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Sample records for angiotensin ii inhibits

  1. Angiotensin converting enzyme inhibition does not affect the response to exogenous angiotensin II in the human forearm.

    PubMed Central

    Lyons, D; Stewart, D; Webster, J; Benjamin, N

    1994-01-01

    Suppression of endogenous levels of angiotensin II by angiotensin converting enzyme inhibition, may result in up-regulation of vascular AT1 receptors. We have evaluated the effects of orally administered enalapril on angiotensin II induced vasoconstriction in the human forearm. Subjects received in random order, enalapril (20 mg) or matched placebo daily for 2 weeks. Forearm blood flow response to increasing doses of angiotensin II was measured using venous occlusion plethysmography at the beginning of the study and at the end of each 2 week treatment period. Treatment with enalapril significantly reduced plasma angiotensin II levels and supine blood pressure compared with placebo. The percentage reductions in forearm blood flow in the infused arm, in response to the maximum dose of angiotensin II (50,000 fmol min-1) were 48.1 +/- 3.6% at baseline, 57.5 +/- 3.6% on placebo and 54.5 +/- 4.2% on enalapril. The differences were not significantly different. This demonstrates that suppression of plasma angiotensin II for a 14 day period does not enhance the response to exogenous intra-arterial angiotensin II in the human forearm of healthy salt replete subjects. PMID:7893582

  2. Angiotensin II diminishes the effect of SGK1 on the WNK4-mediated inhibition of ROMK1 channels.

    PubMed

    Yue, Peng; Sun, Peng; Lin, Dao-Hong; Pan, Chunyang; Xing, Wenming; Wang, WenHui

    2011-02-01

    ROMK1 channels are located in the apical membrane of the connecting tubule and cortical collecting duct and mediate the potassium secretion during normal dietary intake. We used a perforated whole-cell patch clamp to explore the effect of angiotensin II on these channels in HEK293 cells transfected with green fluorescent protein (GFP)-ROMK1. Angiotensin II inhibited ROMK1 channels in a dose-dependent manner, an effect abolished by losartan or by inhibition of protein kinase C. Furthermore, angiotensin II stimulated a protein kinase C-sensitive phosphorylation of tyrosine 416 within c-Src. Inhibition of protein tyrosine kinase attenuated the effect of angiotensin II. Western blot studies suggested that angiotensin II inhibited ROMK1 channels by enhancing its tyrosine phosphorylation, a notion supported by angiotensin II's failure to inhibit potassium channels in cells transfected with the ROMK1 tyrosine mutant (R1Y337A). However, angiotensin II restored the with-no-lysine kinase-4 (WNK4)-induced inhibition of R1Y337A in the presence of serum-glucocorticoids-induced kinase 1 (SGK1), which reversed the inhibitory effect of WNK4 on ROMK1. Moreover, protein tyrosine kinase inhibition abolished the angiotensin II-induced restoration of WNK4-mediated inhibition of ROMK1. Angiotensin II inhibited ROMK channels in the cortical collecting duct of rats on a low sodium diet, an effect blocked by protein tyrosine kinase inhibition. Thus, angiotensin II inhibits ROMK channels by two mechanisms: increasing tyrosine phosphorylation of the channel and synergizing the WNK4-induced inhibition. Hence, angiotensin II may have an important role in suppressing potassium secretion during volume depletion. PMID:20927043

  3. Gynura procumbens causes vasodilation by inhibiting angiotensin II and enhancing bradykinin actions.

    PubMed

    Poh, Ting-Fung; Ng, Hien-Kun; Hoe, See-Ziau; Lam, Sau-Kuen

    2013-05-01

    Previous studies showed that Gynura procumbens reduced blood pressure by blocking calcium channels and inhibiting the angiotensin-converting enzyme activity. The present experiments were to further explore the effects and mechanisms of a purer aqueous fraction (FA-I) of G. procumbens on angiotensin I (Ang I)-induced and angiotensin II (Ang II)-induced contraction of aortic rings and also on the bradykinin (BK) effect on cardiovascular system. Rat aortic rings suspended in organ chambers were used to investigate the vascular reactivity of FA-I. Effect of FA-I on BK was studied by in vitro and in vivo methods. Results show that FA-I significantly (P < 0.05) decreased the contraction evoked by Ang I and Ang II. In the presence of indomethacin (10 µM) or N-nitro-L-arginine methyl ester (0.1 µM), the inhibitory effect of FA-I on Ang II-induced contraction of aortic rings was reduced. Besides, FA-I potentiated the vasorelaxant effect and enhanced the blood pressure-lowering effect of BK. In conclusion, FA-I reduced the contraction evoked by Ang II probably via the endothelium-dependent pathways, which involve activation of the release of nitric oxide and prostaglandins. The inhibition of angiotensin-converting enzyme activity by FA-I may contribute to the potentiation of the effects of BK on cardiovascular system. PMID:23328388

  4. 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

  5. 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. PMID:25469849

  6. Intrarenal mouse renin-angiotensin system during ANG II-induced hypertension and ACE inhibition.

    PubMed

    Gonzalez-Villalobos, Romer A; Satou, Ryousuke; Ohashi, Naro; Semprun-Prieto, Laura C; Katsurada, Akemi; Kim, Catherine; Upchurch, G M; Prieto, Minolfa C; Kobori, Hiroyuki; Navar, L Gabriel

    2010-01-01

    Angiotensin-converting enzyme (ACE) inhibition (ACEi) ameliorates the development of hypertension and the intrarenal ANG II augmentation in ANG II-infused mice. To determine if these effects are associated with changes in the mouse intrarenal renin-angiotensin system, the expression of angiotensinogen (AGT), renin, ACE, angiotensin type 1 receptor (AT(1)R) mRNA (by quanitative RT-PCR) and protein [by Western blot (WB) and/or immunohistochemistry (IHC)] were analyzed. C57BL/6J male mice (9-12 wk old) were distributed as controls (n = 10), ANG II infused (ANG II = 8, 400 ng x kg(-1) x min(-1) for 12 days), ACEi only (ACEi = 10, lisinopril, 100 mg/l), and ANG II infused + ACEi (ANG II + ACEi = 11). When compared with controls (1.00), AGT protein (by WB) was increased by ANG II (1.29 +/- 0.13, P < 0.05), and this was not prevented by ACEi (ACEi + ANG II, 1.31 +/- 0.14, P < 0.05). ACE protein (by WB) was increased by ANG II (1.21 +/- 0.08, P < 0.05), and it was reduced by ACEi alone (0.88 +/- 0.07, P < 0.05) or in combination with ANG II (0.80 +/- 0.07, P < 0.05). AT(1)R protein (by WB) was increased by ANG II (1.27 +/- 0.06, P < 0.05) and ACEi (1.17 +/- 0.06, P < 0.05) but not ANG II + ACEi [1.15 +/- 0.06, not significant (NS)]. Tubular renin protein (semiquantified by IHC) was increased by ANG II (1.49 +/- 0.23, P < 0.05) and ACEi (1.57 +/- 0.15, P < 0.05), but not ANG II + ACEi (1.10 +/- 0.15, NS). No significant changes were observed in AGT, ACE, or AT(1)R mRNA. In summary, reduced responses of intrarenal tubular renin, ACE, and the AT(1)R protein to the stimulatory effects of chronic ANG II infusions, in the presence of ACEi, are associated with the effects of this treatment to ameliorate augmentations in blood pressure and intrarenal ANG II content during ANG II-induced hypertension. PMID:19846570

  7. Intrarenal mouse renin-angiotensin system during ANG II-induced hypertension and ACE inhibition

    PubMed Central

    Satou, Ryousuke; Ohashi, Naro; Semprun-Prieto, Laura C.; Katsurada, Akemi; Kim, Catherine; Upchurch, G. M.; Prieto, Minolfa C.; Kobori, Hiroyuki; Navar, L. Gabriel

    2010-01-01

    Angiotensin-converting enzyme (ACE) inhibition (ACEi) ameliorates the development of hypertension and the intrarenal ANG II augmentation in ANG II-infused mice. To determine if these effects are associated with changes in the mouse intrarenal renin-angiotensin system, the expression of angiotensinogen (AGT), renin, ACE, angiotensin type 1 receptor (AT1R) mRNA (by quanitative RT-PCR) and protein [by Western blot (WB) and/or immunohistochemistry (IHC)] were analyzed. C57BL/6J male mice (9–12 wk old) were distributed as controls (n = 10), ANG II infused (ANG II = 8, 400 ng·kg−1·min−1 for 12 days), ACEi only (ACEi = 10, lisinopril, 100 mg/l), and ANG II infused + ACEi (ANG II + ACEi = 11). When compared with controls (1.00), AGT protein (by WB) was increased by ANG II (1.29 ± 0.13, P < 0.05), and this was not prevented by ACEi (ACEi + ANG II, 1.31 ± 0.14, P < 0.05). ACE protein (by WB) was increased by ANG II (1.21 ± 0.08, P < 0.05), and it was reduced by ACEi alone (0.88 ± 0.07, P < 0.05) or in combination with ANG II (0.80 ± 0.07, P < 0.05). AT1R protein (by WB) was increased by ANG II (1.27 ± 0.06, P < 0.05) and ACEi (1.17 ± 0.06, P < 0.05) but not ANG II + ACEi [1.15 ± 0.06, not significant (NS)]. Tubular renin protein (semiquantified by IHC) was increased by ANG II (1.49 ± 0.23, P < 0.05) and ACEi (1.57 ± 0.15, P < 0.05), but not ANG II + ACEi (1.10 ± 0.15, NS). No significant changes were observed in AGT, ACE, or AT1R mRNA. In summary, reduced responses of intrarenal tubular renin, ACE, and the AT1R protein to the stimulatory effects of chronic ANG II infusions, in the presence of ACEi, are associated with the effects of this treatment to ameliorate augmentations in blood pressure and intrarenal ANG II content during ANG II-induced hypertension. PMID:19846570

  8. Angiotensin II-stimulated secretion of arginine vasopressin is inhibited by atrial natriuretic peptide in humans.

    PubMed

    Matsukawa, Toshiyoshi; Miyamoto, Takenori

    2011-03-01

    We investigated the effect of the intravenous infusion of atrial natriuretic peptide (ANP) on the response of plasma arginine vasopressin (AVP) levels to intravenous infusion of angiotensin II (ANG II) in healthy individuals. Intravenous infusion of ANP (10 ng·kg(-1)·min(-1)) slightly but significantly decreased plasma AVP levels, while intravenous infusion of ANG II (10 ng·kg(-1)·min(-1)) resulted in slightly increased plasma AVP levels. ANG II infused significant elevations in arterial blood pressure and central venous pressure (CVP). Because the elevation in blood pressure could have potentially inhibited AVP secretion via baroreceptor reflexes, the effect of ANG II on blood pressure was attenuated by the simultaneous infusion of nitroprusside. ANG II alone produced a remarkable increase in plasma AVP levels when infused with nitroprusside, whereas the simultaneous ANP intravenous infusion (10 ng·kg(-1)·min(-1)) abolished the increase in plasma AVP levels induced by ANG II when blood pressure elevation was attenuated by nitroprusside. Thus, ANG II increased AVP secretion and ANP inhibited not only basal AVP secretion but also ANG II-stimulated AVP secretion in humans. These findings support the hypothesis that circulating ANP modulates AVP secretion, in part, by antagonizing the action of circulating ANG II. PMID:21123762

  9. Des-aspartate angiotensin I (DAA-I) reduces endothelial dysfunction in the aorta of the spontaneously hypertensive rat through inhibition of angiotensin II-induced oxidative stress.

    PubMed

    Loh, Wei Mee; Ling, Wei Chih; Murugan, Dharmani D; Lau, Yeh Siang; Achike, Francis I; Vanhoutte, Paul M; Mustafa, Mohd Rais

    2015-08-01

    Des-aspartate angiotensin I (DAA-I), an endogenous nonapeptide, counteracts several effects of angiotensin II on vascular tone. The aim of this study was to investigate the acute protective effect of DAA-I on endothelial function in the spontaneously hypertensive rat (SHR) as well as its effect on angiotensin II-induced contractions and oxidative stress. Aortic rings were incubated with DAA-I (0.1μM) for 30min prior to the assessment of angiotensin II-induced contractions (0.1nM-10μM) in WKY and SHR aortas. Total nitrate and nitrite levels were assessed using a colorimetric method and reactive oxygen species (ROS) were measured by dihydroethidium (DHE) fluorescence and lucigenin-enhanced chemiluminescence. The effect of DAA-I was also assessed against endothelium-dependent and -independent relaxations to acetylcholine and sodium nitroprusside, respectively. Angiotensin II-induced contractions were significantly reduced by DAA-I, losartan and tempol. Incubation with ODQ (soluble guanylyl cyclase inhibitor) and removal of the endothelium prevented the reduction of angiotensin II-induced contractions by DAA-I. Total nitrate and nitrite levels were increased in DAA-I, losartan and tempol treated-SHR tissues while ROS level was reduced by DAA-I and the latter inhibitors. In addition, DAA-I significantly improved the impaired acetylcholine-induced relaxation in SHR aortas whilst sodium nitroprusside-induced endothelium-independent relaxation remained unaffected. The present findings indicate that improvement of endothelial function by DAA-I in the SHR aorta is mediated through endothelium-dependent release of nitric oxide and inhibition of angiotensin II-induced oxidative stress. PMID:25869508

  10. 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).

  11. 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

  12. 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.

  13. The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition

    PubMed Central

    Siddiquee, K; Hampton, J; McAnally, D; May, LT; Smith, LH

    2013-01-01

    Background and Purpose The apelin receptor (APJ) is often co-expressed with the angiotensin II type-1 receptor (AT1) and acts as an endogenous counter-regulator. Apelin antagonizes Ang II signalling, but the precise molecular mechanism has not been elucidated. Understanding this interaction may lead to new therapies for the treatment of cardiovascular disease. Experimental Approach The physical interaction of APJ and AT1 receptors was detected by co-immunoprecipitation and bioluminescence resonance energy transfer (BRET). Functional and pharmacological interactions were measured by G-protein-dependent signalling and recruitment of β-arrestin. Allosterism and cooperativity between APJ and AT1 were measured by radioligand binding assays. Key Results Apelin, but not Ang II, induced APJ : AT1 heterodimerization forced AT1 into a low-affinity state, reducing Ang II binding. Likewise, apelin mediated a concentration-dependent depression in the maximal production of inositol phosphate (IP1) and β-arrestin recruitment to AT1 in response to Ang II. The signal depression approached a limit, the magnitude of which was governed by the cooperativity indicative of a negative allosteric interaction. Fitting the data to an operational model of allosterism revealed that apelin-mediated heterodimerization significantly reduces Ang II signalling efficacy. These effects were not observed in the absence of apelin. Conclusions and Implications Apelin-dependent heterodimerization between APJ and AT1 causes negative allosteric regulation of AT1 function. As AT1 is significant in the pathogenesis of cardiovascular disease, these findings suggest that impaired apelin and APJ function may be a common underlying aetiology. Linked Article This article is commented on by Goupil et al., pp. 1101–1103 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12040 PMID:22935142

  14. Angiotensin II-inhibition: effect on Alzheimer’s pathology in the aged triple transgenic mouse

    PubMed Central

    Ferrington, Linda; Palmer, Laura E.; Love, Seth; Horsburgh, Karen J; Kelly, Paul AT; Kehoe, Patrick G

    2012-01-01

    Reducing excessive accumulation of amyloid-β (Aβ) in Alzheimer's disease (AD) is a key objective of most AD therapies, and inhibition of angiotensin-converting enzyme (ACE) may delay onset or progression of AD. The effects of an ACE-inhibitor (ACE-I) and an angiotensin II receptor blocker (ARB) on Aβ and tau pathology in a triple transgenic (3xTGAD) mouse model of AD were investigated. 9-10month 3xTGAD mice were treated with ARB, ACE-I or vehicle for 6 months. Mean arterial blood pressure (MABP) was measured periodically and mice were assessed behaviourally. Aβ, phospho-tau, amyloid precursor protein (APP) and ACE activity were analysed. MABP was significantly reduced at 2 weeks and 3 months in the ACE-I group and at 3 months in the ARB group, compared to vehicle. Neither drug altered performance of 3xTGAD mice in Morris Water Maze or T-maze, nor were Aβ, tau immunolabelling or APP levels altered. ACE-I significantly reduced ACE activity in kidney. Prolonged treatment with ACE-I or ARB does not affect Aβ or phospho-tau accumulation in brains of aged 3xTGAD mice. PMID:22611468

  15. 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.

