similar efficacy in lowering blood pressure to other classes of antihypertensive agents and their antihypertensive effect is potentiated when they are given concomitantly with low-dose thiazide diuretics. AT1 receptor antagonists are eliminated predominantly by the hepatic route but most are not subject to extensive metabolism and interactions with other drugs are uncommon. This is an advantage in the elderly, who are often receiving multiple medications which increases the risk for adverse drug interactions. Dose adjustments are not usually required in the elderly unless there is plasma volume depletion. Although plasma AT1 receptor antagonist concentrations are generally higher in the elderly than in younger subjects, this pharmacokinetic difference may be balanced by decreased activation of the circulating renin-angiotensin-aldosterone system in the elderly. Recent clinical studies in high-risk hypertensive patients with left ventricular hypertrophy or in patients with diabetic nephropathy or heart failure have demonstrated that AT1 receptor antagonists can improve clinical outcomes to a similar or sometimes greater extent than other

  11. Aldosterone-induced brain MAPK signaling and sympathetic excitation are angiotensin II type-1 receptor dependent.

    PubMed

    Zhang, Zhi-Hua; Yu, Yang; Wei, Shun-Guang; Felder, Robert B

    2012-02-01

    Angiotensin II (ANG II)-induced mitogen-activated protein kinase (MAPK) signaling upregulates angiotensin II type-1 receptors (AT(1)R) in hypothalamic paraventricular nucleus (PVN) and contributes to AT(1)R-mediated sympathetic excitation in heart failure. Aldosterone has similar effects to increase AT(1)R expression in the PVN and sympathetic drive. The present study was undertaken to determine whether aldosterone also activates the sympathetic nervous system via MAPK signaling and, if so, whether its effect is independent of ANG II and AT(1)R. In anesthetized rats, a 4-h intravenous infusion of aldosterone induced increases (P < 0.05) in phosphorylated (p-) p44/42 MAPK in PVN, PVN neuronal excitation, renal sympathetic nerve activity (RSNA), mean blood pressure (MBP), and heart rate (HR). Intracerebroventricular or bilateral PVN microinjection of the p44/42 MAPK inhibitor PD-98059 reduced the aldosterone-induced RSNA, HR, and MBP responses. Intracerebroventricular pretreatment (5 days earlier) with pooled small interfering RNAs targeting p44/42 MAPK reduced total and p-p44/42 MAPK, aldosterone-induced c-Fos expression in the PVN, and the aldosterone-induced increases in RSNA, HR, and MBP. Intracerebroventricular infusion of either the mineralocorticoid receptor antagonist RU-28318 or the AT(1)R antagonist losartan blocked aldosterone-induced phosphorylation of p44/42 MAPK and prevented the increases in RSNA, HR, and MBP. These data suggest that aldosterone-induced sympathetic excitation depends upon that AT(1)R-induced MAPK signaling in the brain. The short time course of this interaction suggests a nongenomic mechanism, perhaps via an aldosterone-induced transactivation of the AT(1)R as described in peripheral tissues.

  12. Pravastatin activates activator protein 2 alpha to argument the angiotensin II-induced abdominal aortic aneurysms.

    PubMed

    Ma, Hui; Liang, Wen-Jing; Shan, Mei-Rong; Wang, Xue-Qing; Zhou, Sheng-Nan; Chen, Yuan; Guo, Tao; Li, Peng; Yu, Hai-Ya; Liu, Chao; Yin, Ya-Ling; Wang, Yu-Lin; Dong, Bo; Pang, Xin-Yan; Wang, Shuang-Xi

    2017-02-04

    We have previously reported that activation of AMP-activated kinase alpha 2 (AMPKα2) by nicotine or angiotensin II (AngII) instigates formation of abdominal aortic aneurysms (AAA) in Apoe-/- mice. Statins, used to treat hyperlipidemia widely, activate AMPK in vascular cells. We sought to examine the effects of pravastatin on AAA formation and uncover the molecular mechanism. The AAA model was induced by AngII and evaluated by incidence, elastin degradation, and maximal abdominal aortic diameter in Apoe-/- mice. The phosphorylated levels of AMPKα2 and activator protein 2 alpha (AP-2α) were examined in cultured vascular smooth muscle cells (VSMCs) or in mice. We observed that pravastatin (50 mg/kg/day, 8 weeks) remarkably increased the AngII-induced AAA incidence in mice. In VSMCs, pravastatin increased the levels of pAMPK, pAP-2α, and MMP2 in both basal and AngII-stressed conditions, which were abolished by tempol and compound C. Pravastatin-upregulated MMP2 was abrogated by AMPKα2 or AP-2α siRNA. Lentivirus-mediated gene silence of AMPKα2 or AP-2α abolished pravastatin-worsened AAA formations in AngII-infused Apoe-/- mice. Clinical investigations demonstrated that both AMPKα2 and AP-2α phosphorylations were increased in AAA patients or human subjects taking pravastatin. In conclusion, pravastatin promotes AAA formation through AMPKα2-dependent AP-2α activations.

  13. LOX-1 dependent overexpression of immunoglobulins in cardiomyocytes in response to angiotensin II.

    PubMed

    Kang, Bum-Yong; Hu, Changping; Prayaga, Sastry; Khaidakov, Magomed; Sawamura, Tatsuya; Seung, Ki-Bae; Mehta, Jawahar L

    2009-02-06

    LOX-1, a cell surface lectin-like receptor, is upregulated by oxidized low-density lipoprotein (ox-LDL) and angiotensin II (Ang II), and plays an important role in host defense. The specific C-type lectin domain on LOX-1 is essential for ox-LDL binding and internalization, generation of oxidant species and eliciting immune response. Here, we show that LOX-1 deletion alters genes that relate to immune response. Microarray (and qPCR) analysis of cardiac tissues showed downregulated expression of several immunoglobulins (Igk-V8, Igk-C, Igh-6, Igj, Ighg, Igh, and Igl-V1) in the LOX-1 knockout (KO) mice [p<0.05 vs. the wild-type (WT) mice]. The expression of these immunoglobulins was upregulated several-fold in the LOX-1 KO mice hearts when these mice were infused with Ang II (p<0.05, vs. WT mice). Importantly, cultured mouse HL-1 cardiomyocytes expressed these immunoglobulins, and pretreatment of cardiomyocytes with a specific anti-LOX-1 antibody enhanced the generation of immunoglobulins upon subsequent exposure to Ang II. These observations mirrored the data obtained from WT and LOX-1 KO mice hearts in the resting state and following Ang II infusion. This study provides first set of data on immunoglobulin expression in cardiac tissues of WT and LOX-1 KO mice and in cultured HL-1 cardiomyocytes, and demonstrates that LOX-1 inactivation leads to upregulation of immunoglobulins in cardiomyocytes upon challenge with Ang II.

  14. Increased dietary sodium alters Fos expression in the lamina terminalis during intravenous angiotensin II infusion.

    PubMed

    Bealer, Steven L; Metcalf, Cameron S; Heyborne, Ryan

    2007-03-01

    These studies examined the effects of increased dietary sodium on expression of Fos, the protein product of c-fos, in forebrain structures in the rat following intravenous infusion with angiotensin II (AngII). Animals were provided with either tap water (Tap) or isotonic saline solution (Iso) as their sole drinking fluid for 3-5 weeks prior to testing. Rats were then implanted with catheters in a femoral artery and vein. The following day, the conscious, unrestrained animals received iv infusion of either isotonic saline (Veh), AngII, or phenylephrine (Phen) for 2 h. Blood pressure and heart rate were monitored continuously throughout the procedure. Brains were subsequently processed for evaluation of Fos-like immunoreactivity (Fos-Li IR) in the organum vasculosum of the lamina terminalis (OVLT), the subfornical organ (SFO), and the median preoptic nucleus (MnPO). Fos-Li IR was significantly increased in the SFO and OVLT of animals consuming both Tap and Iso following AngII, but not Phen, compared to Veh infusions. Furthermore, Fos-Li IR in the MnPO was increased following AngII infusion in rats consuming a high sodium diet, but not in animals drinking Tap. These data suggest that increased dietary sodium sensitizes the MnPO neurons to excitatory input from brain areas responding to circulating AngII.

  15. Nox4-generated superoxide drives angiotensin II-induced neural stem cell proliferation.

    PubMed

    Topchiy, Elena; Panzhinskiy, Evgeniy; Griffin, W Sue T; Barger, Steven W; Das, Mita; Zawada, W Michael

    2013-01-01

    Reactive oxygen species (ROS) have been reported to affect neural stem cell self-renewal and therefore may be important for normal development and may influence neurodegenerative processes when ROS activity is elevated. To determine if increasing production of superoxide, via activation of NADPH oxidase (Nox), increases neural stem cell proliferation, 100 nM angiotensin II (Ang II) - a strong stimulator of Nox - was applied to cultures of a murine neural stem cell line, C17.2. Twelve hours following a single treatment with Ang II, there was a doubling of the number of neural stem cells. This increase in neural stem cell numbers was preceded by a gradual elevation of superoxide levels (detected by dihydroethidium fluorescence) from the steady state at 0, 5, and 30 min and gradually increasing from 1 h to the maximum at 12 h, and returning to baseline at 24 h. Ang II-dependent proliferation was blocked by the antioxidant N-acetyl-L-cysteine. Confocal microscopy revealed the presence of two sources of intracellular ROS in C17.2 cells: (i) mitochondrial and (ii) extramitochondrial; the latter indicative of the involvement of one or more specific isoforms of Nox. Of the Nox family, mRNA expression for one member, Nox4, is abundant in neural stem cell cultures, and Ang II treatment resulted in elevation of the relative levels of Nox4 protein. SiRNA targeting of Nox4 mRNA reduced both the constitutive and Ang II-induced Nox4 protein levels and attenuated Ang II-driven increases in superoxide levels and stem cell proliferation. Our findings are consistent with our hypothesis that Ang II-induced proliferation of neural stem cells occurs via Nox4-generated superoxide, suggesting that an Ang II/Nox4 axis is an important regulator of neural stem cell self-renewal and as such may fine-tune normal, stress- or disease-modifying neurogenesis.

  16. Nox4-generated superoxide drives angiotensin II-induced neural stem cell proliferation

    PubMed Central

    Topchiy, Elena; Panzhinskiy, Evgeniy; Griffin, W. Sue T.; Barger, Steven W.; Das, Mita; Zawada, W. Michael

    2013-01-01

    Reactive oxygen species (ROS) have been reported to affect neural stem cell self-renewal and therefore may be important for normal development and may influence neurodegenerative processes when ROS activity is elevated. To determine if increasing production of superoxide, via activation of NADPH oxidase (Nox), increases neural stem cell proliferation, 100nM angiotensin II (Ang II) – a strong stimulator of Nox – was applied to cultures of a murine neural stem cell line C17.2. Twelve hours following a single treatment with Ang II there was a doubling of the number of neural stem cells. This increase in neural stem cell numbers was preceded by a gradual elevation of superoxide levels (detected by dihydroethidium, DHE, fluorescence) from the steady state at 0, 5, and 30 minutes and gradually increasing from one hour to the maximum at 12 h, and returning to baseline at 24 h. Ang II-dependent proliferation was blocked by the antioxidant N-acetyl-L-cysteine (NAC). Confocal microscopy revealed the presence of two sources of intracellular ROS in C17.2 cells: i) mitochondrial and ii) extramitochondrial; the latter indicative of involvement of one or more specific isoforms of Nox. Of the Nox family, mRNA expression for one member, Nox4, is abundant in neural stem cell cultures, and Ang II treatment resulted in elevation of the relative levels of Nox4 protein. SiRNA targeting of Nox4 mRNA reduced both the constitutive and Ang II-induced Nox4 protein levels and attenuated Ang II-driven increases in superoxide levels and stem cell proliferation. Our findings are consistent with our hypothesis that Ang II-induced proliferation of neural stem cells occurs via Nox4-generated superoxide, suggesting that an Ang II/Nox4 axis is an important regulator of neural stem cell self-renewal and as such may fine-tune normal or stress- or disease-modifying neurogenesis. PMID:23751520

  17. TNF receptor 1 signaling is critically involved in mediating angiotensin-II-induced cardiac fibrosis.

    PubMed

    Duerrschmid, Clemens; Crawford, Jeffrey R; Reineke, Erin; Taffet, George E; Trial, Joann; Entman, Mark L; Haudek, Sandra B

    2013-04-01

    Angiotensin-II (Ang-II) is associated with many conditions involving heart failure and pathologic hypertrophy. Ang-II induces the synthesis of monocyte chemoattractant protein-1 that mediates the uptake of CD34(+)CD45(+) monocytic cells into the heart. These precursor cells differentiate into collagen-producing fibroblasts and are responsible for the Ang-II-induced development of non-adaptive cardiac fibrosis. In this study, we demonstrate that in vitro, using a human monocyte-to-fibroblast differentiation model, Ang-II required the presence of tumor necrosis factor-alpha (TNF) to induce fibroblast maturation from monocytes. In vivo, mice deficient in both TNF receptors did not develop cardiac fibrosis in response to 1week Ang-II infusion. We then subjected mice deficient in either TNF receptor 1 (TNFR1-KO) or TNF receptor 2 (TNFR2-KO) to continuous Ang-II infusion. Compared to wild-type, in TNFR1-KO, but not in TNFR2-KO hearts, collagen deposition was greatly attenuated, and markedly fewer CD34(+)CD45(+) cells were present. Quantitative RT-PCR demonstrated a striking reduction of key fibrosis-related, as well as inflammation-related mRNA expression in Ang-II-treated TNFR1-KO hearts. TNFR1-KO animals also developed less cardiac remodeling, cardiac hypertrophy, and hypertension compared to wild-type and TNFR2-KO in response to Ang-II. Our data suggest that TNF induced Ang-II-dependent cardiac fibrosis by signaling through TNFR1, which enhances the generation of monocytic fibroblast precursors in the heart.