  16. Angiotensin II inhibits insulin-stimulated phosphorylation of eukaryotic initiation factor 4E-binding protein-1 in proximal tubular epithelial cells.

    PubMed Central

    Senthil, D; Faulkner, J L; Choudhury, G G; Abboud, H E; Kasinath, B S

    2001-01-01

    Interaction between angiotensin II, which binds a G-protein-coupled receptor, and insulin, a ligand for receptor tyrosine kinase, was examined in renal proximal tubular epithelial cells. Augmented protein translation by insulin involves activation of eukaryotic initiation factor 4E (eIF4E) which follows the release of the factor from a heterodimeric complex by phosphorylation of its binding protein, 4E-BP1. Angiotensin II (1 nM) or insulin (1 nM) individually stimulated 4E-BP1 phosphorylation. However, pre-incubation with angiotensin II abrogated insulin-induced phosphorylation of 4E-BP1, resulting in persistent binding to eIF4E. Although angiotensin II and insulin individually activated phosphoinositide 3-kinase and extracellular signal-regulated kinase (ERK)-1/-2-type mitogen-activated protein (MAP) kinase, pre-incubation with angiotensin II abolished insulin-induced stimulation of these kinases, suggesting more proximal events in insulin signalling may be intercepted. Pretreatment with angiotensin II markedly inhibited insulin-stimulated tyrosine phosphorylation of insulin-receptor beta-chain and insulin-receptor substrate 1. Losartan prevented angiotensin II inhibition of insulin-induced ERK-1/-2-type MAP kinase activation and 4E-BP1 phosphorylation, suggesting mediation of the effect of angiotensin II by its type 1 receptor. Insulin-stimulated de novo protein synthesis was also abolished by pre-incubation with angiotensin II. These data show that angiotensin II inhibits 4E-BP1 phosphorylation and stimulation of protein synthesis induced by insulin by interfering with proximal events in insulin signalling. Our data provide a mechanistic basis for insulin insensitivity induced by angiotensin II. PMID:11695995

  17. Qiliqiangxin inhibits angiotensin II-induced transdifferentiation of rat cardiac fibroblasts through suppressing interleukin-6

    PubMed Central

    Zhou, Jingmin; Jiang, Kun; Ding, Xuefeng; Fu, Mingqiang; Wang, Shijun; Zhu, Lingti; He, Tao; Wang, Jingfeng; Sun, Aijun; Hu, Kai; Chen, Li; Zou, Yunzeng; Ge, Junbo

    2015-01-01

    Qiliqiangxin (QL), a traditional Chinese medicine, had long been used to treat chronic heart failure. Recent studies revealed that differentiation of cardiac fibroblasts (CFs) into myofibroblasts played an important role in cardiac remodelling and development of heart failure, however, little was known about the underlying mechanism and whether QL treatment being involved. This study aimed to investigate the effects of QL on angiotensin II (AngII)-induced CFs transdifferentiation. Study was performed on in vitro cultured CFs from Sprague–Dawley rats. CFs differentiation was induced by AngII, which was attenuated by QL through reducing transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA). Our data showed that AngII-induced IL-6 mRNA as well as typeI and typeIII collagens were reduced by QL. IL-6 deficiency could suppress TGF-β1 and α-SMA, and both IL-6 siRNA and QL-mediated such effect was reversed by foresed expression of recombined IL-6. Increase in actin stress fibres reflected the process of CFs differentiation, we found stress fibres were enhanced after AngII stimulation, which was attenuated by pre-treating CFs with QL or IL-6 siRNA, and re-enhanced after rIL-6 treatment. Importantly, we showed that calcineurin-dependent NFAT3 nuclear translocation was essential to AngII-mediated IL-6 transcription, QL mimicked the effect of FK506, the calcineurin inhibitor, on suppression of IL-6 expression and stress fibres formation. Collectively, our data demonstrated the negative regulation of CFs differentiation by QL through an IL-6 transcriptional mechanism that depends on inhibition of calcineurin/NFAT3 signalling. PMID:25752645

  18. Aldosterone response to angiotensin II during hypoxemia

    SciTech Connect

    Colice, G.L.; Ramirez, G.

    1986-07-01

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

  19. 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.

  20. Calpain Inhibition Attenuates Angiotensin II-induced Abdominal Aortic Aneurysms and Atherosclerosis in LDL Receptor Deficient Mice

    PubMed Central

    Subramanian, Venkateswaran; Uchida, Haruhito Adam; Ijaz, Talha; Moorleghen, Jessica J.; Howatt, Deborah A.; Balakrishnan, Anju

    2011-01-01

    Chronic infusion of angiotensin II (AngII) augments atherosclerosis and abdominal aortic aneurysm (AAAs) formation in hypercholesterolemic mice. AngII-induced AAAs are associated with medial macrophage accumulation and matrix metalloproteinase (MMP) activation. Inhibition of calpain, a calcium-activated neutral cysteine protease, by overexpression of its endogenous inhibitor, calpastatin, attenuates AngII-induced leukocyte infiltration, perivascular inflammation, and MMP activation in mice. The purpose of this study was to define whether pharmacological inhibition of calpain influences AngII-induced AAAs in hypercholesterolemic mice. Male LDL receptor −/− mice were fed a fat-enriched diet and administered with either vehicle or a calpain-specific inhibitor, BDA-410 (30 mg/kg/day) for 5 weeks. After 1 week of feeding, mice were infused with AngII (1,000 ng/kg/min) for 4 weeks. AngII-infusion profoundly increased aortic calpain protein and activity. BDA-410 administration had no effect on plasma cholesterol concentrations or AngII-increased systolic blood pressure. Calpain inhibition significantly attenuated AngII-induced AAA formation and atherosclerosis development. BDA-410 administration attenuated activation of MMP12, pro-inflammatory cytokines (IL-6, MCP-1) and macrophage infiltration into the aorta. BDA-410 administration significantly attenuated thioglycollate-elicited macrophage accumulation in the peritoneal cavity. We conclude that calpain inhibition using BDA-410 attenuated AngII-induced AAA formation and atherosclerosis development in LDL receptor −/− mice. PMID:21964156

  1. NF-kappaB inhibition ameliorates angiotensin II-induced inflammatory damage in rats.

    PubMed

    Muller, D N; Dechend, R; Mervaala, E M; Park, J K; Schmidt, F; Fiebeler, A; Theuer, J; Breu, V; Ganten, D; Haller, H; Luft, F C

    2000-01-01

    We recently reported that the activation of nuclear factor-kappaB (NF-kappaB) promotes inflammation in rats harboring both human renin and angiotensinogen genes (double-transgenic rats [dTGR]). We tested the hypothesis that the antioxidant pyrrolidine dithiocarbamate (PDTC) inhibits NF-kappaB and ameliorates renal and cardiac end-organ damage. dTGR feature hypertension, severe renal and cardiac damage, and a 40% mortality rate at 7 weeks. Electrophoretic mobility shift assay showed increased NF-kappaB DNA binding activity in hearts and kidneys of dTGR. Chronic PDTC (200 mg/kg SC) treatment decreased blood pressure (162+/-8 versus 190+/-7 mm Hg; P=0.02) in dTGR compared with dTGR controls. The cardiac hypertrophy index was also significantly reduced (4.90+/-0.1 versus 5.77+/-0.1 mg/g; P<0. 001). PDTC reduced 24-hour albuminuria by >95% (2.5+/-0.8 versus 57. 1+/-8.7 mg/d; P<0.001) and prevented death. Vascular injury was ameliorated in small renal and cardiac vessels. Electrophoretic mobility shift assay showed that PDTC inhibited NF-kappaB binding activity in heart and kidney, whereas AP-1 activity in the kidney was not decreased. dTGR exhibited increased left ventricular c-fos and c-jun mRNA expression. PDTC treatment reduced c-fos but not c-jun mRNA. Immunohistochemistry showed increased p65 NF-kappaB subunit expression in the endothelium and smooth muscle cells of damaged small vessels, as well as infiltrating cells in glomeruli, tubules, and collecting ducts of dTGR. PDTC markedly reduced the immunoreactivity of p65. PDTC also prevented the NF-kappaB-dependent transactivation of the intercellular adhesion molecule ICAM-1 and inducible nitric oxide synthase. Monocyte infiltration was markedly increased in dTGR kidneys and hearts. Chronic treatment reduced monocyte/macrophage infiltration by 72% and 64%, respectively. Thus, these results demonstrate that PDTC inhibits NF-kappaB activity, ameliorates inflammation, and protects against angiotensin II-induced end

  2. Somatostatin analog (SMS 201-995) inhibits the basal and angiotensin II-stimulated sup 3 H-thymidine uptake by rat adrenal glands

    SciTech Connect

    Pawlikowski, M.; Lewinski, A.; Sewerynek, E.; Szkudlinski, M.; Kunert-Radek, J.; Wajs, E. )

    1990-02-14

    The effects of a long-acting somatostatin analog SMS 201-995 injections on the basal and angiotensin II-stimulated ({sup 3}H)-thymidine uptake by the rat adrenal glands incubated in vitro were examined. It was shown that SMS 201-995 significantly inhibited the ({sup 3}H)-thymidine uptake and, additionally, suppressed the stimulatory effect of a single angiotensin II injection.

  3. Klotho inhibits angiotensin II-induced cardiomyocyte hypertrophy through suppression of the AT1R/beta catenin pathway.

    PubMed

    Yu, Liangzhu; Meng, Wei; Ding, Jieqiong; Cheng, Menglin

    2016-04-29

    Myocardial hypertrophy is an independent risk factor for cardiac morbidity and mortality. The antiaging protein klotho reportedly possesses a protective role in cardiac diseases. However, the precise mechanisms underlying the cardioprotective effects of klotho remain unknown. This study was aimed to determine the effects of klotho on angiotensin II (Ang II)-induced hypertrophy in neonatal rat cardiomyocytes and the possible mechanism of actions. We found that klotho significantly inhibited Ang II-induced hypertrophic growth of neonatal cardiomyocytes, as evidenced by decreased [(3)H]-Leucine incorporation, cardiomyocyte surface area and β-myosin heavy chain (β-MHC) mRNA expression. Meanwhile, klotho inhibited Ang II-stimulated activation of the Wnt/β-catenin pathway in cardiomyocytes, as evidenced by decreased protein expression of active β-catenin, downregulated protein and mRNA expression of the β-catenin target genes c-myc and cyclin D1, and increased β-catenin phosphorylation. Inhibition of the Wnt/β-catenin pathway by the specific inhibitor XAV939 markedly attenuated Ang II-induced cardiomyocyte hypertrophy. The further study revealed that klotho treatment significantly downregulated protein expression of Ang II receptor type I (AT1R) but not type II (AT2R). The AT1R antagonist losartan inhibited Ang II-stimulated activation of the Wnt/β-catenin pathway and cardiomyocyte hypertrophy. Our findings suggest that klotho inhibits Ang II-induced cardiomyocyte hypertrophy through suppression of the AT1R/β-catenin signaling pathway, which may provide new insights into the mechanism underlying the protective effects of klotho in heart diseases, and raise the possibility that klotho may act as an endogenous antihypertrophic factor by inhibiting the Ang II signaling pathway. PMID:26970306

  4. Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II-Induced Vascular Remodeling via Downregulation of β-Catenin.

    PubMed

    Cui, Mingli; Cai, Zhaohua; Chu, Shichun; Sun, Zhe; Wang, Xiaolei; Hu, Liuhua; Yi, Jing; Shen, Linghong; He, Ben

    2016-01-01

    Angiotensin II (Ang II) is the predominant effector peptide of the renin-angiotensin system. Ang II contributes to vascular remodeling in many cardiovascular diseases (eg, hypertension, atherosclerosis, restenosis, and aneurysm). Orphan nuclear receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II-induced vascular remodeling. Nur77 expression was initially found to be elevated in medial vascular smooth muscle cells (VSMCs) of thoracic aortas from mice continuously infused with Ang II for 2 weeks using a subcutaneous osmotic minipump. Cellular studies revealed that Nur77 expression was upregulated by Ang II via the MAPK/PKA-CREB signaling pathway. Ang II-induced proliferation, migration, and phenotypic switching were significantly enhanced in VSMCs isolated from Nur77(-/-) mice compared with wild-type VSMCs. Consistent with the role in VSMCs, we found that compared with wild-type mice, Nur77(-/-) mice had elevated aortic medial areas and luminal diameters, more severe elastin disruption and collagen deposition, increased VSMC proliferation and matrix metalloproteinase production, and decreased VSMC-specific genes SM-22α and α-actin expression, after 2 weeks of exogenous Ang II administration. The results of additional experiments suggested that Nur77 suppressed Ang II-induced β-catenin signaling pathway activation by promoting β-catenin degradation and inhibiting its transcriptional activity. Our findings indicated that Nur77 is a critical negative regulator of Ang II-induced VSMC proliferation, migration, and phenotypic switching via the downregulation of β-catenin activity. Nur77 may reduce Ang II-induced vascular remodeling involved in many cardiovascular diseases. PMID:26597820

  5. p38 MAPK Inhibition Improves Synaptic Plasticity and Memory in Angiotensin II-dependent Hypertensive Mice

    PubMed Central

    Dai, Hai-long; Hu, Wei-yuan; Jiang, Li-hong; Li, Le; Gaung, Xue-feng; Xiao, Zhi-cheng

    2016-01-01

    The pathogenesis of hypertension-related cognitive impairment has not been sufficiently clarified, new molecular targets are needed. p38 MAPK pathway plays an important role in hypertensive target organ damage. Activated p38 MAPK was seen in AD brain tissue. In this study, we found that long-term potentiation (LTP) of hippocampal CA1 was decreased, the density of the dendritic spines on the CA1 pyramidal cells was reduced, the p-p38 protein expression in hippocampus was elevated, and cognitive function was impaired in angiotensin II-dependent hypertensive C57BL/6 mice. In vivo, using a p38 heterozygous knockdown mice (p38KI/+) model, we showed that knockdown of p38 MAPK in hippocampus leads to the improvement of cognitive function and hippocampal synaptic plasticity in angiotensin II-dependent p38KI/+ hypertensive mice. In vitro, LTP was improved in hippocampal slices from C57BL/6 hypertensive mice by treatment with p38MAPK inhibitor SKF86002. Our data demonstrated that p38 MAPK may be a potential therapeutic target for hypertension-related cognitive dysfunction. PMID:27283322

  6. p38 MAPK Inhibition Improves Synaptic Plasticity and Memory in Angiotensin II-dependent Hypertensive Mice.