  18. 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

  19. Intravital Imaging Reveals Angiotensin II-Induced Transcytosis of Albumin by Podocytes.

    PubMed

    Schießl, Ina Maria; Hammer, Anna; Kattler, Veronika; Gess, Bernhard; Theilig, Franziska; Witzgall, Ralph; Castrop, Hayo

    2016-03-01

    Albuminuria is a hallmark of kidney disease of various etiologies and usually caused by deterioration of glomerular filtration barrier integrity. We recently showed that angiotensin II (Ang II) acutely increases albumin filtration in the healthy kidney. Here, we used intravital microscopy to assess the effects of Ang II on podocyte function in rats. Acute infusion of 30, 60, or 80 ng/kg per minute Ang II enhanced the endocytosis of albumin by activation of the type 1 Ang II receptor and resulted in an average (±SEM) of 3.7±2.2, 72.3±18.6 (P<0.001), and 239.4±34.6 µm(3) (P<0.001) albumin-containing vesicles per glomerulus, respectively, compared with none at baseline or 10 ng/kg per minute Ang II. Immunostaining of Ang II-infused kidneys confirmed the presence of albumin-containing vesicles, which colocalized with megalin, in podocin-positive cells. Furthermore, podocyte endocytosis of albumin was markedly reduced in the presence of gentamicin, a competitive inhibitor of megalin-dependent endocytosis. Ang II infusion increased the concentration of albumin in the subpodocyte space, a potential source for endocytic protein uptake, and gentamicin further increased this concentration. Some endocytic vesicles were acidified and colocalized with LysoTracker. Most vesicles migrated from the capillary to the apical aspect of the podocyte and were eventually released into the urinary space. This transcytosis accounted for approximately 10% of total albumin filtration. In summary, the transcellular transport of proteins across the podocyte constitutes a new pathway of glomerular protein filtration. Ang II enhances the endocytosis and transcytosis of plasma albumin by podocytes, which may eventually impair podocyte function.

  20. LOX-1 deletion limits cardiac angiogenesis in mice given angiotensin II.

    PubMed

    Wang, Xianwei; Khaidakov, Magomed; Guo, Zhikun; Ding, Zufeng; He, Quanzhong; Mehta, Jawahar L

    2014-10-01

    Lectin-like oxidized low-density lipoprotein (ox-LDL) receptor-1 (LOX-1) is a major receptor for ox-LDL in endothelial cells. Its activation regulates endothelial proliferation, differentiation, migration and apoptosis. Recent in vitro studies show that LOX-1 activation by ox-LDL and angiotensin II (Ang II) induces angiogenesis via activation of NADPH oxidase and subsequent increase in ROS production. In this study, we investigated the effect of LOX-1 gene deletion (LOX-1 knockout or KO mice) on angiogenesis in response to prolonged Ang II infusion in vivo. Our studies showed that Ang II (vs. saline) infusion enhanced capillary formation in subcutaneously injected Matrigel® plugs. Ang II infusion also resulted in marked angiogenesis in the hearts as determined by CD31 immunopositivity. There was an increased expression (RT-PCR and Western blotting) of CD31 and VEGF in the hearts of mice infused with Ang II, indicating pro-angiogenic miliue. More importantly, LOX-1 KO mice reveled markedly limited angiogenesis in the Matrigel® plugs as well as in the hearts despite similar infusion with Ang II (all P < 0.05 vs. wild-type mice). In addition, the hearts of LOX-1 KO mice had attenuated expression of pro-inflammatory and angiogenic signals MCP-1 and IL-1β following Ang II Infusion. Lastly, the rise in blood pressure in response to Ang II was less in the LOX-1 KO mice (P < 0.05 vs. wild-type mice). Our findings suggest that LOX-1 participates in angiogenesis in hypertension, which may be related to a state of inflammation.

  1. Purkinje cells express Angiotensin II AT(2) receptors at different developmental stages.

    PubMed

    Arce, María E; Sánchez, Susana I; Aguilera, Francisco López; Seguin, Leonardo R; Seltzer, Alicia M; Ciuffo, Gladys M

    2011-02-01

    Angiotensin II (Ang II) binds and activates two major receptors subtypes, namely AT(1) and AT(2). In the fetus, AT(2) receptors predominate in all tissues and decline shortly after birth, being restricted to a few organs including brain. Interpretation of the function of Ang II in the cerebellum requires a thorough understanding of the localization of Ang II receptors. The aim of the present paper is to evaluate the localization of Ang II AT(2) receptors in the Purkinje cell (PC) layer during development. By binding autoradiography, a clear complementary pattern of AT(1) and AT(2) binding labeled by [(125)I] Ang II was observed in young rats within the cerebellar cortex. This pattern was present at the stages P8 and P15, but not at P30 and P60, where AT(2) binding appears low and superimposed with AT(1) binding. We demonstrate that AT(2) antibodies recognized postmitotic Purkinje cells, labeling the somata of these cells at all the stages studied, from P8 to P60, suggesting that PCs express these receptors from early stages of development until adulthood. In P8 and P15 animals, we observed a clear correspondence between immunolabeling and the well-defined layer observed by binding autoradiography. Confocal analysis allowed us to discard the co-localization of AT(2) receptors with glial fibrillary acidic protein (GFAP), a glial marker. Double immunolabeling allowed us to demonstrate the co-localization of Ang II AT(2) receptors with zebrin II, a specific PC marker. Since PCs are the sole output signal from the cerebellar cortex and considering the role of cerebellum in movement control, the specific receptor localization suggests a potential role for Ang II AT(2) receptors in the cerebellar function.

  2. Sex differences in T-lymphocyte tissue infiltration and development of angiotensin II hypertension.

    PubMed

    Pollow, Dennis P; Uhrlaub, Jennifer; Romero-Aleshire, Melissa J; Sandberg, Kathryn; Nikolich-Zugich, Janko; Brooks, Heddwen L; Hay, Meredith

    2014-08-01

    There is extensive evidence that activation of the immune system is both necessary and required for the development of angiotensin II (Ang II)-induced hypertension in males. The purpose of this study was to determine whether sex differences exist in the ability of the adaptive immune system to induce Ang II-dependent hypertension and whether central and renal T-cell infiltration during Ang II-induced hypertension is sex dependent. Recombinant activating gene-1 (Rag-1)(-/-) mice, lacking both T and B cells, were used. Male and female Rag-1(-/-) mice received adoptive transfer of male CD3(+) T cells 3 weeks before 14-day Ang II infusion (490 ng/kg per minute). Blood pressure was monitored via tail cuff. In the absence of T cells, systolic blood pressure responses to Ang II were similar between sexes (Δ22.1 mm Hg males versus Δ18 mm : Hg females). After adoptive transfer of male T cells, Ang II significantly increased systolic blood pressure in males (Δ37.7 mm : Hg; P<0.05) when compared with females (Δ13.7 mm : Hg). Flow cytometric analysis of total T cells and CD4(+), CD8(+), and regulatory Foxp3(+)-CD4(+) T-cell subsets identified that renal lymphocyte infiltration was significantly increased in males versus females in both control and Ang II-infused animals (P<0.05). Immunohistochemical staining for CD3(+)-positive T cells in the subfornical organ region of the brain was increased in males when compared with that in females. These results suggest that female Rag-1(-/-) mice are protected from male T-cell-mediated increases in Ang II-induced hypertension when compared with their male counterparts, and this protection may involve sex differences in the magnitude of T-cell infiltration of the kidney and brain.

  3. Vasopressin and angiotensin II in reflex regulation of ACTH, glucocorticoids, and renin: effect of water deprivation

    NASA Technical Reports Server (NTRS)

    Brooks, V. L.; Keil, L. C.

    1992-01-01

    Angiotensin II (ANG II) and vasopressin participate in baroreflex regulation of adrenocorticotropic hormone (ACTH), glucocorticoid, and renin secretion. The purpose of this study was to determine whether this participation is enhanced in water-deprived dogs, with chronically elevated plasma ANG II and vasopressin levels, compared with water-replete dogs. The baroreflex was assessed by infusing increasing doses of nitroprusside (0.3, 0.6, 1.5, and 3.0 micrograms.kg-1.min-1) in both groups of animals. To quantitate the participation of ANG II and vasopressin, the dogs were untreated or pretreated with the competitive ANG II antagonist saralasin, a V1-vasopressin antagonist, or combined V1/V2-vasopressin antagonist, either alone or in combination. The findings were as follows. 1) Larger reflex increases in ANG II, vasopressin, and glucocorticoids, but not ACTH, were produced in water-deprived dogs compared with water-replete dogs. 2) ANG II blockade blunted the glucocorticoid and ACTH responses to hypotension in water-deprived dogs, but not water-replete dogs. In contrast, vasopressin blockade reduced the ACTH response only in water-replete dogs. 3) Vasopressin or combined vasopressin and ANG II blockade reduced the plasma level of glucocorticoids related either to the fall in arterial pressure or to the increase in plasma ACTH concentration in water-replete dogs, and this effect was enhanced in water-deprived dogs. 4) In both water-deprived and water-replete animals, saralasin and/or a V1-antagonist increased the renin response to hypotension, but a combined V1/V2-antagonist did not. These results reemphasize the importance of endogenous ANG II and vasopressin in the regulation of ACTH, glucocorticoid, and renin secretion.(ABSTRACT TRUNCATED AT 250 WORDS).

  4. Mitogen-activated protein kinase-activated protein kinase 2 in angiotensin II-induced inflammation and hypertension: regulation of oxidative stress.

    PubMed

    Ebrahimian, Talin; Li, Melissa Wei; Lemarié, Catherine A; Simeone, Stefania M C; Pagano, Patrick J; Gaestel, Matthias; Paradis, Pierre; Wassmann, Sven; Schiffrin, Ernesto L

    2011-02-01

    Vascular oxidative stress and inflammation play an important role in angiotensin II-induced hypertension, and mitogen-activated protein kinases participate in these processes. We questioned whether mitogen-activated protein kinase-activated protein kinase 2 (MK2), a downstream target of p38 mitogen-activated protein kinase, is involved in angiotensin II-induced vascular responses. In vivo experiments were performed in wild-type and Mk2 knockout mice infused intravenously with angiotensin II. Angiotensin II induced a 30 mm Hg increase in mean blood pressure in wild-type that was delayed in Mk2 knockout mice. Angiotensin II increased superoxide production and vascular cell adhesion molecule-1 in blood vessels of wild-type but not in Mk2 knockout mice. Mk2 knockdown by small interfering RNA in mouse mesenteric vascular smooth muscle cells caused a 42% reduction in MK2 protein and blunted the angiotensin II-induced 40% increase of MK2 expression. Mk2 knockdown blunted angiotensin II-induced doubling of intracellular adhesion molecule-1 expression, 2.4-fold increase of nuclear p65, and 1.4-fold increase in Ets-1. Mk2 knockdown abrogated the angiotensin II-induced 4.7-fold and 1.3-fold increase of monocyte chemoattractant protein-1 mRNA and protein. Angiotensin II enhanced reactive oxygen species levels (by 29%) and nicotinamide adenine dinucleotide phosphate oxidase activity (by 48%), both abolished by Mk2 knockdown. Reduction of MK2 blocked angiotensin II-induced p47phox translocation to the membrane, associated with a 53% enhanced catalase expression. Angiotensin II-induced increase of MK2 was prevented by the nicotinamide adenine dinucleotide phosphate oxidase inhibitor Nox2ds-tat. Mk2 small interfering RNA prevented the angiotensin II-induced 30% increase of proliferation. In conclusion, MK2 plays a critical role in angiotensin II signaling, leading to hypertension, oxidative stress via activation of p47phox and inhibition of antioxidants, and vascular inflammation

  5. Angiotensin II type-1 receptor (AT1R) regulates expansion, differentiation, and functional capacity of antigen-specific CD8+ T cells

    PubMed Central

    Silva-Filho, João Luiz; Caruso-Neves, Celso; Pinheiro, Ana Acacia Sá

    2016-01-01

    Angiotensin II (Ang II) and its receptor AT1 (AT1R), an important effector axis of renin-angiotensin system (RAS), have been demonstrated to regulate T-cell responses. However, these studies characterized Ang II and AT1R effects using pharmacological tools, which do not target only Ang II/AT1R axis. The specific role of AT1R expressed by antigen-specific CD8+ T cells is unknown. Then we immunized transgenic mice expressing a T-cell receptor specific for SIINFEKL epitope (OT-I mice) with sporozoites of the rodent malaria parasite Plasmodium berghei expressing the cytotoxic epitope SIINFEKL. Early priming events after immunization were not affected but the expansion and contraction of AT1R-deficient (AT1R−/−) OT-I cells was decreased. Moreover, they seemed more activated, express higher levels of CTLA-4, PD-1, LAG-3, and have decreased functional capacity during the effector phase. Memory AT1R−/− OT-I cells exhibited higher IL-7Rα expression, activation, and exhaustion phenotypes but less cytotoxic capacity. Importantly, AT1R−/− OT-I cells show better control of blood parasitemia burden and ameliorate mice survival during lethal disease induced by blood-stage malaria. Our study reveals that AT1R in antigen-specific CD8+ T cells regulates expansion, differentiation, and function during effector and memory phases of the response against Plasmodium, which could apply to different infectious agents. PMID:27782175