    PubMed

    Dai, Hai-Long; Hu, Wei-Yuan; Jiang, Li-Hong; Li, Le; Gaung, Xue-Feng; Xiao, Zhi-Cheng

    2016-01-01

    The pathogenesis of hypertension-related cognitive impairment has not been sufficiently clarified, new molecular targets are needed. p38 MAPK pathway plays an important role in hypertensive target organ damage. Activated p38 MAPK was seen in AD brain tissue. In this study, we found that long-term potentiation (LTP) of hippocampal CA1 was decreased, the density of the dendritic spines on the CA1 pyramidal cells was reduced, the p-p38 protein expression in hippocampus was elevated, and cognitive function was impaired in angiotensin II-dependent hypertensive C57BL/6 mice. In vivo, using a p38 heterozygous knockdown mice (p38(KI/+)) model, we showed that knockdown of p38 MAPK in hippocampus leads to the improvement of cognitive function and hippocampal synaptic plasticity in angiotensin II-dependent p38(KI/+) hypertensive mice. In vitro, LTP was improved in hippocampal slices from C57BL/6 hypertensive mice by treatment with p38MAPK inhibitor SKF86002. Our data demonstrated that p38 MAPK may be a potential therapeutic target for hypertension-related cognitive dysfunction. PMID:27283322

  7. Atorvastatin inhibits the apoptosis of human umbilical vein endothelial cells induced by angiotensin II via the lysosomal-mitochondrial axis.

    PubMed

    Chang, Ye; Li, Yuan; Ye, Ning; Guo, Xiaofan; Li, Zhao; Sun, Guozhe; Sun, Yingxian

    2016-09-01

    This study was aimed to evaluate lysosomes-mitochondria cross-signaling in angiotensin II (Ang II)-induced apoptosis of human umbilical vein endothelial cells (HUVECs) and whether atorvastatin played a protective role via lysosomal-mitochondrial axis. Apoptosis was detected by flow cytometry, Hoechst 33342 and AO/EB assay. The temporal relationship of lysosomal and mitochondrial permeabilization was established. Activity of Cathepsin D (CTSD) was suppressed by pharmacological and genetic approaches. Proteins production were measured by western blotting. Our study showed that Ang II could induce the apoptosis of HUVECs in a dose-depended and time-depended manner. Exposure to 1 μM Ang II for 24 h resulted in mitochondrial depolarization, cytochrome c release, and increased ROS production. Lysosomal permeabilization and CTSD redistribution into the cytoplasm occurred several hours prior to mitochondrial dysfunction. These effects were all suppressed by atorvastatin. Either pharmacological or genetic inhibition of CTSD preserved mitochondrial function and decreased apoptosis in HUVECs. Most importantly, we found that the protective effect of atorvastatin was significantly greater than pharmacological or genetic inhibition of CTSD. Finally, overexpression of CTSD without exposure to Ang II had no effect on mitochondrial function and apoptosis. Our data strongly suggested that Ang II induced apoptosis through the lysosomal-mitochondrial axis in HUVECs. Furthermore, atorvastatin played an important role in the regulation of lysosomes and mitochondria stability, resulting in an antagonistic role against Ang II on HUVECs. PMID:27394920

  8. RAMP1 Augments Cerebrovascular Responses to CGRP And Inhibits Angiotensin II-Induced Vascular Dysfunction

    PubMed Central

    Chrissobolis, Sophocles; Zhang, Zhongming; Kinzenbaw, Dale A.; Lynch, Cynthia M.; Russo, Andrew F.; Faraci, Frank M.

    2010-01-01

    Background and Purpose Receptors for calcitonin gene-related peptide (CGRP) are composed of the calcitonin-like receptor in association with receptor activity-modifying protein-1 (RAMP1). CGRP is an extremely potent vasodilator and may protect against vascular disease through other mechanisms. Methods We tested the hypothesis that overexpression of RAMP1 enhances vascular effects of CGRP using transgenic mice with ubiquitous expression of human RAMP1 (hRAMP1). Because angiotensin II (Ang II) is a key mediator of vascular disease, we also tested the hypothesis that RAMP1 protects against Ang II-induced vascular dysfunction. Results Responses to CGRP in carotid and basilar arteries in vitro as well as cerebral arterioles in vivo were selectively enhanced in hRAMP1 transgenic mice compared to littermate controls (P<0.05), and this effect was prevented by a CGRP receptor antagonist (P<0.05). Thus, vascular responses to CGRP are normally RAMP1-limited. Responses of carotid arteries were examined in vitro following overnight incubation with vehicle or Ang II. In arteries from control mice, Ang II selectively impaired responses to the endothelium-dependent agonist acetylcholine by ∼50% (P<0.05) via a superoxide-mediated mechanism. In contrast, Ang II did not impair responses to acetylcholine in hRAMP1 transgenic mice. Conclusions RAMP1 overexpression increases CGRP-induced vasodilation and protects against Ang II-induced endothelial dysfunction. These findings suggest that RAMP1 may be a new therapeutic target to regulate CGRP-mediated effects during disease including pathophysiological states where Ang II plays a major role. PMID:20814003

  9. Renal Inhibition of Heme Oxygenase-1 Increases Blood Pressure in Angiotensin II-Dependent Hypertension.

    PubMed

    Csongradi, Eva; Storm, Megan V; Stec, David E

    2012-01-01

    The goal of this study was to test the hypothesis that renal medullary heme oxygenase (HO) acts as a buffer against Ang-II dependent hypertension. To test this hypothesis, renal medullary HO activity was blocked using QC-13, an imidazole-dioxolane HO-1 inhibitor, or SnMP, a classical porphyrin based HO inhibitor. HO inhibitors were infused via IRMI catheters throughout the study starting 3 days prior to implantation of an osmotic minipump which delivered Ang II or saline vehicle. MAP was increased by Ang II infusion and further increased by IRMI infusion of QC-13 or SnMP. MAP averaged 113 ± 3, 120 ± 7, 141 ± 2, 153 ± 2, and 154 ± 3 mmHg in vehicle, vehicle + IRMI QC-13, Ang II, Ang II + IRMI QC-13, and Ang II + IRMI SnMP treated mice, respectively (n = 6). Inhibition of renal medullary HO activity with QC-13 in Ang II infused mice was also associated with a significant increase in superoxide production as well as significant decreases in antioxidant enzymes catalase and MnSOD. These results demonstrate that renal inhibition of HO exacerbates Ang II dependent hypertension through a mechanism which is associated with increases in superoxide production and decreases in antioxidant enzymes. PMID:22164328

  10. Angiotensin II and angiotensin II receptor blocker modulate the arrhythmogenic activity of pulmonary veins

    PubMed Central

    Chen, Yi-Jen; Chen, Yao-Chang; Tai, Ching-Tai; Yeh, Hung-I; Lin, Cheng-I; Chen, Shih-Ann

    2005-01-01

    Angiotensin II receptor blockers (AIIRBs) have been shown to prevent atrial fibrillation. The pulmonary veins (PVs) are the most important focus for the generation of atrial fibrillation. The aim of this study was to evaluate whether angiotensin II or AIIRB may change the arrhythmogenic activity of the PVs. Conventional microelectrodes and whole-cell patch clamps were used to investigate the action potentials (APs) and ionic currents in isolated rabbit PV tissue and single cardiomyocytes before and after administering angiotensin II or losartan (AIIRB). In the tissue preparations, angiotensin II induced delayed after-depolarizations (1, 10, and 100 nM) and accelerated the automatic rhythm (10 and 100 nM). Angiotensin II (100 nM) prolonged the AP duration and increased the contractile force (10 and 100 nM). Losartan (1 and 10 μM) inhibited the automatic rhythm. Losartan (10 μM) prolonged the AP duration and reduced the contractile force (1 and 10 μM). Angiotensin II reduced the transient outward potassium current (Ito) but increased the L-type calcium, delayed rectifier potassium (IK), transient inward (Iti), pacemaker, and Na+–Ca2+ exchanger (NCX) currents in the PV cardiomyocytes. Losartan decreased the Ito, IK, Iti, and NCX currents. In conclusion, angiotensin II and AIIRB modulate the PV electrical activity, which may play a role in the pathophysiology of atrial fibrillation. PMID:16273119

  11. Long-term angiotensin II AT1 receptor inhibition produces adipose tissue hypotrophy accompanied by increased expression of adiponectin and PPARgamma.

    PubMed

    Zorad, Stefan; Dou, Jing-tao; Benicky, Julius; Hutanu, Daniel; Tybitanclova, Katarina; Zhou, Jin; Saavedra, Juan M

    2006-12-15

    To clarify the mechanism of the effects of angiotensin II AT(1) receptor antagonists on adipose tissue, we treated 8 week-old male Wistar Kyoto rats with the angiotensin II AT(1) receptor antagonist Candesartan cilexetil (10 mg/kg/day) for 18 weeks. Candesartan cilexetil reduced body weight gain, decreased fat tissue mass due to hypotrophy of epididymal and retroperitoneal adipose tissue and decreased adipocyte size without changing the number of adipocytes. Candesartan cilexetil decreased serum leptin levels and epididymal leptin mRNA, increased serum adiponectin levels and epididymal adiponectin mRNA, decreased epididymal tumor necrosis factor alpha (TNFalpha) mRNA, and increased fatty acid synthase mRNA. Considered free of peroxisome proliferator-activated receptor gamma (PPARgamma) agonist activity, Candesartan cilexetil increased epididymal expression of PPARgamma mRNA. The effects of Candesartan cilexetil on adipokine production and release may be attributable to PPARgamma activation and/or decrease in adipocyte cell size. In addition, Candesartan cilexetil treatment increased the expression of epididymal angiotensin II AT(2) receptor mRNA and protein and decreased the expression of renin receptor mRNA. These results suggest that Candesartan cilexetil influences lipid metabolism in adipose tissue by promoting adipose tissue rearrangement and modulating adipokine expression and release. These effects are probably consequences of local angiotensin II AT(1) receptor inhibition, angiotensin II AT(2) receptor stimulation, and perhaps additional angiotensin II-independent mechanisms. Our results indicate that the activity of local renin-angiotensin system plays an important role in adipose tissue metabolism. The decrease in the pro-inflammatory cytokine TNFalpha and the increase in the anti-inflammatory adipokine adiponectin indicate that Candesartan cilexetil may exert significant anti-inflammatory properties. PMID:17064684

  12. In vitro inhibition of [3H]-angiotensin II binding on the human AT1 receptor by proanthocyanidins from Guazuma ulmifolia bark.

    PubMed

    Caballero-George, Catherina; Vanderheyden, Patrick M L; De Bruyne, Tess; Shahat, Abdel-Atty; Van den Heuvel, Hilde; Solis, Pablo N; Gupta, Mahabir P; Claeys, Magda; Pieters, Luc; Vauquelin, Georges; Vlietinck, Arnold J

    2002-12-01

    A bioassay-guided fractionation of the 70% acetone extract of the bark of Guazuma ulmifolia Lam. on the inhibition of angiotensin II binding to the AT 1 receptor led to the isolation and identification of bioactive oligomeric and polymeric proanthocyanidins consisting mainly of (-)-epicatechin units. The displacement of [3H]-angiotensin II binding was dose-dependent and correlated with the degree of polymerization of the different fractions containing proanthocyanidins. A strong displacement was seen for the residual fraction suggesting that the most active substances corresponding to the highly polymerized proanthocyanidins. Angiotensin II AT 1 receptor binding might be considered as a potentially interesting biological activity of proanthocyanidins contributing to the very broad spectrum of biological activities of the condensed tannins. PMID:12494331

  13. Bletilla striata polysaccharide inhibits angiotensin II-induced ROS and inflammation via NOX4 and TLR2 pathways.

    PubMed

    Yue, Long; Wang, Wang; Wang, Yan; Du, Ting; Shen, Weiping; Tang, Huiling; Wang, Ying; Yin, Hongping

    2016-08-01

    In the current study, we analyzed the functions and mechanisms of Bletilla striata polysaccharide b (BSPb) against Angiotensin II (Ang II)-induced oxidative stress and inflammation in human mesangial cells (HMCs). It was found that BSPb could inhibit generation of Ang II-induced reactive oxygen species (ROS) and activation of proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) in a dose-dependent manner. Further studies revealed that BSPb effectively blocked upregulation of NADPH oxidase 4 (NOX4). Moreover, knockdown of NOX4 significantly impaired the anti-oxidative function of BSPb. In addition, BSPb decreased overexpression of Toll-like receptor 2 (TLR2) induced by Ang II. Blocking TLR2 expression impaired the anti-inflammatory effects of BSPb. In conclusion, BSPb was found to possess anti-oxidative stress and anti-inflammatory functions against Ang II-induced ROS generation and proinflammatory cytokines activation. The NOX4 and TLR2 pathways played important roles in the biological effects mediated by BSPb. PMID:27151672

  14. Proximal tubule NHE3 activity is inhibited by beta-arrestin-biased angiotensin II type 1 receptor signaling.

    PubMed

    Carneiro de Morais, Carla P; Polidoro, Juliano Z; Ralph, Donna L; Pessoa, Thaissa D; Oliveira-Souza, Maria; Barauna, Valério G; Rebouças, Nancy A; Malnic, Gerhard; McDonough, Alicia A; Girardi, Adriana C C

    2015-10-15

    Physiological concentrations of angiotensin II (ANG II) upregulate the activity of Na(+)/H(+) exchanger isoform 3 (NHE3) in the renal proximal tubule through activation of the ANG II type I (AT1) receptor/G protein-coupled signaling. This effect is key for maintenance of extracellular fluid volume homeostasis and blood pressure. Recent findings have shown that selective activation of the beta-arrestin-biased AT1 receptor signaling pathway induces diuresis and natriuresis independent of G protein-mediated signaling. This study tested the hypothesis that activation of this AT1 receptor/beta-arrestin signaling inhibits NHE3 activity in proximal tubule. To this end, we determined the effects of the compound TRV120023, which binds to the AT1R, blocks G-protein coupling, and stimulates beta-arrestin signaling on NHE3 function in vivo and in vitro. NHE3 activity was measured in both native proximal tubules, by stationary microperfusion, and in opossum proximal tubule (OKP) cells, by Na(+)-dependent intracellular pH recovery. We found that 10(-7) M TRV120023 remarkably inhibited proximal tubule NHE3 activity both in vivo and in vitro. Additionally, stimulation of NHE3 by ANG II was completely suppressed by TRV120023 both in vivo as well as in vitro. Inhibition of NHE3 activity by TRV120023 was associated with a decrease in NHE3 surface expression in OKP cells and with a redistribution from the body to the base of the microvilli in the rat proximal tubule. These findings indicate that biased signaling of the beta-arrestin pathway through the AT1 receptor inhibits NHE3 activity in the proximal tubule at least in part due to changes in NHE3 subcellular localization. PMID:26246427

  15. Angiotensin II receptor expression and inhibition in the chronically hypoxic rat lung.

    PubMed Central

    Zhao, L.; al-Tubuly, R.; Sebkhi, A.; Owji, A. A.; Nunez, D. J.; Wilkins, M. R.