  6. Effect of Cyclosporin A and Angiotensin II on cytosolic calcium levels in primary human gingival fibroblasts

    PubMed Central

    Supraja, Ajitkumar; Dinesh, Murugan Girija; Rajasekaran, Subbarayan; Balaji, Thodur Madapusi; Rao, Suresh Ranga

    2016-01-01

    Background: To evaluate the effect of Cyclosporin A (CsA) and angiotensin II (Ang II) on cytosolic calcium levels in cultured human gingival fibroblasts (HGFs). Materials and Methods: Healthy gingival samples from six volunteers were obtained, and primary HGFs were cultured. Cell viability and proliferation assay were performed to identify the ideal concentrations of CsA and Ang II. Cytosolic calcium levels in cultured gingival fibroblasts treated with CsA and Ang II were studied using colorimetric assay, confocal and fluorescence imaging. Statistical analyses were done using SPSS software and GraphPad Prism. Results: Higher levels of cytosolic levels were evident in cells treated with CsA and Ang II when compared to control group and was statistically significant (P < 0.05) in both colorimetric assay and confocal imaging. Fluorescent images of the cultured HGFs revealed the same. Conclusion: Thus calcium being a key player in major cellular functions, plays a major role in the pathogenesis of drug-induced gingival overgrowth. PMID:27857765

  7. NLRP3 Deficiency Improves Angiotensin II-Induced Hypertension But Not Fetal Growth Restriction During Pregnancy.

    PubMed

    Shirasuna, Koumei; Karasawa, Tadayoshi; Usui, Fumitake; Kobayashi, Motoi; Komada, Tadanori; Kimura, Hiroaki; Kawashima, Akira; Ohkuchi, Akihide; Taniguchi, Shun'ichiro; Takahashi, Masafumi

    2015-11-01

    Preeclampsia is a pregnancy-specific syndrome characterized by elevated blood pressure, proteinuria, and intrauterine growth restriction (IUGR). Although sterile inflammation appears to be involved, its pathogenesis remains unclear. Recent evidence indicates that sterile inflammation is mediated through the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes, composed of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1. Here we investigated the role of the NLRP3 inflammasomes in the pathogenesis of preeclampsia using Nlrp3(-/-) and Asc(-/-) (Nlrp3 and Asc deficient) pregnant mice. During pregnancy in mice, continuous infusion of high-dose angiotensin II (AngII) induced hypertension, proteinuria, and IUGR, whereas infusion of low-dose AngII caused hypertension alone. AngII-induced hypertension was prevented in Nlrp3(-/-) mice but not in Asc(-/-), indicating that NLRP3 contributes to gestational hypertension independently of ASC-mediated inflammasomes. Although NLRP3 deficiency had no effect on IUGR, it restored the IL-6 up-regulation in the placenta and kidney of AngII-infused mice. Furthermore, treatment with hydralazine prevented the development of gestational hypertension but not IUGR or IL-6 expression in the placenta and kidney. These findings demonstrate that NLRP3 contributes to the development of gestational hypertension independently of the inflammasomes and that IUGR and kidney injury can occur independent of blood pressure elevation during pregnancy.

  8. Attenuation of myocardial fibrosis with curcumin is mediated by modulating expression of angiotensin II AT1/AT2 receptors and ACE2 in rats

    PubMed Central

    Pang, Xue-Fen; Zhang, Li-Hui; Bai, Feng; Wang, Ning-Ping; Garner, Ron E; McKallip, Robert J; Zhao, Zhi-Qing

    2015-01-01

    Curcumin is known to improve cardiac function by balancing degradation and synthesis of collagens after myocardial infarction. This study tested the hypothesis that inhibition of myocardial fibrosis by curcumin is associated with modulating expression of angiotensin II (Ang II) receptors and angiotensin-converting enzyme 2 (ACE2). Male Sprague Dawley rats were subjected to Ang II infusion (500 ng/kg/min) using osmotic minipumps for 2 and 4 weeks, respectively, and curcumin (150 mg/kg/day) was fed by gastric gavage during Ang II infusion. Compared to the animals with Ang II infusion, curcumin significantly decreased the mean arterial blood pressure during the course of the observation. The protein level of the Ang II type 1 (AT1) receptor was reduced, and the Ang II type 2 (AT2) receptor was up-regulated, evidenced by an increased ratio of the AT2 receptor over the AT1 receptor in the curcumin group (1.2±0.02%) vs in the Ang II group (0.7±0.03%, P<0.05). These changes were coincident with less locally expressed AT1 receptor and enhanced AT2 receptor in the intracardiac vessels and intermyocardium. Along with these modulations, curcumin significantly decreased the populations of macrophages and alpha smooth muscle actin-expressing myofibroblasts, which were accompanied by reduced expression of transforming growth factor beta 1 and phosphorylated-Smad2/3. Collagen I synthesis was inhibited, and tissue fibrosis was attenuated, as demonstrated by less extensive collagen-rich fibrosis. Furthermore, curcumin increased protein level of ACE2 and enhanced its expression in the intermyocardium relative to the Ang II group. These results suggest that curcumin could be considered as an add-on therapeutic agent in the treatment of fibrosis-derived heart failure patient who is intolerant of ACE inhibitor therapy. PMID:26648693

  9. Angiotensin II and aldosterone increase with fasting in breeding adult male northern elephant seals (Mirounga angustirostris).

    PubMed

    Ortiz, Rudy M; Crocker, Daniel E; Houser, Dorian S; Webb, Paul M

    2006-01-01

    The renin-angiotensin-aldosterone system (RAAS) appears to contribute significantly to osmoregulation of fasting northern elephant seal (Mirounga angustirostris) pups; however, RAAS has not been characterized in fasting adult seals. Therefore, this study examined the contribution of RAAS to water turnover rates in fasting adult male northern elephant seals. Blood samples were obtained twice during their breeding fast at an interval of 6.5 wk, and water efflux rate was estimated by isotopic dilution during the same period. Serum electrolytes (Na+, K+, Cl-) and osmolality were unaltered between the two sampling periods, indicating ionic and osmotic homeostasis during the fast. Despite the lack of an increase in vasopressin, serum angiotensin II and aldosterone were increased and were significantly and positively correlated. Changes in aldosterone concentration and water efflux rate were significantly and negatively correlated, suggesting that the greater the increase in aldosterone, the smaller the loss of water. Adult male seals maintain ionic and osmotic homeostasis similar to that of fasting weaned pups, and this homeostasis appears to be mediated, at least in part, by RAAS, which probably contributes to increased water retention as well. The hormonal mechanisms by which northern elephant seals maintain water and electrolyte balance during fasting conditions appear to be similar regardless of age.

  10. Effect of interactions between nitric oxide and angiotensin II on pressure diuresis and natriuresis.

    PubMed

    Madrid, M I; García-Salom, M; Tornel, J; De Gasparo, M; Fenoy, F J

    1997-11-01

    The present study examined the effect of an angiotensin II AT1 or AT2 receptor antagonist on the impairment of the pressure diuresis and natriuresis response produced by nitric oxide (NO) synthesis blockade. N omega-nitro-L-arginine methyl ester (L-NAME, 37 nmol.kg-1.min-1) lowered renal blood flow and reduced the slopes of the pressure diuresis and natriuresis responses by 44 and 40%, respectively. Blockade of AT1 receptors with valsartan increased slightly sodium and water excretion at low renal perfusion pressure (RPP). Blockade of AT2 receptors with PD-123319 had no effect on renal function. The administration of valsartan or PD-123319 to rats given L-NAME had no effect on the renal vasoconstriction induced by NO synthesis blockade. In addition, in rats given L-NAME, valsartan elevated baseline excretory values at all RPP studied, but it had no effect on the sensitivity of the pressure diuresis and natriuresis response. However, the administration of PD-123319 to L-NAME-pretreated rats shifted the slopes of the pressure diuresis and natriuresis responses toward control values, indicating that the impairment produced by NO synthesis blockade on pressure diuresis is dependent on the activation of AT2 angiotensin receptors.

  11. A functional siRNA screen identifies genes modulating angiotensin II-mediated EGFR transactivation

    PubMed Central

    George, Amee J.; Purdue, Brooke W.; Gould, Cathryn M.; Thomas, Daniel W.; Handoko, Yanny; Qian, Hongwei; Quaife-Ryan, Gregory A.; Morgan, Kylie A.; Simpson, Kaylene J.; Thomas, Walter G.; Hannan, Ross D.

    2013-01-01

    Summary The angiotensin type 1 receptor (AT1R) transactivates the epidermal growth factor receptor (EGFR) to mediate cellular growth, however, the molecular mechanisms involved have not yet been resolved. To address this, we performed a functional siRNA screen of the human kinome in human mammary epithelial cells that demonstrate a robust AT1R–EGFR transactivation. We identified a suite of genes encoding proteins that both positively and negatively regulate AT1R–EGFR transactivation. Many candidates are components of EGFR signalling networks, whereas others, including TRIO, BMX and CHKA, have not been previously linked to EGFR transactivation. Individual knockdown of TRIO, BMX or CHKA attenuated tyrosine phosphorylation of the EGFR by angiotensin II stimulation, but this did not occur following direct stimulation of the EGFR with EGF, indicating that these proteins function between the activated AT1R and the EGFR. Further investigation of TRIO and CHKA revealed that their activity is likely to be required for AT1R–EGFR transactivation. CHKA also mediated EGFR transactivation in response to another G protein-coupled receptor (GPCR) ligand, thrombin, indicating a pervasive role for CHKA in GPCR–EGFR crosstalk. Our study reveals the power of unbiased, functional genomic screens to identify new signalling mediators important for tissue remodelling in cardiovascular disease and cancer. PMID:24046455

  12. Deletion of microsomal prostaglandin E synthase-1 increases sensitivity to salt loading and angiotensin II infusion.

    PubMed

    Jia, Zhanjun; Zhang, Aihua; Zhang, Hui; Dong, Zheng; Yang, Tianxin

    2006-11-24

    Microsomal prostaglandin E synthase-1 (mPGES-1), a membrane-associated protein, is critically involved in the inflammatory response and may be involved in physiological processes as well. The present study examined the role of mPGES-1 in regulation of sodium balance and blood pressure in the settings of salt loading and angiotensin II infusion. mPGES-1 -/- mice developed severe and progressive hypertension associated with an inappropriate increase in sodium balance when fed a high-salt diet. These mice exhibited a significantly impaired ability to excrete an acute enteral load of NaCl. Under these 2 settings of salt loading, urinary excretion of prostaglandin E(2) and nitrate/nitrite were remarkably increased in wild-type animals but not in mPGES-1 -/- mice. The changes of urinary cGMP paralleled that of urinary nitrate/nitrite. mPGES-1 -/- mice exhibited a remarkable inhibition of high salt-induced increase in gene expression of all 3 NO synthase isoforms, whereas these mice had upregulated expression of NO synthase III but not NO synthase I and NO synthase II at basal state. Chronic salt loading remarkably induced mPGES-1 protein expression exclusively in the distal nephron. In primary cultures of CD cells, mPGES-1 expression was significantly increased following exposure to hypertonic NaCl, in parallel with increased prostaglandin E(2) release. These findings have revealed a mPGES-1/prostaglandin E(2)/NO/cGMP pathway that appears to be critically important for salt adaptation. In addition, we provide evidence that mPGES-1 deficiency sensitized the hypertensive effect of angiotensin II. Overall, this study has characterized the natriuretic and antihypertensive role of mPGES-1 that likely contributes to blood pressure homeostasis.

  13. The effects of angiotensin II and the oxidative stress mediator 4-hydroxynonenal on human osteoblast-like cell growth: possible relevance to otosclerosis.

    PubMed

    Rudić, Milan; Milković, Lidija; Žarković, Kamelija; Borović-Šunjić, Suzana; Sterkers, Olivier; Waeg, Georg; Ferrary, Evelyne; Bozorg Grayeli, Alexis; Žarković, Neven

    2013-04-01

    Otosclerosis is a complex disease characterized by an abnormal bone turnover of the otic capsule resulting in conductive hearing loss. Recent findings have shown that angiotensin II (Ang II), a major effector peptide of the renin-angiotensin system, plays an important role in the pathophysiology of otosclerosis, most likely by its proinflammatory effects on the bone cells. Because reactive oxygen species play a role both in inflammation and in the cellular signaling pathway of Ang II, the appearance of protein adducts of the "second messenger of free radicals," the aldehyde 4-hydroxynonenal (HNE), in otosclerotic bone has been analyzed. Immunohistochemical analysis of HNE-modified proteins in tissue samples of the stapedial bones performed on 15 otosclerotic patients and 6 controls revealed regular HNE-protein adducts present in the subperiosteal parts of control bone specimens, whereas irregular areas of a pronounced HNE-protein adduct presence were found within stapedial bone in cases of otosclerosis. To study possible interference by HNE and Ang II in human bone cell proliferation, differentiation, and induction of apoptosis we used an in vitro model of osteoblast-like cells. HNE interacted with Ang II in a dose-dependent manner, both by forming HNE-Ang II adducts, as revealed by immunoblotting, and by modifying its effects on cultured cells. Namely, treatment with 0.1 nM Ang II and 2.5 μM HNE stimulated proliferation, whereas treatment with 10 μM HNE or in combination with Ang II (0.1, 0.5, and 1 nM) decreased cell proliferation. Moreover, 10 μM HNE alone and with Ang II (except if 1 nM Ang II was used) increased cellular differentiation and apoptosis. HNE at 5 μM did not affect differentiation nor significantly change apoptosis. On the other hand, when cells were treated with lower concentrations of HNE and Ang II we observed a decrease in cellular differentiation (combination of 1.0 or 2.5 μM HNE with 0.1 nM Ang II) and decrease in apoptosis (0.1 and 0

  14. Fructose stimulates Na/H exchange activity and sensitizes the proximal tubule to angiotensin II.

    PubMed

    Cabral, Pablo D; Hong, Nancy J; Hye Khan, Md Abdul; Ortiz, Pablo A; Beierwaltes, William H; Imig, John D; Garvin, Jeffrey L

    2014-03-01

    The proximal nephron reabsorbs 60% to 70% of the fluid and sodium and most of the filtered bicarbonate via Na/H exchanger 3. Enhanced proximal nephron transport is implicated in hypertension. Our findings show that a fructose-enriched diet causes salt sensitivity. We hypothesized that fructose stimulates luminal Na/H exchange activity and sensitizes the proximal tubule to angiotensin II. Na/H exchange was measured in rat proximal tubules as the rate of intracellular pH (pHi) recovery in fluorescent units/s. Replacing 5 mmol/L glucose with 5 mmol/L fructose increased the rate of pHi recovery (1.8±0.6 fluorescent units/s; P<0.02; n=8). Staurosporine, a protein kinase C inhibitor, blocked this effect. We studied whether this effect was because of the addition of fructose or removal of glucose. The basal rate of pHi recovery was first tested in the presence of a 0.6-mmol/L glucose and 1, 3, or 5 mmol/L fructose added in a second period. The rate of pHi recovery did not change with 1 mmol/L but it increased with 3 and 5 mmol/L of fructose. Adding 5 mmol/L glucose caused no change. Removal of luminal sodium blocked pHi recovery. With 5.5 mmol/L glucose, angiotensin II (1 pmol/L) did not affect the rate of pHi recovery (change, -1.1±0.5 fluorescent units/s; n=9) but it increased the rate of pHi recovery with 0.6 mmol/L glucose/5 mmol/L fructose (change, 4.0±2.2 fluorescent units/s; P<0.02; n=6). We conclude that fructose stimulates Na/H exchange activity and sensitizes the proximal tubule to angiotensin II. This mechanism is likely dependent on protein kinase C. These results may partially explain the mechanism by which a fructose diet induces hypertension.

  15. Exercise training enhances baroreflex sensitivity by an angiotensin II-dependent mechanism in chronic heart failure.

    PubMed

    Mousa, Tarek M; Liu, Dongmei; Cornish, Kurtis G; Zucker, Irving H

    2008-03-01

    Exercise training (EX) has become an important modality capable of enhancing the quality of life and survival of patients with chronic heart failure (CHF). Although 4 wk of EX in animals with CHF evoked a reduction in renal sympathetic nerve activity and ANG II plasma levels and an enhancement in baroreflex sensitivity at rest (Liu JL, Irvine S, Reid IA, Patel KP, Zucker IH, Circulation 102: 1854-1862, 2000; Liu JL, Kulakofsky J, Zucker IH, J Appl Physiol 92: 2403-2408, 2002), it is unclear whether these phenomena are causally related. CHF was induced in rabbits by ventricular pacing (360-380 beats/min) for 3 wk. CHF rabbits were EX for 4 wk at 15-18 m/min, 6 days/wk, 30-40 min/day. Three groups of rabbits were studied: CHF (with no EX), CHF-EX, and CHF-EX + ANG II infusion [in which ANG II levels were kept at or near levels observed in CHF (non-EX) rabbits by subcutaneous osmotic minipump infusion]. EX prevented the increase in plasma ANG II levels shown in CHF rabbits. CHF and CHF-EX + ANG II infusion rabbits had significantly depressed baroreflex sensitivity slopes (P < 0.01 for sodium nitroprusside and P < 0.001 for phenylephrine) and higher baseline renal sympathetic nerve activities than CHF-EX animals. EX downregulated mRNA and protein expression of ANG II type 1 receptors in the rostral ventrolateral medulla in CHF rabbits. This was prevented by ANG II infusion. These data are consistent with the view that the reduction in sympathetic nerve activity and the improvement in baroreflex function in CHF after EX are due to the concomitant reduction in ANG II and angiotensin receptors in the central nervous system.

  16. Fenofibrate Therapy Restores Antioxidant Protection and Improves Myocardial Insulin Resistance in a Rat Model of Metabolic Syndrome and Myocardial Ischemia: The Role of Angiotensin II.

    PubMed

    Ibarra-Lara, Luz; Sánchez-Aguilar, María; Sánchez-Mendoza, Alicia; Del Valle-Mondragón, Leonardo; Soria-Castro, Elizabeth; Carreón-Torres, Elizabeth; Díaz-Díaz, Eulises; Vázquez-Meza, Héctor; Guarner-Lans, Verónica; Rubio-Ruiz, María Esther

    2016-12-28

    Renin-angiotensin system (RAS) activation promotes oxidative stress which increases the risk of cardiac dysfunction in metabolic syndrome (MetS) and favors local insulin resistance. Fibrates regulate RAS improving MetS, type-2 diabetes and cardiovascular diseases. We studied the effect of fenofibrate treatment on the myocardic signaling pathway of Angiotensin II (Ang II)/Angiotensin II type 1 receptor (AT1) and its relationship with oxidative stress and myocardial insulin resistance in MetS rats under heart ischemia. Control and MetS rats were assigned to the following groups: (a) sham; (b) vehicle-treated myocardial infarction (MI) (MI-V); and (c) fenofibrate-treated myocardial infarction (MI-F). Treatment with fenofibrate significantly reduced triglycerides, non-high density lipoprotein cholesterol (non-HDL-C), insulin levels and insulin resistance index (HOMA-IR) in MetS animals. MetS and MI increased Ang II concentration and AT1 expression, favored myocardial oxidative stress (high levels of malondialdehyde, overexpression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4), decreased total antioxidant capacity and diminished expression of superoxide dismutase (SOD)1, SOD2 and catalase) and inhibited expression of the insulin signaling cascade: phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PkB, also known as Akt)/Glut-4/endothelial nitric oxide synthase (eNOS). In conclusion, fenofibrate treatment favors an antioxidant environment as a consequence of a reduction of the Ang II/AT1/NOX4 signaling pathway, reestablishing the cardiac insulin signaling pathway. This might optimize cardiac metabolism and improve the vasodilator function during myocardial ischemia.

  17. Interaction of angiotensin II and nitric oxide in isolated perfused afferent arterioles of mice.

    PubMed

    Patzak, A; Mrowka, R; Storch, E; Hocher, B; Persson, P B

    2001-06-01

    The present study was performed to evaluate angiotensin II (Ang II)-nitric oxide (NO) interaction in afferent arterioles (Af) of wild-type mice and mice that are homozygous (-/-) for disruption of the endothelial NO synthase (eNOS) gene. Af were microperfused, and the dose responses were assessed for the NO precursor L-arginine (n = 4), NO inhibitor NG-nitro-L-arginine methyl ester (L-NAME, n = 5), L-NAME after pretreatment with L-arginine (n = 5), Ang II (n = 8), and Ang II after pretreatment with L-NAME (n = 7). Acute administration of L-arginine and L-NAME (both in doses from 10(-6) to 10(-3) mol/L) did not change arteriolar diameter. Moreover, pretreatment with L-arginine did not change the response to L-NAME. However, Ang II, applied in doses of 10(-12), 10(-10), 10(-8), and 10(-6) mol/L, significantly reduced the lumen to 66.5 +/- 7.0% and 62.2 +/- 8.0% at 10(-8) and 10(-6) mol/L Ang II, respectively. The contraction was augmented after L-NAME pretreatment (19.5 +/- 13.6% and 25.5 +/- 10.2% at 10(-8) and 10(-6) mol/L Ang II, respectively). In eNOS (-/-) mice (n = 8), the response to Ang II also was enhanced (9.1 +/- 6.0% and 11.2 +/- 8.2% at 10(-8) and 10(-6) mol/L Ang II, respectively). Female mice did not differ from male mice in their reactivity to Ang II (n = 9) and Ang II + L-NAME pretreatment (n = 11). The study shows that (1) it is feasible to microperfuse mouse Af, (2) the basal production of endothelial NO is very low and not inducible by L-arginine in Af of mice, and (3) a counteracting effect of NO is initiated by Ang II. High Ang II sensitivity in eNOS (-/-) mice underscores the considerable role of endothelial-derived NO to balance Ang II vasoconstriction in Af.

  18. Use of Antihypertensive Drugs and Ischemic Stroke Severity – Is There a Role for Angiotensin-II?

    PubMed Central

    Bots, Michiel L.; Selvarajah, Sharmini; Abdul Aziz, Zariah; Sidek, Norsima Nazifah; Spiering, Wilko; Kappelle, L. Jaap; Vaartjes, Ilonca

    2016-01-01

    Background The increase in angiotensin II (Ang II) formation by selected antihypertensive drugs is said to exhibit neuroprotective properties, but this translation into improvement in clinical outcomes has been inconclusive. We undertook a study to investigate the relationship between types of antihypertensive drugs used prior to a stroke event and ischemic stroke severity. We hypothesized that use of antihypertensive drugs that increase Ang II formation (Ang II increasers) would reduce ischemic stroke severity when compared to antihypertensive drugs that suppress Ang II formation (Ang II suppressors). Methods From the Malaysian National Neurology Registry, we included hypertensive patients with first ischemic stroke who presented within 48 hours from ictus. Antihypertensive drugs were divided into Ang II increasers (angiotensin-I receptor blockers (ARBs), calcium channel blockers (CCBs) and diuretics) and Ang II suppressors (angiotensin-converting-enzyme inhibitors (ACEIs) and beta blockers). We evaluated stroke severity during admission with the National Institute of Health Stroke Scale (NIHSS). We performed a multivariable logistic regression with the score being dichotomized at 15. Scores of less than 15 were categorized as less severe stroke. Results A total of 710 patients were included. ACEIs was the most commonly prescribed antihypertensive drug in patients using Ang II suppressors (74%) and CCBs, in patients prescribed with Ang II increasers at 77%. There was no significant difference in the severity of ischemic stroke between patients who were using Ang II increasers in comparison to patients with Ang II suppressors (OR: 1.32, 95%CI: 0.83–2.10, p = 0.24). Conclusion In our study, we found that use of antihypertensive drugs that increase Ang II formation was not associated with less severe ischemic stroke as compared to use of antihypertensive drugs that suppress Ang II formation. PMID:27846309

  19. Chemical modifications of the vasoconstrictor peptide angiotensin II by nitrogen oxides (NO, HNO2, HOONO)--evaluation by mass spectrometry.

    PubMed

    Ducrocq, C; Dendane, M; Laprévote, O; Serani, L; Das, B C; Bouchemal-Chibani, N; Doan, B T; Gillet, B; Karim, A; Carayon, A; Payen, D

    1998-04-01

    Nitric oxide (NO) and angiotensin II are natural regulators of blood pressure. Under aerobic conditions, NO is transformed into its higher oxides (N2O4, NO2, NO/NO2 or N2O3) and oxoperoxonitrate (currently named peroxynitrite) by coupling with superoxide. Previous studies have shown that these reactive nitrogen species should be involved in vivo in the transformation of cysteine and tyrosine into the corresponding nitrosothiol and 3-nitrotyrosine. In the present study, attention has been focused on the relative reactivities of HNO2, peroxynitrite, and NO in the presence of dioxygen, towards the arginine and tyrosine residues of the peptide angiotensin II. Nitration of the tyrosine residue is clearly the main reaction with peroxynitrite. By contrast, besides 20% of nitration of the tyrosine residue, NO in the presence of dioxygen leads to nitrosation reactions with the arginine residue similar to those observed with HNO2 at pH 5, possibly through the intermediate N2O3 reactive species. Angiotensin II is converted for the most part to peptides having lost either a terminal amine function or the whole guanido group, leading respectively to citrulline-containing angiotensin II or to a diene derivative. Identification established mainly by tandem mass spectrometry of peptidic by-products allows us to propose a cascade of nitrosations of all the amine functions of the arginine residue. Further in vivo studies show that transformations of the arginine residue in angiotensin II do not alter its vasoconstrictive properties, whereas nitration of the tyrosine residue totally inhibits them.

  20. Forced swimming test increases superoxide anion positive cells and angiotensin II positive cells in the cerebrum and cerebellum of the rat.