    1996-01-01

    1. Angiotensin II (AII) binding density and the effect of chronic AII receptor blockade were examined in the rat model of hypoxia-induced pulmonary hypertension. 2. [125I]-[Sar1,Ile2]AII binding capacity was increased in lung membranes from rats exposed to hypoxia (10% fractional inspired O2) for 7 days compared to normal rats (Bmax 108 +/- 12 vs 77 +/- 3 fmol mg-1 protein; P < 0.05), with no significant change in dissociation constant. Competition with specific AII receptor subtype antagonists demonstrated that AT1 is the predominant subtype in both normal and hypoxic lung. 3. Rats treated intravenously with the AT1 antagonist, GR138950C, 1 mg kg-1 day-1 rather than saline alone during 7 days of exposure to hypoxia developed less pulmonary hypertension (pulmonary arterial pressure: 21.3 +/- 1.7 vs 28.3 +/- 1.1 mmHg; P < 0.05), right ventricular hypertrophy (right/left ventricle weight ratio: 0.35 +/- 0.01 vs 0.45 +/- 0.01; P < 0.05) and pulmonary artery remodelling (abundance of thick-walled pulmonary vessels: 9.6 +/- 1.4% vs 20.1 +/- 0.9%; P < 0.05). 4. The reduction in cardiac hypertrophy and pulmonary remodelling with the AT1 antagonist was greater than that achieved by a dose of sodium nitroprusside (SNP) that produced a comparable attenuation of the rise in pulmonary arterial pressure during hypoxia. 5. The data suggest that AII, via the AT1 receptor, has a role in the early pathogenesis of hypoxia-induced pulmonary hypertension in the rat. PMID:8937726

  16. Angiotensin II and gene expression in the kidney.

    PubMed

    Klahr, S; Morrissey, J

    1998-01-01

    Angiotensin II, a potent vasoconstrictor, has a key role in renal injury and in the progression of chronic renal disease of diverse causes. In vascular smooth muscle cells, angiotensin II modulates growth, which may lead to hypertrophy and also may inhibit mitogen-stimulated DNA synthesis. The effects of angiotensin II on responsive cells are mediated by two classes of receptors, AT-1 and AT-2. Information obtained in the last decade indicates that angiotensin II increases the production of several autocrine factors, including transforming growth factor beta1 (TGF-beta1), tumor necrosis factor-alpha (TNF-alpha), and platelet-derived growth factor A chain (PDGF). Angiotensin also increases the release of other growth factors such as endothelin, platelet-activating factor (PAF), and interleukin 6. In addition, it increases the "activity" of nuclear factor-kappaB (NF-kappaB) and the synthesis of angiotensinogen. The emerging picture indicates that the actions of angiotensin II may be related to factors that are released or upregulated by angiotensin II, possibly through NF-kappaB activation. It appears likely that many of the effects of angiotensin II on renal disease may be mediated by TGF-beta1, TNF-alpha, and changes in the activity of NF-kappaB. The use of ACE inhibitors or antagonists of AT-1 or AT-2 receptors in experimental animals decreases the levels of angiotensin II or limits its action, thereby interfering with the production and effects of the factors described. PMID:9428470

  17. Conditional expression of the type 2 angiotensin II receptor in mesenchymal stem cells inhibits neointimal formation after arterial injury.

    PubMed

    Feng, Jian; Liu, Jian-Ping; Miao, Li; He, Guo-Xiang; Li, De; Wang, Hai-Dong; Jing, Tao

    2014-10-01

    Percutaneous coronary interventions (PCIs) are an effective treatment for obstructive coronary artery diseases. However, the procedure's success is limited by remodeling and formation of neointima. In the present study, we engineered rat mesenchymal stem cells (MSCs) to express type 2 angiotensin II receptor (AT2R) using a tetracycline-regulated system that can strictly regulate AT2R expression. We tested the ability of the modified MSCs to reduce neointima formation following arterial injury. We subjected rats to balloon injury, and reverse transcriptase polymerase chain reaction (RT-PCR) indicated no significant AT2R expression in normal rat arteries. Low expression of AT2R was observed at 28 days after balloon-induced injury. Interestingly, MSCs alone were unable to reduce neointimal hyperplasia after balloon-induced injury; after transplantation of modified MSCs, doxycycline treatment significantly upregulated neointimal AT2R expression and inhibited osteopontin mRNA expression, as well as neointimal formation. Taken together, these results suggest that transplantation of MSCs conditionally expressing AT2R could effectively suppress neointimal hyperplasia following balloon-induced injury. Therefore, MSCs with a doxycycline-controlled gene induction system may be useful for the management of arterial injury after PCI. PMID:25119854

  18. Naked Polyamidoamine Polymers Intrinsically Inhibit Angiotensin II-Mediated EGFR and ErbB2 Transactivation in a Dendrimer Generation- and Surface Chemistry-Dependent Manner.

    PubMed

    Akhtar, Saghir; El-Hashim, Ahmed Z; Chandrasekhar, Bindu; Attur, Sreeja; Benter, Ibrahim F

    2016-05-01

    The effects of naked polyamidoamine (PAMAM) dendrimers on renin-angiotensin system (RAS) signaling via Angiotensin (Ang) II-mediated transactivation of the epidermal growth factor receptor (EGFR) and the closely related family member ErbB2 (HER2) were investigated. In primary aortic vascular smooth muscle cells, a cationic fifth-generation (G5) PAMAM dendrimer dose- and time-dependently inhibited Ang II/AT1 receptor-mediated transactivation of EGFR and ErbB2 as well as their downstream signaling via extracellular-regulated kinase 1/2 (ERK1/2). Inhibition even occurred at noncytotoxic concentrations at short (1 h) exposure times and was dependent on dendrimer generation (G7 > G6 > G5 > G4) and surface group chemistry (amino > carboxyl > hydroxyl). Mechanistically, the cationic G5 PAMAM dendrimer inhibited Ang II-mediated transactivation of EGFR and ErbB2 via inhibition of the nonreceptor tyrosine kinase Src. This novel, early onset, intrinsic biological action of PAMAM dendrimers as inhibitors of the Ang II/AT1/Src/EGFR-ErbB2/ERK1/2 signaling pathway could have important toxicological and pharmacological implications. PMID:26985693

  19. Angiotensin II type 1 receptor antagonists inhibit basal as well as low-density lipoprotein and platelet-activating factor-stimulated human monocyte chemoattractant protein-1.

    PubMed

    Proudfoot, Julie M; Croft, Kevin D; Puddey, Ian B; Beilin, Lawrence J

    2003-06-01

    Monocyte chemoattractant protein-1 (MCP-1) is a potent chemotactic agent for monocytes and other cells and is thought to be involved in atherosclerosis, recruiting monocytes to the subendothelial space or to the site of inflammation. Angiotensin II has been demonstrated, at least in animal models, to stimulate MCP-1 expression. We investigated the effect of the angiotensin II type 1 (AT1) receptor antagonists irbesartan and losartan on MCP-1 production by freshly isolated human monocytes. Irbesartan and losartan inhibited basal MCP-1 production in a dose-dependent manner. Low-density lipoprotein (LDL) stimulated MCP-1 in a concentration-dependent manner, with 200 microg/ml LDL protein giving a 2-fold increase in MCP-1. Irbesartan and losartan dose dependently blocked LDL-stimulated MCP-1. An angiotensin II type 2 receptor antagonist, S-(+)-1-([4-(dimethylamino)-3-methylphenyl]methyl)-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo(4,5-c)pyridine-6-carboxylic acid (PD123319), had no significant effect on basal MCP-1 levels or LDL-stimulated MCP-1. After noting homology between the AT1 receptor and the platelet-activating factor (PAF) receptor, we showed that irbesartan inhibited both [3H]PAF binding to human monocytes and carbamyl-PAF stimulation of MCP-1. However, irbesartan affinity for the PAF receptor was 700 times less than PAF, suggesting that there may be another mechanism for irbesartan inhibition of PAF-stimulated MCP-1. This is the first report showing that AT1 receptor antagonists inhibit basal as well as LDL- and PAF-stimulated MCP-1 production in freshly isolated human monocytes. PMID:12626661

  20. Cardamonin inhibits angiotensin II-induced vascular smooth muscle cell proliferation and migration by downregulating p38 MAPK, Akt, and ERK phosphorylation.

    PubMed

    Shen, Yan-Jing; Zhu, Xue-Xin; Yang, Xian; Jin, Bo; Lu, Jin-Jian; Ding, Bin; Ding, Zhi-Shan; Chen, Su-Hong

    2014-07-01

    Cardamonin is a chalconoid isolated from various herbs, such as Alpinia katsumadai and Carya cathayensis Sarg. This study examined the effect of cardamonin on angiotensin II (Ang II)-induced proliferation and migration in rat vascular smooth muscle cells (VSMCs) as well as its underlying mechanisms. The results showed that cardamonin significantly inhibited Ang II-induced proliferation and migration in rat VSMCs in a concentration-dependent manner. Moreover, cardamonin suppressed Ang II-induced phosphorylation of p38 MAPK, Akt, and extracellular regulated protein kinase (ERK). These findings indicate that the downregulation of p38 MAPK, Akt, and ERK phosphorylation might be, at least in part, involved in cardamonin-suppressed proliferation and migration induced by Ang II in rat VSMCs. As proliferation and migration of VSMCs play critical roles in the pathogenesis of atherosclerosis, cardamonin might be a potential candidate for atherosclerosis treatment. PMID:24595849

  1. Binding, degradation and pressor activity of angiotensins II and III after aminopeptidase inhibition with amastatin and bestatin

    SciTech Connect

    Abhold, R.H.; Sullivan, M.J.; Wright, J.W.; Harding, J.W.

    1987-09-01

    In the metabolism of angiotensin peptides by tissue angiotensinases, aminopeptidases A, B, M and leucine aminopeptidase have been identified as being particularly effective. Because the inhibitory actions of amastatin (AM) and bestatin (BE) are relatively specific for these aminopeptidases, we have examined the effects of these inhibitors on the binding, degradation and pressor activity of angiotensin II (AII) and angiotensin III (AIII). Within 30 min at 37 degrees C, significant metabolism of /sup 125/I-AII and /sup 125/I-AIII by homogenates of a block of tissue containing hypothalamus, thalamus, septum and anteroventral third ventricle regions of the brain was observed. A majority of /sup 125/I-AIII metabolism was due to soluble peptidases, whereas that of /sup 125/I-AII primarily resulted from membrane-bound peptidases. AM, BE and reduced incubation temperatures significantly decreased the metabolism of /sup 125/I-AII and /sup 125/I-AIII. After appropriate adjustments to reflect the proportion of intact radioligand bound, temperature- or inhibitor-induced decreases in metabolism were matched by corresponding increases in specific binding. Heat-treated bovine serum albumin, as a nonspecific peptidase inhibitor, had no effect on either the metabolism or binding of the ligands used. In accordance with their actions in vitro, i.c.v. administration of AM and BE prolonged the pressor activity of subsequently applied AII and AIII. Unexpectedly, the amplitude of the pressor response to AIII was increased by BE, whereas that to AII was decreased by AM. The results of this study indicate that the metabolism of AII and AIII by aminopeptidases is relatively specific and acts to modulate the actions of these peptides.

  2. Knocking out Angiotensin II in the Heart

    PubMed Central

    Zablocki, Daniela; Sadoshima, Junichi

    2011-01-01

    Despite ongoing medical advances, cardiovascular disease continues to be a leading health concern. The renin-angiotensin system (RAS) plays an important role in regulating cardiovascular function, and is, therefore, the subject of extensive study. Several of the drugs currently used to treat hypertension and heart failure are designed to target Ang II synthesis and function, but none have been able to completely block the effects of RAS signaling thus far. This review discusses current and emerging approaches towards inhibiting cardiac RAS function in order to further improve cardiovascular disease outcomes. PMID:21234717

  3. Caveolin 1 is critical for abdominal aortic aneurysm formation induced by angiotensin II and inhibition of lysyl oxidase.

    PubMed

    Takayanagi, Takehiko; Crawford, Kevin J; Kobayashi, Tomonori; Obama, Takashi; Tsuji, Toshiyuki; Elliott, Katherine J; Hashimoto, Tomoki; Rizzo, Victor; Eguchi, Satoru

    2014-06-01

    Although AngII (angiotensin II) and its receptor AT1R (AngII type 1 receptor) have been implicated in AAA (abdominal aortic aneurysm) formation, the proximal signalling events primarily responsible for AAA formation remain uncertain. Caveolae are cholesterol-rich membrane microdomains that serve as a signalling platform to facilitate the temporal and spatial localization of signal transduction events, including those stimulated by AngII. Cav1 (caveolin 1)-enriched caveolae in vascular smooth muscle cells mediate ADAM17 (a disintegrin and metalloproteinase 17)-dependent EGFR (epidermal growth factor receptor) transactivation, which is linked to vascular remodelling induced by AngII. In the present study, we have tested our hypothesis that Cav1 plays a critical role for the development of AAA at least in part via its specific alteration of AngII signalling within caveolae. Cav1-/- mice and the control wild-type mice were co-infused with AngII and β-aminopropionitrile to induce AAA. We found that Cav1-/- mice with the co-infusion did not develop AAA compared with control mice in spite of hypertension. We found an increased expression of ADAM17 and enhanced phosphorylation of EGFR in AAA. These events were markedly attenuated in Cav1-/- aortas with the co-infusion. Furthermore, aortas from Cav1-/- mice with the co-infusion showed less endoplasmic reticulum stress, oxidative stress and inflammatory responses compared with aortas from control mice. Cav1 silencing in cultured vascular smooth muscle cells prevented AngII-induced ADAM17 induction and activation. In conclusion, Cav1 appears to play a critical role in the formation of AAA and associated endoplasmic reticulum/oxidative stress, presumably through the regulation of caveolae compartmentalized signals induced by AngII. PMID:24329494

  4. Mitogen-activated protein kinase kinase 1/2 inhibition and angiotensin II converting inhibition in mice with cardiomyopathy caused by lamin A/C gene mutation

    SciTech Connect

    Muchir, Antoine; Wu, Wei; Sera, Fusako; Homma, Shunichi; Worman, Howard J.