    PubMed

    Pedreanez, Adriana; Arcaya, Jose Luis; Carrizo, Edgardo; Mosquera, Jesus

    2006-12-11

    Situations of stress are capable of inducing depression and oxidative stress in the brain. Previous reports have shown that angiotensin II (Ang II) induces the production of superoxide anion (O(2)(-)), and impairment of endothelial function in cerebral microvessels in vivo. Substances that reduce angiotensin functions may be important in the treatment of depression. These data suggest a role for both Ang II and O(2)(-) in depression; thus, the aim of this study was to determine the effect of forced swimming test (FST), a model of stress/depression, on the cellular expression of Ang II and O(2)(-) in the central nervous system. To induce stress/depression, rats were subjected to FST daily (30 min) for 15 days. Unstressed animals were used as controls. Motor activity was automatically analyzed daily before swimming. Cerebrum and cerebellum frozen sections were studied for O(2)(-) by a histochemical method and for Ang II producing cells by a polyclonal antibody. In the FST group, struggle time, total horizontal activity, ambulatory movements, and vertical movements, were significantly decreased when the data from the 1st and 15th day were compared. Food intake and body weight gain also decreased when unstressed and FST rats were compared at the 15th day. Increased number of cerebrum and cerebellum O(2)(-), and Ang II positive cells, were observed in FST rats. Significant correlation was found between O(2)(-) positive cells and Ang II positive cell in the cerebrum. These results suggest that stress/depression situations could be involved in the increase of Ang II and oxidative stress in the central nervous system, with possible implications in the depressive condition.

  1. Exogenous administration of thiosulfate, a donor of hydrogen sulfide, attenuates angiotensin II-induced hypertensive heart disease in rats

    PubMed Central

    Snijder, P M; Frenay, A R; de Boer, R A; Pasch, A; Hillebrands, J L; Leuvenink, H G D; van Goor, H

    2015-01-01

    Background and Purpose Hypertension is an important mediator of cardiac damage and remodelling. Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter with cardioprotective properties. However, it is not yet in clinical use. We, therefore, investigated the protective effects of sodium thiosulfate (STS), a clinically applicable H2S donor substance, in angiotensin II (Ang II)-induced hypertensive cardiac disease in rats. Experimental Approach Male Sprague Dawley rats were infused with Ang II (435 ng kg min−1) or saline (control) for 3 weeks via s.c. placed osmotic minipumps. During these 3 weeks, rats received i.p. injections of either STS, NaHS or vehicle (0.9% NaCl). Key Results Compared with controls, Ang II infusion caused an increase in systolic and diastolic BP with associated cardiac damage as evidenced by cardiac hypertrophy, an increase in atrial natriuretic peptide (ANP) mRNA, cardiac fibrosis and increased oxidative stress. Treatment with NaHS and STS prevented the development of hypertension and the increase in ANP mRNA levels. Furthermore, the degree of cardiac hypertrophy, the extent of histological fibrosis in combination with the expression of profibrotic genes and the levels of oxidative stress were all significantly decreased. Conclusions and Implications Ang II-induced hypertensive cardiac disease can be attenuated by treatment with STS and NaHS. Although BP regulation is the most plausible mechanism of cardiac protection, the antifibrotic and antioxidant properties of released sulfide may also contribute to their effects. Our data show that H2S might be a valuable addition to the already existing antihypertensive and cardioprotective therapies. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6 PMID:24962324

  2. Increased nitric oxide bioavailability in adult GRK2 hemizygous mice protects against angiotensin II-induced hypertension.

    PubMed

    Avendaño, María S; Lucas, Elisa; Jurado-Pueyo, María; Martínez-Revelles, Sonia; Vila-Bedmar, Rocío; Mayor, Federico; Salaices, Mercedes; Briones, Ana M; Murga, Cristina

    2014-02-01

    G protein-coupled receptor kinase 2 (GRK2) is a ubiquitous serine/threonine protein kinase able to phosphorylate and desensitize the active form of several G protein-coupled receptors. Given the lack of selective inhibitors for GRK2, we investigated the effects elicited by GRK2 inhibition in vascular responses using global adult hemizygous mice (GRK2(+/-)). The vasodilator responses to acetylcholine or isoproterenol were increased in aortas and mesenteric resistance arteries from GRK2(+/-) mice compared with wild-type (WT) littermates. After angiotensin II (AngII) infusion, GRK2(+/-) mice were partially protected against hypertension, vascular remodeling, and mechanical alterations, even when resting basal blood pressures were not significantly different. AngII infusion also (1) increased GRK2 levels in WT but not in GRK2(+/-) vessels; (2) increased vasoconstrictor responses to phenylephrine in WT but not in GRK2(+/-) mice; and (3) decreased vasodilator responses to acetylcholine and vascular pAkt and eNOS levels more in WT than in GRK2(+/-) animals. Vascular NO production and the modulation of vasoconstrictor responses by endothelial-derived NO remained enhanced in GRK2(+/-) mice infused with AngII. Thus, GRK2(+/-) mice are resistant to the development of vascular remodeling and mechanical alterations, endothelial dysfunction, increased vasoconstrictor responses, and hypertension induced by AngII at least partially through the preservation of NO bioavailability. In conclusion, our results describe an important role for GRK2 in systemic hypertension and further establish that an inhibition of GRK2 could be a beneficial treatment for this condition.

  3. Angiotensin II in the brain and pituitary: contrasting roles in the regulation of adenohypophyseal secretion.

    PubMed

    Ganong, W F

    1989-01-01

    Angiotensin II (AII) is present in gonadotropes in rats, and there are AII receptors on lactotropes and corticotropes. AII may be a paracrine mediator that stimulates the secretion of prolactin and adrenocorticotropin (ACTH) at the level of the pituitary, but additional research is needed to define its exact role. Angiotensinogen may also reach the gonadotropes via a paracrine route. On the other hand, there is considerable evidence that brain AII stimulates the secretion of luteinizing hormone (LH) by increasing the secretion of LH-releasing hormone, and that this effect is due to AII-mediated release of norepinephrine from noradrenergic nerve terminals in the preoptic region of the hypothalamus. In addition, brain AII inhibits the secretion of prolactin, probably by increasing the release of dopamine into the portal hypophyseal vessels. Circulating AII stimulates the secretion of a third anterior pituitary hormone, ACTH, by acting on one or more of the circumventricular organs to increase the secretion of corticotropin-releasing hormone.

  4. Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists.

    PubMed

    Lamotte, Yann; Faucher, Nicolas; Sançon, Julien; Pineau, Olivier; Sautet, Stéphane; Fouchet, Marie-Hélène; Beneton, Véronique; Tousaint, Jean-Jacques; Saintillan, Yannick; Ancellin, Nicolas; Nicodeme, Edwige; Grillot, Didier; Martres, Paul

    2014-02-15

    Identification of indazole derivatives acting as dual angiotensin II type 1 (AT1) receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ) agonists is described. Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPARγ agonists with loss of AT1 receptor antagonist activity. Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity. Among the new compounds, 38 was identified as a potent AT1 receptor antagonist (IC50=0.006 μM) and partial PPARγ agonist (EC50=0.25 μM, 40% max) with good oral bioavailability in rat. The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat).

  5. Changes in blood pressure and dipsogenic responsiveness to angiotensin II during chronic exposure of rats to cold

    SciTech Connect

    Fregly, M.J.; Shechtman, O.; van Bergen, P.; Reeber, C.; Papanek, P.E. )

    1991-03-11

    To assess the role of the renin-angiotensin (RA) system in the development of cold-induced hypertension in rats, systolic blood pressure (SBP), plasma renin activity (PRA), and the dipsogenic responsiveness to s.c. administration of angiotensin II (AII) were measured weekly for 4 weeks. SBP increased significantly during the third week of exposure to cold (5C), compared to warm-adapted controls. A significant increase in SBP occurred during the third week of cold. In contrast, (PRA) increased within the first week of cold, and declined thereafter to reach the level of the control by the third week. By the fourth week, PRA decreased to a level significantly below that of control. The dipsogenic responsiveness to acute administration of AII increased significantly by the third week of cold and remained significantly elevated during the fourth week. There was a significant direct relationship between dipsogenic responsiveness to AII and SBP in the cold-treated but not the control group. There was also a significant indirect linear relationship between PRA and dipsogenic responsiveness to AII. Cold-treated rats had significant increases in urinary norepinephrine output and weights of heart, kidneys, adrenals, and brown adipose tissue. Thus, the results suggest, but do not prove, either that the elevation of blood pressure under these conditions may be induced by changes in the RA system. The results suggest further that the reduction in the drinking response to AII accompanying increases in PRA may be related to changes in the regulation of central receptors for AII.

  6. c-Abl mediates angiotensin II-induced apoptosis in podocytes

    PubMed Central

    Chen, Xinghua; Ren, Zhilong; Liang, Wei; Zha, Dongqing; Liu, Yipeng; Chen, Cheng; Singhal, Pravin C.; Ding, Guohua

    2013-01-01

    Backgroud Angiotensin II (Ang II) has been reported to cause podocyte apoptosis in rats both in vivo and in vitro studies. However, the underlying mechanisms are poorly understood. In the present study, we investigated the role of the nonreceptor tyrosine kinase c-Abl in Ang II-induced podocyte apoptosis. Methods Male Sprague-Dawley rats in groups of 12 were administered either Ang II (400 kg-1·kg-1·min-1) or Ang II + STI-571 (50 mg·kg-1·d-1) by osmotic minipumps. In addition, 12 rats-receiving normal saline served as the control. Glomeruli c-Abl expression was carried out by real time PCR, Western blotting and immunolabeled, and occurrence of apoptosis was carried out by TUNEL staining and transmission electron microscopic analysis. In vitro studies, conditionally immortalized mouse podocytes were treated with Ang II (10-9-10-6 M) in the presence or absence of either c-Abl inhibitor, Src-I1, specific c-Abl siRNA, or c-Abl plasmid alone. Quantification of podocyte c-Abl expression and c-Abl phosphorylation at Y245 and Y412 was carried out by real time PCR, Western blotting and immunofluorescence imaging. The nuclear c-Abl and p53 were quantified by co-immunoprecipitation and Western blotting studies. Podocyte apoptosis was analysed by flow cytometry and Hoechst-33342 staining. Results c-Abl expression was demonstrated in rat kidney podocytes in vivo and cultured mouse podocytes in vitro. Ang II-receiving rats displayed enhanced podocyte c-Abl expression. And Ang II significantly stimulated c-Abl expression in cultured podocytes. Furthermore Ang II upregulated podocyte c-Abl phosphorylation at Y245 and Y412. Ang II also induced an increase of nuclear p53 protein and nuclear c-Abl-p53 complexes in podocytes and podocyte apoptosis. Down-regulation of c-Abl expression by c-Abl inhibitor (Src-I1) as well as specific siRNA inhibited Ang II-induced podocyte apoptosis; conversely, podoctyes transfected with c-Abl plasmid displayed enhanced apoptosis. Conclusions These

  7. Enhanced Distal Nephron Sodium Reabsorption in Chronic Angiotensin II Infused Mice

    PubMed Central

    Zhao, Di; Seth, Dale M.; Navar, L. Gabriel

    2009-01-01

    Chronic angiotensin II (Ang II) infusions enhance urinary excretion of angiotensinogen suggesting augmentation of distal nephron sodium reabsorption. To assess if chronic Ang II infusions (15 ng/min for 2 weeks) enhance distal nephron sodium reabsorption, we compared sodium excretion before and following blockade of the two main distal nephron sodium transporters by iv amiloride (5 mg/kg body weight) plus bendroflumethiazide (12 mg/kg body weight) in male C57/BL6 anesthetized control mice (n=10) and in chronic Ang II-infused mice (n=8). Chronic Ang II infusions increased systolic blood pressure to 141±6 mm Hg compared to 106±4 mm Hg in control mice. After anesthesia, mean arterial pressure averaged 97±4 mm Hg in chronic Ang II-infused mice compared with 94±3 mm Hg in control mice allowing comparison of renal function at similar arterial pressures. Ang II-infused mice had lower urinary sodium excretion (0.16±0.04 versus 0.30±0.05 μEq/min, P<0.05), higher distal sodium reabsorption (1.74±0.18 versus 1.12±0.18 μEq/min, P<0.05) and higher fractional reabsorption of distal sodium delivery (91.1±1.8% versus 77.9±4.3 %, P<0.05) than control mice. Urinary Ang II concentrations, measured during distal blockade, were greater in Ang II infused mice (1235.0±277.2 versus 468.9±146.9 fmol/ml, P<0.05). In chronic Ang II-infused mice treated with spironolactone (n=5), fractional reabsorption of distal sodium delivery was similarly augmented as in chronic Ang II infused mice (94.6±1.7%, P<0.01). These data provide in vivo evidence that there is enhanced distal sodium reabsorption dependent on sodium channel and Na+-Cl− cotransporter activity and increased urinary Ang II concentrations in mice infused chronically with Ang II. PMID:19487583

  8. N-acetylcysteine alleviates angiotensin II-mediated renal fibrosis in mouse obstructed kidneys

    PubMed Central

    Shen, Yang; Miao, Nai-jun; Xu, Jin-lan; Gan, Xin-xin; Xu, Dan; Zhou, Li; Xue, Hong; Zhang, Wei; Lu, Li-min

    2016-01-01

    Aim: To investigate the effects of ROS scavenger N-acetylcysteine (NAC) on angiotensin II (Ang II)-mediated renal fibrosis in vivo and in vitro. Methods: Mice were subjected to unilateral ureteral obstruction (UUO), and then treated with vehicle or NAC (250 mg/kg, ip) for 7 days. Histological changes of the obstructed kidneys were observed with Masson's trichrome staining. ROS levels were detected with DHE staining. The expression of relevant proteins in the obstructed kidneys was assessed using Western blotting assays. Cultured rat renal fibroblast NRK-49F cells were used for in vitro experiments. Results: In the obstructed kidneys, Ang II levels were significantly elevated, and collagen I was accumulated in the interstitial spaces. Furthermore, ROS production and the expression of p47 (a key subunit of NADPH oxidase complexes) were increased in a time-dependent manner; the expression of fibronectin, α-SMA and TGF-β were upregulated. Administration of NAC significantly alleviated the fibrotic responses in the obstructed kidneys. In cultured NRK-49F cells, treatment with Ang II (0.001–10 μmol/L) increased the expression of fibronectin, collagen I, α-SMA and TGF-β in dose-dependent and time-dependent manners. Ang II also increased ROS production and the phosphorylation of Smad3. Pretreatment with NAC (5 μmol/L) blocked Ang II-induced oxidative stress and ECM production in the cells. Conclusion: In mouse obstructed kidneys, the fibrotic responses result from Ang II upregulation can be alleviated by the ROS scavenger N-acetylcysteine. PMID:27041464

  9. Nardosinone protects H9c2 cardiac cells from angiotensin II-induced hypertrophy.

    PubMed

    Du, Meng; Huang, Kun; Gao, Lu; Yang, Liu; Wang, Wen-shuo; Wang, Bo; Huang, Kai; Huang, Dan

    2013-12-01

    Pathological cardiac hypertrophy induced by angiotensin II (AngII) can subsequently give rise to heart failure, a leading cause of mortality. Nardosinone is a pharmacologically active compound extracted from the roots of Nardostachys chinensis, a well-known traditional Chinese medicine. In order to investigate the effects of nardosinone on AngII-induced cardiac cell hypertrophy and the related mechanisms, the myoblast cell line H9c2, derived from embryonic rat heart, was treated with nardosinone (25, 50, 100, and 200 μmol/L) or AngII (1 μmol/L). Then cell surface area and mRNA expression of classical markers of hypertrophy were detected. The related protein levels in PI3K/Akt/mTOR and MEK/ERK signaling pathways were examined by Western blotting. It was found that pretreatment with nardosinone could significantly inhibit the enlargement of cell surface area induced by AngII. The mRNA expression of ANP, BNP and β-MHC was obviously elevated in AngII-treated H9c2 cells, which could be effectively blocked by nardosinone at the concentration of 100 μmol/L. Further study revealed that the protective effects of nardosinone might be mediated by repressing the phosphorylation of related proteins in PI3K/Akt and MEK/ERK signaling pathways. It was suggested that the inhibitory effect of nardosinone on Ang II-induced hypertrophy in H9c2 cells might be mediated by targeting PI3K/Akt and MEK/ERK signaling pathways.

  10. Angiotensin II disproportionally attenuates dynamic vagal and sympathetic heart rate controls.

    PubMed

    Kawada, Toru; Mizuno, Masaki; Shimizu, Shuji; Uemura, Kazunori; Kamiya, Atsunori; Sugimachi, Masaru

    2009-05-01

    To better understand the pathophysiological role of angiotensin II (ANG II) in the dynamic autonomic regulation of heart rate (HR), we examined the effects of intravenous administration of ANG II (10 microg.kg(-1).h(-1)) on the transfer function from vagal or sympathetic nerve stimulation to HR in anesthetized rabbits with sinoaortic denervation and vagotomy. In the vagal stimulation group (n = 7), we stimulated the right vagal nerve for 10 min using binary white noise (0-10 Hz). The transfer function from vagal stimulation to HR approximated a first-order low-pass filter with pure delay. ANG II attenuated the dynamic gain from 7.6 +/- 0.9 to 5.8 +/- 0.9 beats.min(-1).Hz(-1) (means +/- SD; P < 0.01) without affecting the corner frequency or pure delay. In the sympathetic stimulation group (n = 7), we stimulated the right postganglionic cardiac sympathetic nerve for 20 min using binary white noise (0-5 Hz). The transfer function from sympathetic stimulation to HR approximated a second-order low-pass filter with pure delay. ANG II slightly attenuated the dynamic gain from 10.8 +/- 2.6 to 10.2 +/- 3.1 beats.min(-1).Hz(-1) (P = 0.049) without affecting the natural frequency, damping ratio, or pure delay. The disproportional suppression of the dynamic vagal and sympathetic regulation of HR would result in a relative sympathetic predominance in the presence of ANG II. The reduced high-frequency component of HR variability in patients with cardiovascular diseases, such as myocardial infarction and heart failure, may be explained in part by the peripheral effects of ANG II on the dynamic autonomic regulation of HR.

  11. Vasoconstricting effect of angiotensin II in human hand veins: influence of aging, diabetes mellitus and hypertension.

    PubMed

    Harada, Kazuhiro; Ohmori, Masami; Fujimura, Akio

    2002-09-01

    We examined human hand veins to determine whether venoconstricting response to angiotensin II (Ang II) and noradrenaline (NA) was influenced by aging or such diseases as diabetes mellitus (DM) and hypertension (HT). Twenty healthy male subjects (20-73 years), and 8 male patients with non-insulin-dependent DM and 8 male patients with essential HT were included in this study. A constant dose (50 ng/min) of Ang II or increasing dose (2-256 ng/min) of NA was infused into the dorsal hand vein and its diameter was measured using a linear variable differential transformer. The constant infusion of Ang II caused rapid desensitization or tachyphylaxis. The venoconstriction by Ang II in the 8 elderly subjects (58 to 73 years) was significantly (p<0.05) larger than that in the 8 young subjects (20 to 36 years) from 6 to 18 min after the start of the infusion (after 6 min: 63.6+/-11.6 (mean+/-SD)% vs. 39.9+/-20.8%, 12 min: 34.0+/-11.9% vs. 12.0+/-12.0%). However, the venoconstriction by Ang II in the patients with DM or HT was not significantly different from that in the 9 age-matched control subjects. No significant difference in venoconstrictor response to NA was observed between the young and elderly subjects, nor between the control subjects and the patients with DM or HT. These findings indicated that venoconstrictor response to Ang II might be greater in the elderly but might not be influenced by DM nor HT.

  12. Obligatory Role for B Cells in the Development of Angiotensin II-Dependent Hypertension.

    PubMed

    Chan, Christopher T; Sobey, Christopher G; Lieu, Maggie; Ferens, Dorota; Kett, Michelle M; Diep, Henry; Kim, Hyun Ah; Krishnan, Shalini M; Lewis, Caitlin V; Salimova, Ekaterina; Tipping, Peter; Vinh, Antony; Samuel, Chrishan S; Peter, Karlheinz; Guzik, Tomasz J; Kyaw, Tin S; Toh, Ban-Hock; Bobik, Alexander; Drummond, Grant R

    2015-11-01

    Clinical hypertension is associated with raised serum IgG antibodies. However, whether antibodies are causative agents in hypertension remains unknown. We investigated whether hypertension in mice is associated with B-cell activation and IgG production and moreover whether B-cell/IgG deficiency affords protection against hypertension and vascular remodeling. Angiotensin II (Ang II) infusion (0.7 mg/kg per day; 28 days) was associated with (1) a 25% increase in the proportion of splenic B cells expressing the activation marker CD86, (2) an 80% increase in splenic plasma cell numbers, (3) a 500% increase in circulating IgG, and (4) marked IgG accumulation in the aortic adventitia. In B-cell-activating factor receptor-deficient (BAFF-R(-/-)) mice, which lack mature B cells, there was no evidence of Ang II-induced increases in serum IgG. Furthermore, the hypertensive response to Ang II was attenuated in BAFF-R(-/-) (Δ30±4 mm Hg) relative to wild-type (Δ41±5 mm Hg) mice, and this response was rescued by B-cell transfer. BAFF-R(-/-) mice displayed reduced IgG accumulation in the aorta, which was associated with 80% fewer aortic macrophages and a 70% reduction in transforming growth factor-β expression. BAFF-R(-/-) mice were also protected from Ang II-induced collagen deposition and aortic stiffening (assessed by pulse wave velocity analysis). Finally, like BAFF-R deficiency, pharmacological depletion of B cells with an anti-CD20 antibody attenuated Ang II-induced hypertension by ≈35%. Hence, these studies demonstrate that B cells/IgGs are crucial for the development of Ang II-induced hypertension and vessel remodeling in mice. Thus, B-cell-targeted therapies-currently used for autoimmune diseases-may hold promise as future treatments for hypertension.

  13. Sex-specific T-cell regulation of angiotensin II-dependent hypertension.

    PubMed

    Ji, Hong; Zheng, Wei; Li, Xiangjun; Liu, Jun; Wu, Xie; Zhang, Monan Angela; Umans, Jason G; Hay, Meredith; Speth, Robert C; Dunn, Shannon E; Sandberg, Kathryn

    2014-09-01

    Studies suggest T cells modulate arterial pressure. Because robust sex differences exist in the immune system and in hypertension, we investigated sex differences in T-cell modulation of angiotensin II-induced increases in mean arterial pressure in male (M) and female (F) wild-type and recombination-activating-gene-1-deficient (Rag1(-/-)) mice. Sex differences in peak mean arterial pressure in wild-type were lost in Rag1(-/-) mice (mm Hg: wild-type-F, 136±4.9 versus wild-type-M, 153±1.7; P<0.02; Rag1(-/-)-F, 135±2.1 versus Rag1(-/-)-M, 141±3.8). Peak mean arterial pressure was 13 mm Hg higher after adoptive transfer of male (CD3(M)→Rag1(-/-)-M) versus female (CD3(F)→Rag1(-/-)-M) T cells. CD3(M)→Rag1(-/-)-M mice exhibited higher splenic frequencies of proinflammatory interleukin-17A (2.4-fold) and tumor necrosis factor-α (2.2-fold)-producing T cells and lower plasma levels (13-fold) and renal mRNA expression (2.4-fold) of interleukin-10, whereas CD3(F)→Rag1(-/-)-M mice displayed a higher activation state in general and T-helper-1-biased renal inflammation. Greater T-cell infiltration into perivascular adipose tissue and kidney associated with increased pressor responses to angiotensin II if the T cell donor was male but not female and these sex differences in T-cell subset expansion and tissue infiltration were maintained for 7 to 8 weeks within the male host. Thus, the adaptive immune response and role of pro- and anti-inflammatory cytokine signaling in hypertension are distinct between the sexes and need to be understood to improve therapeutics for hypertension-associated disease in both men and women.

  14. Effect of angiotensin II type 1 receptor blockade on kidney ischemia/reperfusion; a gender-related difference

    PubMed Central

    Moslemi, Fatemeh; Taheri, Pegah; Azimipoor, Mahdis; Ramtin, Sina; Hashemianfar, Mostafa; Momeni- Ashjerdi, Ali; Eshraghi-Jazi, Fatemeh; Talebi, Ardeshir; Nasri, Hamid; Nematbakhsh, Mehdi

    2016-01-01

    Background: Renal ischemia/reperfusion (I/R) injury may be related to activity of reninangiotensin system (RAS), which is gender-related. In this study, it was attempted to compare the effect of angiotensin II (Ang II) receptor type 1 (AT1R) blockade; losartan in I/R injury in male and female rats. Materials and Methods: Male and female Wistar rats were assigned as sham surgery, control I/R groups treated with vehicle, and case I/R groups treated with losartan (30 mg/kg). Vehicle and losartan were given 2 hours before bilateral kidney ischemia induced by clamping renal arteries for 45 minutes followed by 24 hours of renal reperfusion. Results: The I/R injury significantly increased the serum levels of blood urea nitrogen (BUN) and creatinine (Cr), and kidney tissue damage score in both genders. However, losartan decreased these values in female rats significantly (P < 0.05). This was not observed in male rats. Conclusion: Losartan protects the kidney from I/R injury in female but not in male rats possibly because of gender-related difference of RAS. PMID:27689110

  15. Structure-Function Basis of Attenuated Inverse Agonism of Angiotensin II Type 1 Receptor Blockers for Active-State Angiotensin II Type 1 Receptor.

    PubMed

    Takezako, Takanobu; Unal, Hamiyet; Karnik, Sadashiva S; Node, Koichi

    2015-09-01

    Ligand-independent signaling by the angiotensin II type 1 receptor (AT1R) can be activated in clinical settings by mechanical stretch and autoantibodies as well as receptor mutations. Transition of the AT1R to the activated state is known to lower inverse agonistic efficacy of clinically used AT1R blockers (ARBs). The structure-function basis for reduced efficacy of inverse agonists is a fundamental aspect that has been understudied not only in relation to the AT1R but also regarding other homologous receptors. Here, we demonstrate that the active-state transition in the AT1R indeed attenuates an inverse agonistic effect of four biphenyl-tetrazole ARBs through changes in specific ligand-receptor interactions. In the ground state, tight interactions of four ARBs with a set of residues (Ser109(TM3), Phe182(ECL2), Gln257(TM6), Tyr292(TM7), and Asn295(TM7)) results in potent inverse agonism. In the activated state, the ARB-AT1R interactions shift to a different set of residues (Val108(TM3), Ser109(TM3), Ala163(TM4), Phe182(ECL2), Lys199(TM5), Tyr292(TM7), and Asn295(TM7)), resulting in attenuated inverse agonism. Interestingly, V108I, A163T, N295A, and F182A mutations in the activated state of the AT1R shift the functional response to the ARB binding toward agonism, but in the ground state the same mutations cause inverse agonism. Our data show that the second extracellular loop is an important regulator of the functional states of the AT1R. Our findings suggest that the quest for discovering novel ARBs, and improving current ARBs, fundamentally depends on the knowledge of the unique sets of residues that mediate inverse agonistic potency in the two states of the AT1R.