    2014-10-03

    Highlights: • Both ACE and MEK1/2 inhibition are beneficial on cardiac function in Lmna cardiomyopathy. • MEK1/2 inhibitor has beneficial effects beyond ACE inhibition for Lmna cardiomyopathy. • These results provide further preclinical rationale for a clinical trial of a MEK1/2 inhibitor. - Abstract: Background: Mutations in the LMNA gene encoding A-type nuclear lamins can cause dilated cardiomyopathy with or without skeletal muscular dystrophy. Previous studies have shown abnormally increased extracellular signal-regulated kinase 1/2 activity in hearts of Lmna{sup H222P/H222P} mice, a small animal model. Inhibition of this abnormal signaling activity with a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor has beneficial effects on heart function and survival in these mice. However, such treatment has not been examined relative to any standard of care intervention for dilated cardiomyopathy or heart failure. We therefore examined the effects of an angiotensin II converting enzyme (ACE) inhibitor on left ventricular function in Lmna{sup H222P/H222P} mice and assessed if adding a MEK1/2 inhibitor would provide added benefit. Methods: Male Lmna{sup H222P/H222P} mice were treated with the ACE inhibitor benazepril, the MEK1/2 inhibitor selumetinib or both. Transthoracic echocardiography was used to measure left ventricular diameters and fractional shortening was calculated. Results: Treatment of Lmna{sup H222P/H222P} mice with either benazepril or selumetinib started at 8 weeks of age, before the onset of detectable left ventricular dysfunction, lead to statistically significantly increased fractional shortening compared to placebo at 16 weeks of age. There was a trend towards a great value for fractional shortening in the selumetinib-treated mice. When treatment was started at 16 weeks of age, after the onset of left ventricular dysfunction, the addition of selumetinib treatment to benazepril lead to a statistically significant increase in left

  5. Atorvastatin blocks increased l-type Ca2+ current and cell injury elicited by angiotensin II via inhibiting oxide stress.

    PubMed

    Ma, Yanzhuo; Kong, Lingfeng; Qi, Shuying; Wang, Dongmei

    2016-04-01

    Thel-type Ca(2+)current (ICa,l) plays a crucial role in shaping action potential and is involved in cardiac arrhythmia. Statins have been demonstrated to contribute to anti-apoptotic and anti-arrhythmic effects in the heart. Here, we examined whether atorvastatin regulates theICa,land cell injury induced by angiotensin II (AngII) as well as the putative intracellular cascade responsible for the effects. Cultured neonatal rat ventricular myocytes were incubated with AngII for 24 h, and then cell injury and expression levels of Nox2/gp91(phox), p47(phox) ,and Cav1.2 were analyzed. In addition,ICa,lwas recorded using the whole-cell patch-clamp technique, and mechanisms of atorvastatin actions were also investigated. It was found that the number of apoptotic cardiomyocytes was increased and cell viability was significantly decreased after AngII administration. AngII also augmented the expressions of Nox2/gp91(phox)and p47(phox)compared with control cardiomyocytes. Exposure to AngII evokedICa,lin a voltage-dependent manner without affecting theI-Vrelationship. In addition, AngII enhanced membrane Cav1.2 expression. These effects were abolished in the presence of the reactive oxygen species (ROS) scavenger, manganese (III)-tetrakis 4-benzoic acid porphyrin [Mn(III)TBAP], or the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, atorvastatin. These results suggested that atorvastatin mediates cardioprotection against arrhythmias and cell injury by controlling the AngII-ROS cascade. PMID:26940997

  6. Boldine improves endothelial function in diabetic db/db mice through inhibition of angiotensin II-mediated BMP4-oxidative stress cascade

    PubMed Central

    Lau, Yeh Siang; Tian, Xiao Yu; Mustafa, Mohd Rais; Murugan, Dharmani; Liu, Jian; Zhang, Yang; Lau, Chi Wai; Huang, Yu

    2013-01-01

    BACKGROUND AND PURPOSE Boldine is a potent natural antioxidant present in the leaves and bark of the Chilean boldo tree. Here we assessed the protective effects of boldine on endothelium in a range of models of diabetes, ex vivo and in vitro. EXPERIMENTAL APPROACH Vascular reactivity was studied in mouse aortas from db/db diabetic and normal mice. Reactive oxygen species (ROS) production, angiotensin AT1 receptor localization and protein expression of oxidative stress markers in the vascular wall were evaluated by dihydroethidium fluorescence, lucigenin enhanced-chemiluminescence, immunohistochemistry and Western blot respectively. Primary cultures of mouse aortic endothelial cells, exposed to high concentrations of glucose (30 mmol L−1) were also used. KEY RESULTS Oral treatment (20 mg kg−1day−1, 7 days) or incubation in vitro with boldine (1 μmol L−1, 12 h) enhanced endothelium-dependent aortic relaxations of db/db mice. Boldine reversed impaired relaxations induced by high glucose or angiotensin II (Ang II) in non-diabetic mouse aortas while it reduced the overproduction of ROS and increased phosphorylation of eNOS in db/db mouse aortas. Elevated expression of oxidative stress markers (bone morphogenic protein 4 (BMP4), nitrotyrosine and AT1 receptors) were reduced in boldine-treated db/db mouse aortas. Ang II-stimulated BMP4 expression was inhibited by boldine, tempol, noggin or losartan. Boldine inhibited high glucose-stimulated ROS production and restored the decreased phosphorylation of eNOS in mouse aortic endothelial cells in culture. CONCLUSIONS AND IMPLICATIONS Boldine reduced oxidative stress and improved endothelium-dependent relaxation in aortas of diabetic mice largely through inhibiting ROS overproduction associated with Ang II-mediated BMP4-dependent mechanisms. PMID:23992296

  7. Heparin inhibits Angiotensin II-induced vasoconstriction on isolated mouse mesenteric resistance arteries through Rho-A- and PKA-dependent pathways

    PubMed Central

    Xie-Zukauskas, Hui; Das, Jharna; Short, Billie Lou; Gutkind, J. Silvio; Ray, Patricio E.

    2013-01-01

    Heparin is commonly used to treat intravascular thrombosis in children undergoing extracorporeal membrane oxygenation or cardiopulmonary bypass. These clinical circumstances are associated with elevated plasma levels of angiotensin II (Ang II). However, the mechanisms by which heparin modulates vascular reactivity of Ang II remain unclear. We hypothesized that heparin may offset Ang II-induced vasoconstriction on mesenteric resistances arteries through modulating the Rho-A/Rho kinase pathway. Vascular contractility was studied using pressurized, resistance-sized mesenteric arteries from mice. Rho-A activation was measured by pull-down assay, and myosin light chain or PKA phosphorylation by immunoblotting. We found that heparin significantly attenuated vasoconstriction induced by Ang II but not that by KCl. The combined effect of Ang II with heparin was almost abolished by a specific Rho kinase inhibitor Y27632. Ang II stimulated Rho-A activation and myosin light chain phosphorylation, both responses were antagonized by heparin. Moreover, the inhibitory effect of heparin on Ang II-induced vasoconstriction was reversed by Rp-cAMPS (cAMP-dependent PKA inhibitor), blunted by ODQ (soluble guanylate cyclase inhibitor), and mimicked by a cell-permeable cGMP analogue, 8-Br-cGMP, but not by a cAMP analogue. PKC and Src kinase were not involved. We conclude that heparin inhibits Ang II-induced vasoconstriction through Rho-A/Rho kinase- and cGMP/PKA-dependent pathways. PMID:23268358

  8. 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.

  9. Hepatocyte growth factor inhibits apoptosis by the profibrotic factor angiotensin II via extracellular signal-regulated kinase 1/2 in endothelial cells and tissue explants.

    PubMed

    Lee, Young H; Marquez, Ana P; Mungunsukh, Ognoon; Day, Regina M

    2010-12-01

    Hepatocyte growth factor (HGF), an endogenous tissue repair factor, attenuates apoptosis in many primary cell types, but the mechanism is not completely understood. Our laboratory demonstrated that angiotensin (Ang) II activates the intrinsic apoptotic pathway in primary endothelial cells (ECs) via reduction of the antiapoptotic protein Bcl-x(L). Ang II decreased Bcl-x(L) mRNA half-life by reducing its binding to nucleolin, a protein that normally binds a 3' AU-rich region and stabilizes Bcl-x(L) mRNA. We hypothesized HGF may block apoptosis induced by Ang II. We used primary EC and ex vivo cultures of rat lung tissue to investigate HGF inhibition of Ang II-induced apoptosis. Our data indicated HGF abrogated Ang II-induced apoptosis by inhibiting cytochrome c release, caspase-3 activation, and DNA fragmentation. RNA-immunoprecipitation experiments demonstrated that HGF stabilized Bcl-x(L) mRNA by increasing nucleolin binding to the 3'-untranslated region that was associated with cytoplasmic localization of nucleolin. Cytoplasmic localization of nucleolin and Bcl-x(L) mRNA stabilization required HGF activation of extracellular signal-regulated kinase (ERK)1/2, but not phosphatidylinositol 3-kinase. HGF also blocked Ang II-induced caspase-3 activation and lactate dehydrogenase release in tissue explants in an ERK-dependent manner. PMID:20926686

  10. Alpinate oxyphyllae fructus (Alpinia Oxyphylla Miq) extracts inhibit angiotensin-II induced cardiac apoptosis in H9c2 cardiomyoblast cells.

    PubMed

    Chang, Yung-Ming; Tsai, Chuan-Te; Wang, Chiun-Chuang Roger; Chen, Yueh-Sheng; Lin, Yueh-Min; Kuo, Chia-Hua; Tzang, Bor-Show; Chen, Ray-Jade; Tsai, Fuu-Jen; Huang, Chih-Yang

    2013-01-01

    Angiotensin II (Ang II) is a risk factor for cardiovascular disease. We used a traditional Chinese medicine, alpinate oxyphyllae fructus (AOF), to evaluate its effect on Ang II-induced cardiac apoptosis and mitochondrial dysfunction. Ang II-treated H9c2 cells were administered AOF of 20-100 µg/mL concentrations. Ang II significantly increased TUNEL-positive nuclei in the H9c2 cells, effect was inhibited by AOF administration in both pre-treated and post-treated H9c2 cells. Caspases 9 and 3 activities were increased by Ang II and downregulated by AOF administration, especially in pre-treatment. AOF treatment reversed Ang II-induced mitochondria membrane potential instability in H9c2 cells as observed by JC-1 stain assay. Furthermore, pro-apoptotic proteins Bad and cytochrome c increased and decreased respectively under AOF administration. The levels of p-Bad anti-apoptotic protein were significantly increased after AOF treatment. This study indicates that mitochondrial dependent apoptosis induced by Ang II. PMID:23391902

  11. Jia-Shen decoction-medicated serum inhibits angiotensin-II induced cardiac fibroblast proliferation via the TGF-β1/Smad signaling pathway

    PubMed Central

    Cui, Lin; Wang, Youping; Yu, Rui; Li, Bin; Xie, Shiyang; Gao, Yuan; Wang, Xiaoxiao; Zhu, Mingjun

    2016-01-01

    Jia-Shen decoction (JSD) is a traditional Chinese medicine, which is used widely to treat chronic heart failure. However, the underlying mechanism remains to be elucidated. The present study aimed to investigate the mechanism underlying the effects of JSD on cardiac fibroblast (CF) proliferation and differentiation. The CFs were obtained from the hearts of neonatal (1-3-day old) Sprague-Dawley rats and treated with JSD-medicated serum (JSDS) with or without angiotensin II (Ang II). Cell proliferation was assessed using Cell Counting Kit-8 reagent. In addition, the mRNA expression levels of transforming growth factor-β1 (TGF-β1) and phosphorylated small mothers against decapentaplegic (p-Smad)2/3 and their protein expression levels were analyzed. CF proliferation was significantly increased in the Ang II-treated group, compared with the control group (P<0.05). The expression levels of collagen, α-smooth muscle actin, TGF-β1 and p-Smad2/3 were also increased in the Ang II-treated group (P<0.05). Following JSDS treatment, the increased levels of collagen and cell proliferation were inhibited, and the increased expression levels of p-Smad2 and p-Smad3 were also inhibited (P<0.05). These data suggested that JSDS may inhibit CF proliferation via attenuating the TGF-β1/Smad signaling pathway. PMID:27315199

  12. Effects of Angiotensin-II Receptor Blocker on Inhibition of Thrombogenicity in a Canine Atrial Fibrillation Model

    PubMed Central

    Jung, Jae Seung; Kim, Min Kyung; Sim, Jaemin; Kim, Jin Seok; Lim, Hong Euy; Park, Sang Weon; Kim, Young-Hoon

    2016-01-01

    Background and Objectives Angiotensin-II receptor blockers (ARBs) are known to reduce the development of atrial fibrillation (AF) through reverse-remodeling. However, the effect of ARBs on thrombogenicity in AF remains unknown. Materials and Methods Twelve dogs were assigned to control (n=4), ARB (candesartan cilexitil 10 mg/kg/day p.o., 12 weeks; n=4), or sham (n=4) groups. Sustained AF was induced by rapid atrial pacing. Both arterial and venous serum levels of tissue inhibitor of matrix metalloproteinase-1, von Willebrand factor, P-selectin, and vascular cell adhesion molecule-1 (VCAM-1) were measured at baseline and during AF (0, 4, and 12 weeks) with enzyme-linked immunosorbent assay. Biopsies from both atria including the appendages were performed to semi-quantitatively assess endocardial and myocardial fibrosis after 12 weeks. Results The serum levels of bio-markers were not significantly different at baseline or during AF between the control and the candesartan groups. The levels were not significantly different over time, but there was a trend toward a decrease in arterial VCAM-1 from 4 to 12 weeks in the candesartan group compared to the control group. The grades of endocardial fibrosis after 12 weeks but not those of myocardial fibrosis were slightly reduced in the candesartan group compared to the control group. Conclusion This study did not show that the ARB candesartan significantly reverses thrombogenicity or fibrosis during AF. Future studies using a larger number of subjects are warranted to determine the therapeutic effect of renin-angiotensin-aldosterone system blockade on prothrombogenic processes in AF. PMID:27275170

  13. DL0805-2, a novel indazole derivative, relaxes angiotensin II-induced contractions of rat aortic rings by inhibiting Rho kinase and calcium fluxes

    PubMed Central

    Yuan, Tian-yi; Chen, Yu-cai; Zhang, Hui-fang; Li, Li; Jiao, Xiao-zhen; Xie, Ping; Fang, Lian-hua; Du, Guan-hua

    2016-01-01

    Aim: DL0805-2 [N-(1H-indazol-5-yl)-1-(4-methylbenzyl) pyrrolidine-3-carboxamide] is a DL0805 derivative with more potent vasorelaxant activity and lower toxicity. This study was conducted to investigate the vasorelaxant mechanisms of DL0805-2 on angiotensin II (Ang II)-induced contractions of rat thoracic aortic rings in vitro. Methods: Rat thoracic aortic rings and rat aortic vascular smooth muscle cells (VSMCs) were pretreated with DL0805-2, and then stimulated with Ang II. The tension of the aortic rings was measured through an isometric force transducer. Ang II-induced protein phosphorylation, ROS production and F-actin formation were assessed with Western blotting and immunofluorescence assays. Intracellular free Ca2+ concentrations were detected with Fluo-3 AM. Results: Pretreatment with DL0805-2 (1–100 μmol/L) dose-dependently inhibited the constrictions of the aortic rings induced by a single dose of Ang II (10−7 mol/L) or accumulative addition of Ang II (10−10–10−7 mol/L). The vasodilatory effect of DL0805-2 was independent of endothelium. In the aortic rings, pretreatment with DL0805-2 (1, 3, and 10 μmol/L) suppressed Ang II-induced Ca2+ influx and intracellular Ca2+ mobilization, and Ang II-induced phosphorylation of two substrates of Rho kinase (MLC and MYPT1). In VSMCs, pretreatment with DL0805-2 (1, 3, and 10 μmol/L) also suppressed Ang II-induced Ca2+ fluxes and phosphorylation of MLC and MYPT1. In addition, pretreatment with DL0805-2 attenuated ROS production and F-actin formation in the cells. Conclusion: DL0805-2 exerts a vasodilatory action in rat aortic rings through inhibiting the Rho/ROCK pathway and calcium fluxes. PMID:27041459

  14. 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.