  16. Structure-Function Basis of Attenuated Inverse Agonism of Angiotensin II Type 1 Receptor Blockers for Active-State Angiotensin II Type 1 Receptor

    PubMed Central

    Unal, Hamiyet; Karnik, Sadashiva S.; Node, Koichi

    2015-01-01

    Ligand-independent signaling by the angiotensin II type 1 receptor (AT1R) can be activated in clinical settings by mechanical stretch and autoantibodies as well as receptor mutations. Transition of the AT1R to the activated state is known to lower inverse agonistic efficacy of clinically used AT1R blockers (ARBs). The structure-function basis for reduced efficacy of inverse agonists is a fundamental aspect that has been understudied not only in relation to the AT1R but also regarding other homologous receptors. Here, we demonstrate that the active-state transition in the AT1R indeed attenuates an inverse agonistic effect of four biphenyl-tetrazole ARBs through changes in specific ligand-receptor interactions. In the ground state, tight interactions of four ARBs with a set of residues (Ser109TM3, Phe182ECL2, Gln257TM6, Tyr292TM7, and Asn295TM7) results in potent inverse agonism. In the activated state, the ARB-AT1R interactions shift to a different set of residues (Val108TM3, Ser109TM3, Ala163TM4, Phe182ECL2, Lys199TM5, Tyr292TM7, and Asn295TM7), resulting in attenuated inverse agonism. Interestingly, V108I, A163T, N295A, and F182A mutations in the activated state of the AT1R shift the functional response to the ARB binding toward agonism, but in the ground state the same mutations cause inverse agonism. Our data show that the second extracellular loop is an important regulator of the functional states of the AT1R. Our findings suggest that the quest for discovering novel ARBs, and improving current ARBs, fundamentally depends on the knowledge of the unique sets of residues that mediate inverse agonistic potency in the two states of the AT1R. PMID:26121982

  17. Interleukin-2/Anti-Interleukin-2 Immune Complex Expands Regulatory T Cells and Reduces Angiotensin II-Induced Aortic Stiffening

    PubMed Central

    Eberson, Lance S.; Secomb, Timothy W.; Larmonier, Nicolas; Larson, Douglas F.

    2014-01-01

    Adaptive immune function is implicated in the pathogenesis of vascular disease. Inhibition of T-lymphocyte function has been shown to reduce hypertension, target-organ damage, and vascular stiffness. To study the role of immune inhibitory cells, CD4+CD25+Foxp3+ regulatory T cells (Tregs), on vascular stiffness, we stimulated the proliferation of Treg lymphocytes in vivo using a novel cytokine immune complex of Interleukin-2 (IL-2) and anti-IL-2 monoclonal antibody clone JES6-1 (mAbCD25). Three-month-old male C57BL/6J mice were treated with IL-2/mAbCD25 concomitantly with continuous infusion of angiotensin type 1 receptor agonist, [Val5]angiotensin II. Our results indicate that the IL-2/mAbCD25 complex effectively induced Treg phenotype expansion by 5-fold in the spleens with minimal effects on total CD4+ and CD8+ T-lymphocyte numbers. The IL-2/mAbCD25 complex inhibited angiotensin II-mediated aortic collagen remodeling and the resulting stiffening, analyzed with in vivo pulse wave velocity and effective Young's modulus. Furthermore, the IL-2/mAbCD25 complex suppressed angiotensin II-mediated Th17 responses in the lymphoid organs and reduced gene expression of IL-17 as well as T cell and macrophage infiltrates in the aortic tissue. This study provides data that support the protective roles of Tregs in vascular stiffening and highlights the use of the IL-2/mAbCD25 complex as a new potential therapy in angiotensin II-related vascular diseases. PMID:25258681

  18. Consequences of postnatal vascular smooth muscle EGFR deletion on acute angiotensin II action.

    PubMed

    Schreier, Barbara; Hünerberg, Mirja; Rabe, Sindy; Mildenberger, Sigrid; Bethmann, Daniel; Heise, Christian; Sibilia, Maria; Offermanns, Stefan; Gekle, Michael

    2016-01-01

    Epi dermal growth factor (EGF) receptor (EGFR) is activated by its canonical ligands and transactivated by various vasoactive substances, e.g. angiotensin II (Ang II). Vascular EGFR has been proposed to be involved in vascular tissue homoeostasis and remodelling. Thus, most studies have focused on its role during long-term vascular changes whereas the relevance for acute regulation of vascular function in vivo and ex vivo is insufficiently understood. To investigate the postnatal role of VSMCs (vascular smooth muscle cells) EGFR in vivo and ex vivo, we generated a mouse model with cell-specific and inducible deletion of VSMC EGFR and studied the effect on basal blood pressure, acute pressure response to, among others, Ang II in vivo as well as ex vivo, cardiovascular tissue homoeostasis and vessel morphometry in male mice. In knockout (KO) animals, systolic, diastolic and mean blood pressures were reduced compared with wild-type (WT). Furthermore, Ang II-induced pressure load was lower in KO animals, as was Ang II-induced force development and extracellular-signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation in aortic rings from KO animals. By contrast, we observed no difference in force development during application of serotonin, KCl, endothelin-1 or endothelin-1-induced pressure load in KO animals. In addition, nitric oxide (NO)-mediated vasodilation was not affected. Heart weight (HW) increase and up-regulation of aortic and cardiac expression of Ccl2 (chemoattractant protein-2) and serpinE1 (plasminogen activator inhibitor 1) during the transition from 4- to 10-months of age were prevented by VSMC EGFR KO. We conclude that VSMC EGFR is involved in basal blood pressure homoeostasis and acute pressure response to Ang II, and thereby contributes to maturation-related remodelling.

  19. Cardiac angiotensin II type I and type II receptors are increased in rats submitted to experimental hypothyroidism

    PubMed Central

    Carneiro-Ramos, M S; Diniz, G P; Almeida, J; Vieira, R L P; Pinheiro, S V B; Santos, R A; Barreto-Chaves, M L M

    2007-01-01

    This study assessed the behaviour of angiotensin II (Ang II) receptors in an experimental hypothyroidism model in male Wistar rats. Animals were subjected to thyroidectomy and resting for 14 days. The alteration of cardiac mass was evaluated by total heart weight (HW), right ventricle weight (RVW), left ventricle weight (LVW), ratio of HW, RVW and LVW to body weight (BW) and atrial natriuretic factor (ANF) expression. Cardiac and plasma Ang II levels and serum T3 and T4 were determined. The mRNA and protein levels of Ang II receptors were investigated by RT-PCR and Western blotting, respectively. Functional analyses were performed using binding assays. T3 and T4 levels and the haemodynamic parameters confirmed the hypothyroid state. HW/BW, RVW/BW and LVW/BW ratios and the ANF expression were lower than those of control animals. No change was observed in cardiac or plasma Ang II levels. Both AT1/AT2 mRNA and protein levels were increased in the heart of hypothyroid animals due to a significant increase of these receptors in the RV. Experiments performed in cardiomyocytes showed a direct effect promoted by low thyroid hormone levels upon AT1 and AT2 receptors, discarding possible influence of haemodynamic parameters. Functional assays showed that both receptors are able to bind Ang II. Herein, we have identified, for the first time, a close and direct relation of elevated Ang II receptor levels in hypothyroidism. Whether the increase in these receptors in hypothyroidism is an alternative mechanism to compensate the atrophic state of heart or whether it may represent a potential means to the progression of heart failure remains unknown. PMID:17540701

  20. Role of the Na+/H+ exchanger 3 in angiotensin II-induced hypertension

    PubMed Central

    Li, Xiao C.; Shull, Gary E.; Miguel-Qin, Elisa

    2015-01-01

    The renal mechanisms responsible for angiotensin II (ANG II)-induced hypertension remain incompletely understood. The present study tested the hypothesis that the Na+/H+ exchanger 3 (NHE3) is required for ANG II-induced hypertension in mice. Five groups of wild-type (Nhe3+/+) and Nhe3−/− mice were treated with vehicle or high pressor doses of ANG II (1.5 mg/kg/day ip, via minipump for 2 wk, or 10 pmol/min iv for 30 min). Under basal conditions, Nhe3−/− mice had significantly lower systolic blood pressure (SBP) and mean intra-arterial pressure (MAP) (P < 0.01), 24 h urine (P < 0.05), urinary Na+ (P < 0.01) and urinary K+ excretion (P < 0.01). In response to ANG II, SBP and MAP markedly increased in Nhe3+/+ mice in a time-dependent manner, as expected (P < 0.01). However, these acute and chronic pressor responses to ANG II were significantly attenuated in Nhe3−/− mice (P < 0.01). Losartan blocked ANG II-induced hypertension in Nhe3+/+ mice but induced marked mortality in Nhe3−/− mice. The attenuated pressor responses to ANG II in Nhe3−/− mice were associated with marked compensatory humoral and renal responses to genetic loss of intestinal and renal NHE3. These include elevated basal plasma ANG II and aldosterone and kidney ANG II levels, salt wasting from the intestines, increased renal AQP1, Na+/HCO3−, and Na+/K+-ATPase expression, and increased PKCα, mitogen-activated protein kinases ERK1/2, and glycogen synthase kinase 3αβ signaling proteins in the proximal tubules (P < 0.01). We concluded that NHE3 in proximal tubules of the kidney, along with NHE3 in intestines, is required for maintaining basal blood pressure as well as the full development of ANG II-induced hypertension. PMID:26242933

  1. Transient Receptor Potential Melastatin 7 Cation Channel Kinase: New Player in Angiotensin II-Induced Hypertension.

    PubMed

    Antunes, Tayze T; Callera, Glaucia E; He, Ying; Yogi, Alvaro; Ryazanov, Alexey G; Ryazanova, Lillia V; Zhai, Alexander; Stewart, Duncan J; Shrier, Alvin; Touyz, Rhian M

    2016-04-01

    Transient receptor potential melastatin 7 (TRPM7) is a bifunctional protein comprising a magnesium (Mg(2+))/cation channel and a kinase domain. We previously demonstrated that vasoactive agents regulate vascular TRPM7. Whether TRPM7 plays a role in the pathophysiology of hypertension and associated cardiovascular dysfunction is unknown. We studied TRPM7 kinase-deficient mice (TRPM7Δkinase; heterozygous for TRPM7 kinase) and wild-type (WT) mice infused with angiotensin II (Ang II; 400 ng/kg per minute, 4 weeks). TRPM7 kinase expression was lower in heart and aorta from TRPM7Δkinase versus WT mice, effects that were further reduced by Ang II infusion. Plasma Mg(2+) was lower in TRPM7Δkinase versus WT mice in basal and stimulated conditions. Ang II increased blood pressure in both strains with exaggerated responses in TRPM7Δkinase versus WT groups (P<0.05). Acetylcholine-induced vasorelaxation was reduced in Ang II-infused TRPM7Δkinase mice, an effect associated with Akt and endothelial nitric oxide synthase downregulation. Vascular cell adhesion molecule-1 expression was increased in Ang II-infused TRPM7 kinase-deficient mice. TRPM7 kinase targets, calpain, and annexin-1, were activated by Ang II in WT but not in TRPM7Δkinase mice. Echocardiographic and histopathologic analysis demonstrated cardiac hypertrophy and left ventricular dysfunction in Ang II-treated groups. In TRPM7 kinase-deficient mice, Ang II-induced cardiac functional and structural effects were amplified compared with WT counterparts. Our data demonstrate that in TRPM7Δkinase mice, Ang II-induced hypertension is exaggerated, cardiac remodeling and left ventricular dysfunction are amplified, and endothelial function is impaired. These processes are associated with hypomagnesemia, blunted TRPM7 kinase expression/signaling, endothelial nitric oxide synthase downregulation, and proinflammatory vascular responses. Our findings identify TRPM7 kinase as a novel player in Ang II-induced hypertension

  2. Neuroanatomical distribution of angiotensin-II-like neuropeptide within the central nervous system of the crab Chasmagnathus; physiological changes triggered by water deprivation.

    PubMed

    Frenkel, Lia; Dimant, Beatriz; Portiansky, Enrique L; Imboden, Hans; Maldonado, Héctor; Delorenzi, Alejandro

    2010-07-01

    The angiotensins constitute a neuropeptidergic system that emerged early in evolution. Their classical osmoregulatory and dipsogenic functions and their mnemonic actions have been demonstrated both in vertebrates and in some invertebrates. Previously, we have shown that, in the euryhaline and semiterrestrial crab Chasmagnathus granulatus, water deprivation correlates with an increased level of brain angiotensin-II-like neuropeptide/s (ANGII-like) and improves memory processes through ANGII receptors. We have proposed that the release of brain angiotensins in response to water shortages is an ancient mechanism for coordinating various functions that, together, enable organisms to tolerate this environmental change. Here, we have evaluated the physiological changes in ANGII-like levels in diverse structures of the central nervous system of these animals during water deprivation. The neuroanatomical distribution of ANGII-like is described in the optic lobes and brain of Chasmagnathus granulatus and the physiological changes in ANGII-like distribution in various brain neuropils is evaluated after water deprivation. Our results indicate that ANGII-like is widely distributed, especially in the medial protocerebrum. After 2 h of water deprivation, ANGII-like immunoreactivity increases in the central body and decreases in the olfactory neuropil and, after 6 h of water deprivation, is markedly reduced in several brain areas. Although further experiments are needed to establish that the angiotensinergic system is involved in the balance of body fluids in this crab, our results suggest that ANGII regulates several functions during water shortages.