  15. Inhibition of Proteasome Activity by Low-dose Bortezomib Attenuates Angiotensin II-induced Abdominal Aortic Aneurysm in Apo E−/− Mice

    PubMed Central

    Ren, Hualiang; Li, Fangda; Tian, Cui; Nie, Hao; Wang, Lei; Li, Hui-Hua; Zheng, Yuehong

    2015-01-01

    Abdominal aortic aneurysm (AAA) is a leading cause of sudden death in aged people. Activation of ubiquitin proteasome system (UPS) plays a critical role in the protein quality control and various diseases. However, the functional role of UPS in AAA formation remains unclear. In this study, we found that the proteasome activities and subunit expressions in AAA tissues from human and angiotensin II (Ang II)-infused apolipoprotein E knockout (Apo E−/−) mice were significantly increased. To investigate the effect of proteasome activation on the AAA formation, Apo E−/− mice were cotreated with bortezomib (BTZ) (a proteasome inhibitor, 50 μg/kg, 2 times per week) and Ang II (1000 ng/kg/min) up to 28 days. Ang II infusion significantly increased the incidence and severity of AAA in Apo E−/− mice, whereas BTZ treatment markedly inhibited proteasome activities and prevented AAA formation. Furthermore, BTZ treatment significantly reduced the inflammation, inhibited the metal matrix metalloprotease activity, and reversed the phenotypic SMC modulation in AAA tissue. In conclusion, these results provide a new evidence that proteasome activation plays a critical role in AAA formation through multiple mechanisms, and suggest that BTZ might be a novel therapeutic target for treatment of AAA formation. PMID:26508670

  16. 12-Lipoxygenase Inhibition on Microalbuminuria in Type-1 and Type-2 Diabetes Is Associated with Changes of Glomerular Angiotensin II Type 1 Receptor Related to Insulin Resistance

    PubMed Central

    Xu, Hong-Zhao; Cheng, Yan-Li; Wang, Wan-Ning; Wu, Hao; Zhang, Yuan-Yuan; Zang, Chong-Sen; Xu, Zhong-Gao

    2016-01-01

    (1) Background: 12-lipoxygenase (12-LO) is involved in the development of diabetic nephropathy (DN). In the present study, we investigated whether 12-LO inhibition may ameliorate type-2 DN (T2DN) by interfering with insulin resistance (IR); (2) Methods: Rat glomerular mesangial cells, glomeruli and skeletal muscles were isolated and used in this study. Kidney histological changes were confirmed by periodic-acid Schiff staining; mRNA expression was detected by competitive reverse transcription polymerase chain reaction; and the protein level was determined by Western blot and the enzyme-linked immunosorbent assay, respectively; (3) Results: The inhibition of 12-LO attenuated microalbuminuria (MAU) increases in type-2 diabetic rats, but not in type-1 diabetic rats. Infusion of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) significantly increased the expression of angiotensin II (Ang II) and Ang II type 1 receptor (AT1R), but decreased the expression of AT1R-associated protein (ATRAP) in rat glomeruli, compared to the control. An in vitro study revealed that both 12(S)-HETE and insulin upregulated AT1R expression in rat mesangial cells. In the presence of p38 mitogen-activated protein kinase (MAPK) inhibitor, SB202190, the 12(S)-HETE-induced ATRAP reduction was significantly abolished. Interestingly, 12-LO inhibition did not influence AT1R expression in type-1 diabetic rats, but significantly abolished the increased AT1R and Ang II expression in glomeruli of type-2 diabetic rats. Furthermore, the inhibition of 12-LO significantly corrected impaired insulin sensitivity and fast serum insulin level, as well as the p-AMP-activated protein kinase (AMPK) reduction in skeletal muscle of type-2 diabetic rats; (4) Conclusion: The inhibition of 12-LO potentially ameliorated MAU by preventing IR through the downregulation of glomerular AT1R expression in T2DN. PMID:27164093

  17. Angiotensin converting enzyme inhibition and the kidney

    NASA Technical Reports Server (NTRS)

    Hollenberg, N. K.

    1988-01-01

    Angiotensin II (Ang II) induces a marked reduction in renal blood flow at doses well below those required to induce a pressor response, and as blood flow falls there is a decline in glomerular filtration rate and sodium excretion. This striking sensitivity of the renal blood supply led many workers to consider the possibility that angiotensin functions as a local renal hormone. As angiotensin converting enzyme (ACE) was found in particular abundance in the lung, it seemed reasonable to suspect that most of the conversion occurred there, and that the function of Ang II would be primarily systemic, rather than intrarenal. In this review, I will explore the evidence that has accumulated on these two possibilities, since they have important implications for our current understanding of normal kidney function and derangements of kidney function in disease.

  18. Improved Glucose-Stimulated Insulin Secretion by Selective Intraislet Inhibition of Angiotensin II Type 1 Receptor Expression in Isolated Islets of db/db Mice

    PubMed Central

    Zhang, Zhen; Liu, Chunyan; Gan, Zhenhua; Yi, Qiuyan; Liu, Yanqing; Wang, Yingzhijie; Lu, Bin; Du, Hong

    2013-01-01

    Recent evidence supported the presence of a local renin-angiotensin system (RAS) in the pancreas, which is implicated in many physiological and pathophysiological processes. We utilized small interfering RNA (siRNA) to investigate the effects of angiotensin II type 1 receptor (AT1R) knockdown on glucose-stimulated insulin secretion (GSIS) in isolated islets of db/db mice and to explore the potential mechanisms involved. We found that Ad-siAT1R treatment resulted in a significant decrease both in AT1R mRNA level and in AT1R protein expression level. With downexpression of AT1R, notable increased insulin secretion and decreased glucagon secretion levels were found by perifusion. Simultaneously, significant increased protein levels of IRS-1 (by 85%), IRS-2 (by 95%), PI3K(85) (by 112.5%), and p-Akt2 (by 164%) were found by western blot. And upregulation of both GLUT-2 (by 190%) and GCK (by 121%) was achieved after AT1R inhibition by Ad-siAT1R. Intraislet AT1R expression level is a crucial physiological regulator of insulin sensitivity of β cell itself and thus affects glucose-induced insulin and glucagon release. Therefore, the characteristics of AT1R inhibitors could make it a potential novel therapeutics for prevention and treatment of type 2 diabetes. PMID:24371439

  19. NADPH Oxidases and Angiotensin II Receptor Signaling

    PubMed Central

    Garrido, Abel Martin; Griendling, Kathy K.

    2010-01-01

    Over the last decade many studies have demonstrated the importance of reactive oxygen species (ROS) production by NADPH oxidases in angiotensin II (Ang II) signaling, as well as a role for ROS in the development of different diseases in which Ang II is a central component. In this review, we summarize the mechanism of activation of NADPH oxidases by Ang II and describe the molecular targets of ROS in Ang II signaling in the vasculature, kidney and brain. We also discuss the effects of genetic manipulation of NADPH oxidase function on the physiology and pathophysiology of the renin angiotensin system. PMID:19059306

  20. Inhibition of Angiotensin II-Induced Cardiac Hypertrophy and Associated Ventricular Arrhythmias by a p21 Activated Kinase 1 Bioactive Peptide

    PubMed Central

    Lin, Wee K.; Zhang, Yanmin; Liu, Wei; Huang, Kai; Terrar, Derek A.; Solaro, R. John; Wang, Xin; Ke, Yunbo; Lei, Ming

    2014-01-01

    Cardiac hypertrophy increases the risk of morbidity and mortality of cardiovascular disease and thus inhibiting such hypertrophy is beneficial. In the present study, we explored the effect of a bioactive peptide (PAP) on angiotensin II (Ang II)-induced hypertrophy and associated ventricular arrhythmias in in vitro and in vivo models. PAP enhances p21 activated kinase 1 (Pak1) activity by increasing the level of phosphorylated Pak1 in cultured neonatal rat ventricular myocytes (NRVMs). Such PAP-induced Pak1 activation is associated with a significant reduction of Ang II-induced hypertrophy in NRVMs and C57BL/6 mice, in vitro and in vivo, respectively. Furthermore, PAP antagonizes ventricular arrhythmias associated with Ang II-induced hypertrophy in mice. Its antiarrhythmic effect is likely to be involved in multiple mechanisms to affect both substrate and trigger of ventricular arrhythmogenesis. Thus our results suggest that Pak1 activation achieved by specific bioactive peptide represents a potential novel therapeutic strategy for cardiac hypertrophy and associated ventricular arrhythmias. PMID:25014109

  1. Oxidative inhibition of the vascular Na+-K+ pump via NADPH oxidase-dependent β1-subunit glutathionylation: implications for angiotensin II-induced vascular dysfunction.

    PubMed

    Liu, Chia-Chi; Karimi Galougahi, Keyvan; Weisbrod, Robert M; Hansen, Thomas; Ravaie, Ramtin; Nunez, Andrea; Liu, Yi B; Fry, Natasha; Garcia, Alvaro; Hamilton, Elisha J; Sweadner, Kathleen J; Cohen, Richard A; Figtree, Gemma A

    2013-12-01

    Glutathionylation of the Na(+)-K(+) pump's β1-subunit is a key molecular mechanism of physiological and pathophysiological pump inhibition in cardiac myocytes. Its contribution to Na(+)-K(+) pump regulation in other tissues is unknown, and cannot be assumed given the dependence on specific β-subunit isoform expression and receptor-coupled pathways. As Na(+)-K(+) pump activity is an important determinant of vascular tone through effects on [Ca(2+)]i, we have examined the role of oxidative regulation of the Na(+)-K(+) pump in mediating angiotensin II (Ang II)-induced increases in vascular reactivity. β1-subunit glutathione adducts were present at baseline and increased by exposure to Ang II in rabbit aortic rings, primary rabbit aortic vascular smooth muscle cells (VSMCs), and human arterial segments. In VSMCs, Ang II-induced glutathionylation was associated with marked reduction in Na(+)-K(+)ATPase activity, an effect that was abolished by the NADPH oxidase inhibitory peptide, tat-gp91ds. In aortic segments, Ang II-induced glutathionylation was associated with decreased K(+)-induced vasorelaxation, a validated index of pump activity. Ang II-induced oxidative inhibition of Na(+)-K(+) ATPase and decrease in K(+)-induced relaxation were reversed by preincubation of VSMCs and rings with recombinant FXYD3 protein that is known to facilitate deglutathionylation of β1-subunit. Knock-out of FXYD1 dramatically decreased K(+)-induced relaxation in a mouse model. Attenuation of Ang II signaling in vivo by captopril (8 mg/kg/day for 7 days) decreased superoxide-sensitive DHE levels in the media of rabbit aorta, decreased β1-subunit glutathionylation, and enhanced K(+)-induced vasorelaxation. Ang II inhibits the Na(+)-K(+) pump in VSMCs via NADPH oxidase-dependent glutathionylation of the pump's β1-subunit, and this newly identified signaling pathway may contribute to altered vascular tone. FXYD proteins reduce oxidative inhibition of the Na(+)-K(+) pump and may have an

  2. Angiotensin II reduces calcium uptake into bone.

    PubMed

    Schurman, Scott J; Bergstrom, William H; Shoemaker, Lawrence R; Welch, Thomas R

    2004-01-01

    Children with neonatal Bartter syndrome (NBS) have hypercalciuria, nephrocalcinosis, and osteopenia. A complex of basic-fibroblast growth factor (b-FGF) and a naturally occurring glycosaminoglycan has been identified in the serum and urine of NBS patients. This complex increases bone resorption in a bone disc bioassay system. Angiotensin II (AT II), which is increased in Bartter syndrome, increases the synthesis of b-FGF by cultured endothelial cells. Addition of 10(-8) M AT II to the bioassay, a concentration reported in Bartter syndrome patients, significantly decreased calcium uptake into bone discs [E/C 0.60 (0.04), P < 0.001 compared with buffer, normal E/C >0.90]. Adding b-FGF monoclonal antibody at 10 microg/ml [E/C 0.90 (0.06), P=NS] or indomethacin [E/C 1.00 (0.03), P=NS] to 10(-8 )M AT II neutralized this effect. In separate experiments, newborn rats were given intraperitoneal injections of AT II. Bone discs from these animals were used in the bioassay system and calcium uptake was markedly reduced compared with discs from rats injected with phosphate-buffered saline [AT II 6.6 x 10(-9), E/C 0.10 (0.04), P<0.001, AT II 3.3 x 10(-8), E/C 0.10 (0.05), P<0.001]. AT II decreases calcium uptake in the bone disc bioassay system. This effect can be abrogated by antibody to b-FGF or prostaglandin synthetase inhibition. These results support the hypothesis that in children with NBS, elevated levels of AT II stimulate local skeletal b-FGF synthesis, with a resultant increase in bone resorption via a prostaglandin-dependent pathway. PMID:14648327

  3. Angiotensin II-inhibiting drugs have no effect on intraneuronal Aβ or oligomeric Aβ levels in a triple transgenic mouse model of Alzheimer's disease

    PubMed Central

    Ferrington, Linda; Miners, J Scott; Palmer, Laura E; Bond, Susan M; Povey, Joanne E; Kelly, Paul AT; Love, Seth; Horsburgh, Karen J; Kehoe, Patrick G

    2011-01-01

    Background: Reducing the excessive accumulation of amyloid β-protein (Aβ) in Alzheimer's disease (AD) is a key objective of most AD therapies. Several studies suggest that pharmacological inhibition of angiotensin-converting enzyme (ACE) or its by-product angiotensin II may delay onset or progression of dementia and it has been suggested that this occurs via regulation of Aβ. Intraneuronal oligomeric accumulation of Aβ is postulated to be one of the earliest pathological events. Thus this study investigated the effect of an ACE-inhibitor, captopril, and two angiotensin II receptor blockers (ARBs), eprosartan and valsartan, on intraneuronal Aβ pathology and oligomeric Aβ levels in a triple transgenic (3xTGAD) mouse model of AD. Methods: Male, adult (3-4 month old) 3xTgAD mice (n=39) were randomly assigned to 4 treatment groups: valsartan (0.17g/l), eprosartan (0.8g/l), captopril (5g/l) or normal drinking water and the drugs given ad libitum for 2 months. Mean arterial blood pressure (MABP) was measured at baseline, at 2 weeks and at 2 months when the mice were sacrificed and the brains hemisected for analysis. One hemisphere was processed for Aβ and amyloid precursor protein (APP) immunohistochemistry and the other for biochemical measurement of oligomeric Aβ and APP. ACE activity was measured in the brain and kidney. Results: MABP was significantly reduced at 2 weeks and 2 months in the ACE-I group (p=0.0006) but was unaltered in the ARB groups compared to vehicle. Neither ACE-I nor ARB treatment altered Aβ and APP immunolabelling or the level of Aβ or APP in brain tissue homogenates. Similarly neither ACE-I nor ARB treatment altered ACE activity in either brain or kidney compared to control tissue. Conclusions: ACE-I or ARB administration over 2 months did not affect APP levels or either intraneuronal Aβ or oligomeric Aβ levels in 3xTGAD mice. While ARBs did not alter MABP, captopril did mediate reductions in MABP in the 3xTGAD mice which appeared to

  4. Sanguinarine inhibits angiotensin II-induced apoptosis in H9c2 cardiac cells via restoring reactive oxygen species-mediated decreases in the mitochondrial membrane potential

    PubMed Central

    LIU, YUAN; JIAO, RONG; MA, ZHEN-GUO; LIU, WEI; WU, QING-QING; YANG, ZHENG; LI, FANG-FANG; YUAN, YUAN; BIAN, ZHOU-YAN; TANG, QI-ZHU

    2015-01-01

    Cell apoptosis induced by Angiotensin II (Ang II) has a critical role in the development of cardiovascular diseases. The aim of the present study was to investigate whether sanguinarine (SAN), a drug which was proved to have anti-oxidant, anti-proliferative and immune enhancing effects, can abolish cell apoptosis induced by Ang II. In the present study, H9c2 cardiac cells were stimulated with 10 µM Ang II with or without SAN. The level of intracellular reactive oxygen species (ROS) generation was assessed using dichlorodihydrofluorescein diacetate, and changes of the mitochondrial membrane potential (MMP) were assessed using JC-1 staining. Furthermore, mRNA expression of NOX2 was determined by reverse transcription quantitative polymerase chain reaction, and apoptosis was detected by Annexin V/propidium iodide staining and flow cytometry. The expression of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) as well as cleaved (c)-caspase 3 and -9 were detected by western blot analysis, and the activity of caspase 3 and -9 was detected using an ELISA. The results of the present study showed that NOX2 expression and ROS generation induced by Ang II were inhibited by SAN, and the Ang 2-induced MMP loss was also ameliorated. Furthermore, Ang II-induced H9c2 cardiac cell apoptosis as well as c-caspase 3 and -9 levels were significantly reduced by SAN. Investigation of the possible pathway involved in the anti-apoptotic effect of SAN showed that the expression of Bcl-2 was decreased, while that of Bax was increased following stimulation with Ang II, which was reversed following treatment with SAN. In addition, Ang II enhanced the activity of caspase 9 and cleaved downstream caspases such as caspase-3, initiating the caspase cascade, while pre-treatment of H9c2 cardiac cells with SAN blocked these effects. In conclusion, the findings of the present study indicated that SAN inhibits the apoptosis of H9c2 cardiac cells induced by Ang II, most likely via restoring

  5. Angiotensin II during Experimentally Simulated Central Hypovolemia

    PubMed Central

    Jensen, Theo Walther; Olsen, Niels Vidiendal

    2016-01-01

    Central hypovolemia, defined as diminished blood volume in the heart and pulmonary vascular bed, is still an unresolved problem from a therapeutic point of view. The development of pharmaceutical agents targeted at specific angiotensin II receptors, such as the non-peptidergic AT2-receptor agonist compound 21, is yielding many opportunities to uncover more knowledge about angiotensin II receptor profiles and possible therapeutic use. Cardiovascular, anti-inflammatory, and neuroprotective therapeutic use of compound 21 have been suggested. However, there has not yet been a focus on the use of these agents in a hypovolemic setting. We argue that the latest debates on the effect of angiotensin II during hypovolemia might guide for future studies, investigating the effect of such agents during experimentally simulated central hypovolemia. The purpose of this review is to examine the role of angiotensin II during episodes of central hypovolemia. To examine this, we reviewed results from studies with three experimental models of simulated hypovolemia: head up tilt table test, lower body negative pressure, and hemorrhage of animals. A systemic literature search was made with the use of PubMed/MEDLINE for studies that measured variables of the renin–angiotensin system or its effect during simulated hypovolemia. Twelve articles, using one of the three models, were included and showed a possible organ-protective effect and an effect on the sympathetic system of angiotensin II during hypovolemia. The results support the possible organ-protective vasodilatory role for the AT2-receptor during hypovolemia on both the kidney and the splanchnic tissue. PMID:26973842

  6. Pioglitazone inhibits angiotensin II-induced atrial fibroblasts proliferation via NF-κB/TGF-β1/TRIF/TRAF6 pathway

    SciTech Connect

    Chen, Xiao-qing; Liu, Xu; Wang, Quan-xing; Zhang, Ming-jian; Guo, Meng; Liu, Fang; Jiang, Wei-feng; Zhou, Li

    2015-01-01

    The exact mechanisms underlying inhibitory effects of pioglitazone (Pio) on Angiotensin II (AngII)-induced atrial fibrosis are complex and remain largely unknown. In the present study, we examined the effect of Pio on AngII-induced mice atrial fibrosis in vivo and atrial fibroblasts proliferation in vitro. In vivo study showed that AngII infusion induced atrial fibrosis and increased expressions of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) and tumor necrosis factor receptor associated factor 6 (TRAF6) in mice models. However, those effects could be attenuated by Pio (P<0.01). As for in vitro experiment, Pio suppressed AngII-induced atrial fibroblasts proliferation via nuclear factor-κB/transforming growth factor-β1/TRIF/TRAF6 signaling pathway in primary cultured mice atrial fibroblasts (P<0.01). In conclusion, suppression of Pio on AngII-induced atrial fibrosis might be related to its inhibitory effects on above signaling pathway. - Highlights: • Angiotensin II increased atrial fibrosis and related gene expressions in mice. • Angiotensin II induced atrial fibroblasts proliferation by activating signaling pathway. • Pioglitazone reversed both aforementioned changes.

  7. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition.

    PubMed

    Hubers, Scott A; Brown, Nancy J

    2016-03-15

    Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension. PMID:26976916

  8. Local nitric oxide release does not affect tachyphylaxis to angiotensin II in dorsal hand veins in man in the presence of prostaglandin synthesis inhibition

    PubMed Central

    de Haas, S L; Wilkinson, I B; Boyd, J L; Webb, D J

    2002-01-01

    Aims Local prostaglandin (PG) production contributes to tachyphylaxis to angiotensin II (ANGII) in veins. Our aim was to assess the hypothesis that local nitric oxide (NO) generation is also, in part, responsible for tachyphylaxis to ANGII in veins, using the Aellig dorsal hand vein technique. Methods Eight healthy male volunteers received 600 mg of aspirin (orally) to inhibit PG production. The venoconstrictor effects of ANGII and noradrenaline (NA) were then compared in dorsal hand veins during co-infusion of the NO synthase inhibitor L-NMMA or saline, on separate occasions. Results ANGII and NA produced a similar degree of initial venoconstriction. However, the response to ANGII was significantly attenuated by 12 min compared with NA (AUC 147 ± 38 vs 196 ± 40, respectively; [95% confidence interval for difference: 7, 92], P = 0.02). Infusion of L-NMMA did not influence the response to ANGII or NA (P = 0.2 and P = 0.3, respectively). Conclusions Tachyphylaxis to ANGII in dorsal hand veins is not dependent on local NO release. PMID:11851644

  9. Identification of the angiotensin II receptor in rat mesenteric artery.

    PubMed Central

    McQueen, J; Murray, G D; Semple, P F

    1984-01-01

    Specific binding sites of high affinity and low capacity for 125I-angiotensin II have been identified in a membrane fraction derived from arterial arcades of the rat mesentery. Heterogeneity of binding sites and extensive tracer degradation necessitated the use of nonlinear regression methods for the analysis of radioligand binding data. Forward and reverse rate constants for the high affinity sites obtained by three experimental approaches were in good agreement and gave a dissociation equilibrium constant (Kd) of 19-74 pM (95% confidence interval). Affinities for a number of angiotensin-related peptides calculated from competitive binding curves were in the order 125I-angiotensin II = angiotensin II greater than angiotensin III greater than [Sar1,Ile8]angiotensin II greater than [Sar1,Gly8]angiotensin II. Angiotensin I and biochemically unrelated peptides had virtually no effect on binding of tracer angiotensin II. The divalent cations Mn2+, Mg2+ and Ca2+ stimulated 125I-angiotensin II binding at concentrations of 2-10 mM, as did Na+ at 50-100 mM. In the presence of Na+ or Li+, K+ had a biphasic effect. The chelating agents EDTA and EGTA were inhibitory, as were the thiol reagents dithiothreitol and cysteine. This study defined angiotensin II binding sites in a vascular target tissue of sufficiently high affinity to interact rapidly with plasma angiotensin II at physiological concentrations. PMID:6095806

  10. L-type calcium channel β subunit modulates angiotensin II responses in cardiomyocytes.

    PubMed

    Hermosilla, Tamara; Moreno, Cristian; Itfinca, Mircea; Altier, Christophe; Armisén, Ricardo; Stutzin, Andres; Zamponi, Gerald W; Varela, Diego

    2011-01-01

    Angiotensin II regulation of L-type calcium currents in cardiac muscle is controversial and the underlying signaling events are not completely understood. Moreover, the possible role of auxiliary subunit composition of the channels in Angiotensin II modulation of L-type calcium channels has not yet been explored. In this work we study the role of Ca(v)β subunits and the intracellular signaling responsible for L-type calcium current modulation by Angiotensin II. In cardiomyocytes, Angiotensin II exposure induces rapid inhibition of L-type current with a magnitude that is correlated with the rate of current inactivation. Semi-quantitative PCR of cardiomyocytes at different days of culture reveals changes in the Ca(v)β subunits expression pattern that are correlated with the rate of current inactivation and with Angiotensin II effect. Over-expression of individual b subunits in heterologous systems reveals that the magnitude of Angiotensin II inhibition is dependent on the Ca(v)β subunit isoform, with Ca(v)β(1b) containing channels being more strongly regulated. Ca(v)β(2a) containing channels were insensitive to modulation and this effect was partially due to the N-terminal palmitoylation sites of this subunit. Moreover, PLC or diacylglycerol lipase inhibition prevents the Angiotensin II effect on L-type calcium channels, while PKC inhibition with chelerythrine does not, suggesting a role of arachidonic acid in this process. Finally, we show that in intact cardiomyocytes the magnitude of calcium transients on spontaneous beating cells is modulated by Angiotensin II in a Ca(v)β subunit-dependent manner. These data demonstrate that Ca(v)β subunits alter the magnitude of inhibition of L-type current by Angiotensin II. PMID:21525790

  11. p21(CIP1/WAF1)-dependent inhibition of cardiac hypertrophy in response to Angiotensin II involves Akt/Myc and pRb signaling.

    PubMed

    Hauck, Ludger; Grothe, Daniela; Billia, Filio

    2016-09-01

    The cyclin-dependent kinase inhibitor p21(CIP1/WAF1) (p21) is highly expressed in the adult heart. However, in response to stress, its expression is downregulated. Therefore, we investigated the role of p21 in the regulation of cardiac hypertrophic growth. At 2 months of age, p21 knockout mice (p21KO) lack an overt cardiac phenotype. In contrast, by 10 months of age, p21KO developed age-dependent cardiac hypertrophy and heart failure. After 3 weeks of trans-aortic banding (TAB), the heart/body weight ratio in 11 week old p21KO mice increased by 57%, as compared to 42% in wild type mice indicating that p21KO have a higher susceptibility to pressure overload-induced cardiac hypertrophy. We then chronically infused 8 week old wild type mice with Angiotensin II (2.0mg/kg/min) or saline subcutaneously by osmotic pumps for 14 days. Recombinant TAT conjugated p21 protein variants (10mg/kg body weight) or saline were intraperitoneally injected once daily for 14 days into Angiotensin II and saline-infused animals. Angiotensin II treated mice developed pathological cardiac hypertrophy with an average increase of 38% in heart/body weight ratios, as compared to saline-treated controls. Reconstitution of p21 function by TAT.p21 protein transduction prevented Angiotensin II-dependent development of cardiac hypertrophy and failure. Taken together, our genetic and biochemical data show an important function of p21 in the regulation of growth-related processes in the heart. PMID:27486069

  12. 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.

  13. 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

  14. Angiotensin II promotes endometrial cancer cell survival.

    PubMed

    Nowakowska, Magdalena; Matysiak-Burzyńska, Zuzanna; Kowalska, Karolina; Płuciennik, Elżbieta; Domińska, Kamila; Piastowska-Ciesielska, Agnieszka W

    2016-08-01

    Endometrial cancer (EC) is one of the most common female cancers. One of the key processes involved in EC development is uncontrolled proliferation stimulated by local factors such as angiotensin. The aim of the present study was to evaluate the influence of angiotensin II (Ang II) on human EC cells. Biological assays and gene expression analysis were performed on three cell lines: ISH, MFE-296 and MFE-280. Our results indicated that at the beginning of cancerogenesis Ang II induced abnormal proliferation at lower doses. We also showed that dose-dependent induction of proliferation was connected with changes in the expression of MKI67, CCND1 and CCNE1 genes in well- and poorly differentiated cancer cells. After Ang II treatment, poorly differentiated endometrial cancer cell line acquired a mesenchymal phenotype, which was characterized by induced expression of EMT-related genes (VIM, CD44, SNAI1, ZEB1 and ZEB2). Our study revealed that Ang II influences EC cells in terms of cancer-related processes, and is responsible for increased proliferation, reduction in apoptosis, increased mobility and modulation of adhesion potential. Its effect and effectiveness appear to be highly connected with the differentiation status of the cancerous cells, as Ang II appears to play a crucial role in the early and late stages of malignant transformation. PMID:27349856

  15. 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. PMID:16478781

  16. Inhibitory effect of reinioside C on vascular smooth muscle cells proliferation induced by angiotensin II via inhibiting NADPH oxidase-ROS-ENK1/2-NF-kappaB-AP-1 pathway.