  3. Anti-Plasmodium Activity of Angiotensin II and Related Synthetic Peptides

    PubMed Central

    Maciel, Ceres; de Oliveira Junior, Vani Xavier; Fázio, Marcos Antonio; Nacif-Pimenta, Rafael; Miranda, Antonio; Pimenta, Paulo F. P.; Capurro, Margareth Lara

    2008-01-01

    Plasmodium species are the causative agents of malaria, the most devastating insect-borne parasite of human populations. Finding and developing new drugs for malaria treatment and prevention is the goal of much research. Angiotensins I and II (ang I and ang II) and six synthetic related peptides designated Vaniceres 1-6 (VC1-VC6) were assayed in vivo and in vitro for their effects on the development of the avian parasite, Plasmodium gallinaceum. Ang II and VC5 injected into the thoraces of the insects reduced mean intensities of infection in the mosquito salivary glands by 88% and 76%, respectively. Although the mechanism(s) of action is not completely understood, we have demonstrated that these peptides disrupt selectively the P.gallinaceum cell membrane. Additionally, incubation in vitro of sporozoites with VC5 reduced the infectivity of the parasites to their vertebrate host. VC5 has no observable agonist effects on vertebrates, and this makes it a promising drug for malaria prevention and chemotherapy. PMID:18820728

  4. β-Carotene Attenuates Angiotensin II-Induced Aortic Aneurysm by Alleviating Macrophage Recruitment in Apoe(-/-) Mice.

    PubMed

    Gopal, Kaliappan; Nagarajan, Perumal; Jedy, Jose; Raj, Avinash T; Gnanaselvi, S Kalai; Jahan, Parveen; Sharma, Yogendra; Shankar, Esaki M; Kumar, Jerald M

    2013-01-01

    Abdominal aortic aneurysm (AAA) is a common chronic degenerative disease characterized by progressive aortic dilation and rupture. The mechanisms underlying the role of α-tocopherol and β-carotene on AAA have not been comprehensively assessed. We investigated if α-tocopherol and β-carotene supplementation could attenuate AAA, and studied the underlying mechanisms utilized by the antioxidants to alleviate AAA. Four-months-old Apoe(-/-) mice were used in the induction of aneurysm by infusion of angiotensin II (Ang II), and were orally administered with α-tocopherol and β-carotene enriched diet for 60 days. Significant increase of LDL, cholesterol, triglycerides and circulating inflammatory cells was observed in the Ang II-treated animals, and gene expression studies showed that ICAM-1, VCAM-1, MCP-1, M-CSF, MMP-2, MMP-9 and MMP-12 were upregulated in the aorta of aneurysm-induced mice. Extensive plaques, aneurysm and diffusion of inflammatory cells into the tunica intima were also noticed. The size of aorta was significantly (P = 0.0002) increased (2.24±0.20 mm) in the aneurysm-induced animals as compared to control mice (1.17±0.06 mm). Interestingly, β-carotene dramatically controlled the diffusion of macrophages into the aortic tunica intima, and circulation. It also dissolved the formation of atheromatous plaque. Further, β-carotene significantly decreased the aortic diameter (1.33±0.12 mm) in the aneurysm-induced mice (β-carotene, P = 0.0002). It also downregulated ICAM-1, VCAM-1, MCP-1, M-CSF, MMP-2, MMP-9, MMP-12, PPAR-α and PPAR-γ following treatment. Hence, dietary supplementation of β-carotene may have a protective function against Ang II-induced AAA by ameliorating macrophage recruitment in Apoe(-/-) mice.

  5. NO and endogenous angiotensin II interact in the generation of renal sympathetic nerve activity in conscious rats.

    PubMed

    McKeogh, Donogh F; O'Donaughy, Theresa L; Brooks, Virginia L

    2004-04-01

    Nitric oxide (NO) appears to inhibit sympathetic tone in anesthetized rats. However, whether NO tonically inhibits sympathetic outflow, or whether endogenous angiotensin II (ANG II) promotes NO-mediated sympathoinhibition in conscious rats is unknown. To address these questions, we determined the effects of NO synthase (NOS) inhibition on renal sympathetic nerve activity (RSNA) and heart rate (HR) in conscious, unrestrained rats on normal (NS), high-(HS), and low-sodium (LS) diets, in the presence and absence of an ANG II receptor antagonist (AIIRA). When arterial pressure was kept at baseline with intravenous hydralazine, NOS inhibition with l-NAME (10 mg/kg i.v.) resulted in a profound decline in RSNA, to 42 +/- 11% of control (P < 0.01), in NS animals. This effect was not sustained, and RSNA returned to control levels by 45 min postinfusion. l-NAME also caused bradycardia, from 432 +/- 23 to 372 +/- 11 beats/min postinfusion (P < 0.01), an effect, which, in contrast, was sustained 60 min postdrug. The effects of NOS inhibition on RSNA and HR did not differ between NS, HS, and LS rats. However, when LS and HS rats were pretreated with AIIRA, the initial decrease in RSNA after l-NAME infusion was absent in the LS rats, while the response in the HS group was unchanged by AIIRA. These findings indicate that, in contrast to our hypotheses, NOS activity provides a stimulatory input to RSNA in conscious rats, and that in LS animals, but not HS animals, this sympathoexcitatory effect of NO is dependent on the action of endogenous ANG II.

  6. Angiotensin II induces apoptosis in intestinal epithelial cells through the AT2 receptor, GATA-6 and the Bax pathway

    SciTech Connect

    Sun, Lihua; Wang, Wensheng; Xiao, Weidong; Liang, Hongyin; Yang, Yang; Yang, Hua

    2012-08-10

    Highlights: Black-Right-Pointing-Pointer Ang II-induced apoptosis in intestinal epithelial cell through AT2 receptor. Black-Right-Pointing-Pointer The apoptosis process involves in the Bax/Bcl-2 intrinsic pathway. Black-Right-Pointing-Pointer GATA-6 short hairpin RNA reduced Bax expression, but not Bcl-2. Black-Right-Pointing-Pointer GATA-6 may play a critical role in apoptosis in response to the Ang II challenge. -- Abstract: Angiotensin II (Ang II) has been shown to play an important role in cell apoptosis. However, the mechanisms of Ang-II-induced apoptosis in intestinal epithelial cells are not fully understood. GATA-6 is a zinc finger transcription factor expressed in the colorectal epithelium, which directs cell proliferation, differentiation and apoptosis. In the present study we investigated the underlying mechanism of which GATA-6 affects Ang-II induced apoptosis in intestinal epithelial cells. The in vitro intestinal epithelial cell apoptosis model was established by co-culturing Caco-2 cells with Ang II. Pretreatment with Angiotensin type 2 (AT2) receptor antagonist, PD123319, significantly reduced the expression of Bax and prevented the Caco-2 cells apoptosis induced by Ang II. In addition, Ang II up-regulated the expression of GATA-6. Interestingly, GATA-6 short hairpin RNA prevented Ang II-induced intestinal epithelial cells apoptosis and reduced the expression of Bax, but not Bcl-2. Taken together, the present study suggests that Angiotensin II promotes apoptosis in intestinal epithelial cells through GATA-6 and the Bax pathway in an AT2 receptor-dependent manner.

  7. Decreased Risk of Radiation Pneumonitis With Incidental Concurrent Use of Angiotensin-Converting Enzyme Inhibitors and Thoracic Radiation Therapy

    SciTech Connect

    Kharofa, Jordan; Cohen, Eric P.; Tomic, Rade; Xiang Qun; Gore, Elizabeth

    2012-09-01

    Purpose: Angiotensin-converting enzyme (ACE) inhibitors have been shown to mitigate radiation-induced lung injury in preclinical models. The aim of this study was to evaluate whether ACE inhibitors decrease the risk of radiation pneumonitis in lung cancer patients receiving thoracic irradiation. Methods and Materials: Patients with Stage I through III small-cell and non-small-cell lung cancer treated definitively with radiation from 2004-2009 at the Clement J. Zablocki Veterans Affairs Medical Center were retrospectively reviewed. Acute pulmonary toxicity was quantified within 6 months of completion of treatment according to the Common Terminology Criteria for Adverse Events version 4. The use of ACE inhibitors, nonsteroidal anti-inflammatory drugs, inhaled glucocorticosteroids, statins, and angiotensin receptor blockers; dose-volume histogram parameters; and patient factors were assessed for association with Grade 2 or higher pneumonitis. Results: A total of 162 patients met the criteria for inclusion. The majority of patients had Stage III disease (64%) and received concurrent chemotherapy (61%). Sixty-two patients were identified as ACE inhibitor users (38%). All patients had acceptable radiation plans based on dose-volume histogram constraints (V20 [volume of lung receiving at least 20 Gy] {<=}37% and mean lung dose {<=}20 Gy) with the exception of 2 patients who did not meet both criteria. Grade 2 or higher pulmonary toxicity occurred in 12 patients (7.4%). The rate of Grade 2 or higher pneumonitis was lower in ACE inhibitor users vs. nonusers (2% vs. 11%, p = 0.032). Rates of Grade 2 or higher pneumonitis were significantly increased in patients aged greater than 70 years (16% vs. 2%, p = 0.005) or in whom V5 (volume of lung receiving at least 5 Gy) was 50% or greater (13% vs. 4%, p = 0.04). V10 (volume of lung receiving at least 10 Gy), V20, V30 (volume of lung receiving at least 30 Gy), and mean lung dose were not independently associated with Grade 2 or

  8. Impact of losartan and angiotensin II on the expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in rat vascular smooth muscle cells.

    PubMed

    Guo, Yan-Song; Wu, Zong-Gui; Yang, Jun-Ke; Chen, Xin-Jing

    2015-03-01

    The present study aimed to investigate the impact of losartan and angiotensin II (AngII) on the expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1), secreted by rat vascular smooth muscle cells (VSMCs). Rat VSMCs were isolated and cultured in different concentrations of AngII and losartan for 24 h and western blot analysis and quantitative polymerase chain reaction were performed to observe the subsequent impact on the gene and protein expression of MMP-9 and TIMP-1. AngII was shown to promote the protein and gene expression of MMP-9 in VSMCs in a concentration-dependent manner. No effect was observed on the expression of TIMP-1, therefore, an increase in the MMP-9/TIMP-1 ratio was observed. Losartan was shown to be able to inhibit MMP-9 protein and gene expression in a concentration-dependent manner, whilst promoting an increase in TIMP-1 expression, thus decreasing the ratio of MMP-9/TIMP-1. The combined action of losartan and AngII resulted in the same directional changes in MMP-9 and TIMP-1 expression as observed for losartan alone. The comparison of AngII, losartan and the combinatory effect on the expression of MMP-9 and TIMP-1 in VSMCs indicated that losartan inhibited the effects of AngII, therefore reducing the MMP-9/TIMP-1 ratio, which may contribute to the molecular mechanism of losartan in preventing atherosclerosis. In atherosclerosis, the development of the extracellular matrix of plaque is closely correlated with the evolution of AS. The balance between MMPs and TIMPs is important in maintaining the dynamic equilibrium between the ECM, and the renin-angiotensin-aldosterone system, which is involved in the pathologenesis of AS, and in which AngII has a central role.

  9. Production of angiotensin II receptors type one (AT1) and type two (AT2) during the differentiation of 3T3-L1 preadipocytes.

    PubMed

    Mallow, H; Trindl, A; Löffler, G

    2000-01-01

    During their development from progenitor cells, adipocytes not only express enzymatic activities necessary for the storage of triglycerides, but also achieve the capability to produce a number of endocrine factors such as leptin, tumor necrosis factor alpha (TNFalpha), complement factors, adiponectin/adipoQ, plasminogen activator inhibitor-1 (PAI-1), angiotensin II and others. Angiotensin II is produced from angiotensinogen by the proteolytic action of renin and angiotensin-converting enzyme; and several data point to the existence of a complete local renin-angiotensin system in adipose tissue, including angiotensin II receptors. In this study, we directly monitored the production of angiotensin II type one receptor (AT1) and angiotensin II type two receptor (AT2) proteins during the adipose conversion of murine 3T3-L1 preadipocytes by immunodetection with specific antibodies. AT1 receptors could be detected throughout the whole differentiation period. The strong AT2 signal in preadipocytes however was completely lost during the course of differentiation, which suggests that expression of AT2 receptors is inversely correlated to the adipose conversion program.

  10. Memory strengthening by a real-life episode during reconsolidation: an outcome of water deprivation via brain angiotensin II.

    PubMed

    Frenkel, Lia; Maldonado, Héctor; Delorenzi, Alejandro

    2005-10-01

    A considerable body of evidence reveals that consolidated memories, recalled by a reminder, enter into a new vulnerability phase during which they are susceptible to disruption again. Consistently, reconsolidation was shown by the amnesic effects induced by administration of consolidation blockers after memory labilization. To shed light on the functional value of reconsolidation, we explored whether an endogenous process activated during a concurrent real-life experience improved this memory phase. Reconsolidation of long-term contextual memory has been well documented in the crab Chasmagnathus. Previously we showed that angiotensin II facilitates memory consolidation. Moreover, water deprivation increases brain angiotensin and improves memory consolidation and retrieval through angiotensin II receptors. Here, we tested whether concurrent water deprivation improves reconsolidation via endogenous angiotensin and therefore strengthens memory. We show that memory reconsolidation, induced by training context re-exposure, is facilitated by a concurrent episode of water deprivation, which induces a raise in endogenous brain angiotensin II. Positive modulation is expressed by full m