    PubMed

    Hong, Dan; Bai, Yong-Ping; Shi, Rui-Zheng; Tan, Gui-Shan; Hu, Chang-Ping; Zhang, Guo-Gang

    2014-09-01

    The proliferation of vascular smooth muscle cells (VSMCs) induced by angiotensin II (Ang II) plays a vital role in the pathogenesis of arteriosclerosis and restenosis. In the present study, the effect of reinioside C, a main active ingredient of Polygala fallax Hemsl, on proliferation of VSMCs induced by Ang II was investigated. It was found that Ang II (1 microM) markedly stimulated proliferation of VSMCs. Pretreatment of reinioside C (3, 10 or 30 microM) concentration-dependently inhibited the proliferative effect of Ang II. To determine the possible mechanism, NADPH oxidase subunits (Nox-1, Nox-4) mRNA expression, intracellular ROS level, phosphorylation of ERK1/2, NF-kappaB activity, and mRNA expression of AP-1 subunits (c-fos, c-jun) and c-myc were measured. The results demonstrated that reinioside C attenuated Ang II-induced NADPH oxidase mRNA expression, generation of ROS, ERK1/2 phosphorylation, activation of NF-kappaB, and mRNA expression of AP-1 and c-myc in VSMCs in a concentration-dependent manner. The effects of Ang II were also inhibited by diphenyleneiodonium (DPI, the NADPH oxidase inhibitor), PD98059 (the ERK1/2 inhibitor) and pyrrolidine dithiocarbamate (PDTC, the NF-kappaB inhibitor). These results suggest reinioside C attenuates Ang II-induced proliferation of VSMCs by inhibiting NADPH oxidase-ROS-ERK1/2-NF-kappaB-AP-1 pathway. PMID:25272943

  17. PKC-dependent extracellular signal-regulated kinase 1/2 pathway is involved in the inhibition of Ib on AngiotensinII-induced proliferation of vascular smooth muscle cells

    SciTech Connect

    Wang Yu; Yan Tianhua; Wang Qiujuan Wang Wei; Xu Jinyi; Wu Xiaoming; Ji Hui

    2008-10-10

    AngiotensinII (AngII) induces vascular smooth muscle cell (VSMC) proliferation, which plays an important role in the development and progression of hypertension. AngII-induced cellular events have been implicated, in part, in the activation of protein kinase C (PKC) and extracellular signal-regulated kinases 1/2 (ERK1/2). In the present study, we investigated the effect of Ib, a novel nonpeptide AngII receptor type 1 (AT{sub 1}) antagonist, on the activation of PKC and ERK1/2 in VSMC proliferation induced by AngII. MTT, and [{sup 3}H]thymidine incorporation assay showed that AngII-induced VSMC proliferation was inhibited significantly by Ib. The specific binding of [{sup 125}I]AngII to AT{sub 1} receptors was blocked by Ib in a concentration-dependent manner with IC{sub 50} value of 0.96 nM. PKC activity assay and Western blot analysis demonstrated that Ib significantly inhibited the activation of PKC and phosphorylation of ERK1/2 induced by AngII, respectively. Furthermore, AngII-induced ERK1/2 activation was obviously blocked by GF109203X, a PKC inhibitor. These findings suggest that the suppression of Ib on AngII-induced VSMC proliferation may be attributed to its inhibitory effect on PKC-dependent ERK1/2 pathway.

  18. Quantitative autoradiography of angiotensin II receptors in the brain and kidney

    SciTech Connect

    Gehlert, D.R.

    1985-01-01

    The renin-angiotensin system is an important component in the regulation of systemic blood pressure. Angiotensin II is the principal effector peptide of this system. Interaction of angiotensin II with specific receptors can produce in several organic systems. When administered into the brain this octa-peptide produces a variety of responses including a stimulation of drinking, increased systemic blood pressure and several neuroendocrine responses. Its effects on the kidney include alterations in arteriolar resistance, mesangial cell contraction and a feedback inhibition of the release of renin. Since this peptide produces profound effects on homeostatis by an interaction with specific receptors, the quantitative technique of in vitro autoradiography was applied to localize receptor populations for angiotensin II. Specific binding sites for a radiolabeled form of angiotensin II were localized in various brain and kidney regions. In the rat brain high densities of angiotensin II receptors were observed in the paraventricular and suprachiasmatic nuclei of the hypothalamus, supraoptic nucleus and the posterior lobe of the pituitary, brain areas in which angiotensin II modified neuroendocrine functions.

  19. Selective inhibition of thromboxane synthesis partially protected while inhibition of angiotensin II formation did not protect rats against acute renal failure induced with glycerol.

    PubMed

    Papanicolaou, N; Hatziantoniou, C; Bariety, J

    1986-01-01

    Acute renal failure (ARF) was induced in 35 week-old conscious female Wistar rats, by intramuscular (IM) injection of glycerol. Intraperitoneal (IP) injection of imidazole, an inhibitor of thromboxane (TXA2) synthesis, partially protected the animals against ARF. This protection was accompanied by a significant decrease in renal TXB2 (the stable chemical metabolite of TXA2) and a significant increase in renal 6-keto-PGF1 alpha (the stable chemical metabolite of PGI2) synthesis. Intraperitoneal injection of captopril (SQ 14225) an angiotensin-converting-enzyme inhibitor, did not protect the animals against ARF. This lack of protection was accompanied by a significant increase in renal TXB2 and a significant decrease in renal 6-keto-PGF1 alpha synthesis. The results suggest that: (a) the renin-angiotensin (R-A) system does not play a role, or has only a secondary one in the development of ARF; (b) thromboxane A2 (the most potent vasoconstrictor and platelet aggregator agent known) is the preponderant agent responsible for the development of this pathological syndrome. PMID:3513208

  20. Human GRK4γ142V Variant Promotes Angiotensin II Type I Receptor-Mediated Hypertension via Renal Histone Deacetylase Type 1 Inhibition.

    PubMed

    Wang, Zheng; Zeng, Chunyu; Villar, Van Anthony M; Chen, Shi-You; Konkalmatt, Prasad; Wang, Xiaoyan; Asico, Laureano D; Jones, John E; Yang, Yu; Sanada, Hironobu; Felder, Robin A; Eisner, Gilbert M; Weir, Matthew R; Armando, Ines; Jose, Pedro A

    2016-02-01

    The influence of a single gene on the pathogenesis of essential hypertension may be difficult to ascertain, unless the gene interacts with other genes that are germane to blood pressure regulation. G-protein-coupled receptor kinase type 4 (GRK4) is one such gene. We have reported that the expression of its variant hGRK4γ(142V) in mice results in hypertension because of impaired dopamine D1 receptor. Signaling through dopamine D1 receptor and angiotensin II type I receptor (AT1R) reciprocally modulates renal sodium excretion and blood pressure. Here, we demonstrate the ability of the hGRK4γ(142V) to increase the expression and activity of the AT1R. We show that hGRK4γ(142V) phosphorylates histone deacetylase type 1 and promotes its nuclear export to the cytoplasm, resulting in increased AT1R expression and greater pressor response to angiotensin II. AT1R blockade and the deletion of the Agtr1a gene normalize the hypertension in hGRK4γ(142V) mice. These findings illustrate the unique role of GRK4 by targeting receptors with opposite physiological activity for the same goal of maintaining blood pressure homeostasis, and thus making the GRK4 a relevant therapeutic target to control blood pressure. PMID:26667412

  1. [Leu]enkephalin stimulates carbohydrate metabolism in isolated hepatocytes and kidney tubule fragments by interaction with angiotensin II receptors.

    PubMed Central

    Hothi, S K; Randall, D P; Titheradge, M A

    1989-01-01

    The possibility that the effects of [Leu]enkephalin in vitro on hepatic carbohydrate metabolism are mediated by interaction with angiotensin II receptors has been examined. Preincubation of hepatocytes with either the angiotensin II receptor antagonist [Sar1,Ile8]angiotensin II or 10 mM-dithiothreitol abolished the ability of both angiotensin II and [Leu]enkephalin to increase phosphorylase a in hepatocytes prepared from fed rats. Dithiothreitol had no effect on the stimulation of phosphorylase in the presence of glucagon or phenylephrine, although it also inhibited the response to vasopressin. [Leu]enkephalin displaced specifically bound 125I-labelled angiotensin II from hepatic plasma membranes over a concentration range of 10(-7)-10(-5) M. This correlated with the dose-response required to stimulate phosphorylase activity in intact hepatocytes and suggests that the effects of the opioid peptides on carbohydrate metabolism in liver are the result of cross-reactivity of the peptides with angiotensin II receptors. Addition of 10(-5) M-[Leu]enkephalin to isolated kidney tubule fragments stimulated gluconeogenesis from 5 mM-pyruvate, the magnitude of stimulation being comparable to that by either angiotensin II or adrenaline. This effect of the opioid peptide was also abolished by pretreatment of the tubules with [Sar1,Ile8]angiotensin II, suggesting that the ability of [Leu]enkephalin to interact with angiotensin II receptors is not restricted to the liver, but may occur in other tissues where both receptors occur together. PMID:2930480

  2. 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.

  3. 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.

  4. 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

    myofibroblasts. They inhibit the angiotensin II-induced proliferation in a PPAR-γ-dependent manner, while at high doses they activate pathways of programmed cell death that are dependent on JNK and PPAR-γ. PMID:22844495

  5. 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. PMID:26674152

  6. Quantitative autoradiography of angiotensin II receptors in the SHR brain

    SciTech Connect

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

    1986-11-01

    Several lines of evidence indicate brain angiotensin II is associated with the elevation of blood pressure seen in the spontaneously hypertensive rat (SHR). These include an increased pressor response to intracerebroventricularly administered angiotensin II and a reduction of blood pressure in response to centrally administered angiotensin II receptor antagonists. Using quantitative receptor autoradiography, we have detected greater angiotensin II receptor binding in a number of discrete brain nuclei of the 6-week-old SHR when compared to age-matched Wistar-Kyoto controls. Tissue sections from various brain regions were labeled with (/sup 125/I)-angiotensin II according to a previously described method. Autoradiograms were generated by apposing the labeled tissue sections to LKB Ultrofilm along with brain paste standards which contained known amounts of (/sup 125/I). Quantitation of the binding, utilizing computer-assisted microdensitometry, indicated greater (/sup 125/I)-angiotensin II binding in several brain areas implicated in cardiovascular control including the subfornical organ, nucleus of the solitary tract, dorsal motor nucleus of the vagus, locus coeruleus, supraoptic nucleus and the organum vasculosum of the lamina terminalis. Scatchard analysis of the binding in the nucleus of the solitary tract indicated an increased receptor number (Bmax) was responsible for the change while binding in two forebrain structures, the subfornical organ and supraoptic nucleus, showed alterations in receptor number and affinity (Kd). Several other brain regions, unrelated to cardiovascular control, exhibited no change in (/sup 125/I)-angiotensin II binding.

  7. 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

  8. N- and C-terminal structure-activity study of angiotensin II on the angiotensin AT2 receptor.

    PubMed

    Bouley, R; Pérodin, J; Plante, H; Rihakova, L; Bernier, S G; Maletínská, L; Guillemette, G; Escher, E

    1998-02-19

    The predominant angiotensin II receptor expressed in the human myometrium is the angiotensin AT2 receptor. This preparation was used for a structure-activity relationship study on angiotensin II analogues modified in positions 1 and 8. The angiotensin AT2 receptor present on human myometrium membranes displayed a high affinity (pKd = 9.18) and was relatively abundant (53-253 fmol/mg of protein). The pharmacological profile was typical of an angiotensin AT2 receptor with the following order of affinities: (angiotensin III > or = angiotensin II > angiotensin I > PD123319 > angiotensin-(1-7) > angiotensin-(1-6) approximately angiotensin IV > Losartan). Modifications of the N-terminal side chain and of the primary amine of angiotensin II were evaluated. Neutralisation of the methylcarboxylate (Asp) to a methylcarboxamide (Asn) or to a hydroxymethyl (Ser) or substitution for a methylsulfonate group (cysteic acid) improved the affinity. Extension from methylcarboxylate (Asp) to ethylcarboxylate (Glu) did not affect the affinity. Introduction of larger side chains such as the bulky p-benzoylphenylalanine (p-Bpa) or the positively charged Lys did not substantially affect the affinity. Complete removal of the side chain (angiotensin III), however, resulted in a significant affinity increase. Removal or acetylation of the primary amine of angiotensin II did not noticeably influence the affinity. Progressive alkylation of the primary amine significantly increased the affinity, betain structures being the most potent. It appears that quite important differences exist between the angiotensin AT1 and AT2 receptors concerning their pharmacological profile towards analogues of angiotensin II modified in position 1. On position 8 of angiotensin II, a structure-activity relationship on the angiotensin AT2 receptor was quite similar to that observed with angiotensin AT1 receptor. Bulky, hydrophobic aromatic residues displayed affinities similar to or even better than [Sarcosine1

  9. Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition.

    PubMed

    de Cavanagh, Elena M V; Inserra, Felipe; Ferder, León

    2015-07-01

    Caloric restriction (CR), renin angiotensin system blockade (RAS-bl), and rapamycin-mediated mechanistic target of rapamycin (mTOR) inhibition increase survival and retard aging across species. Previously, we have summarized CR and RAS-bl's converging effects, and the mitochondrial function changes associated with their physiological benefits. mTOR inhibition and enhanced sirtuin and KLOTHO signaling contribute to the benefits of CR in aging. mTORC1/mTORC2 complexes contribute to cell growth and metabolic regulation. Prolonged mTORC1 activation may lead to age-related disease progression; thus, rapamycin-mediated mTOR inhibition and CR may extend lifespan and retard aging through mTORC1 interference. Sirtuins by deacetylating histone and transcription-related proteins modulate signaling and survival pathways and mitochondrial functioning. CR regulates several mammalian sirtuins favoring their role in aging regulation. KLOTHO/fibroblast growth factor 23 (FGF23) contribute to control Ca(2+), phosphate, and vitamin D metabolism, and their dysregulation may participate in age-related disease. Here we review how mTOR inhibition extends lifespan, how KLOTHO functions as an aging suppressor, how sirtuins mediate longevity, how vitamin D loss may contribute to age-related disease, and how they relate to mitochondrial function. Also, we discuss how RAS-bl downregulates mTOR and upregulates KLOTHO, sirtuin, and vitamin D receptor expression, suggesting that at least some of RAS-bl benefits in aging are mediated through the modulation of mTOR, KLOTHO, and sirtuin expression and vitamin D signaling, paralleling CR actions in age retardation. Concluding, the available evidence endorses the idea that RAS-bl is among the interventions that may turn out to provide relief to the spreading issue of age-associated chronic disease. PMID:25934099

  10. Cilostazol suppresses angiotensin II-induced apoptosis in endothelial cells

    PubMed Central

    SHI, MIAO-QIAN; SU, FEI-FEI; XU, XUAN; LIU, XIONG-TAO; WANG, HONG-TAO; ZHANG, WEI; LI, XUE; LIAN, CHENG; ZHENG, QIANG-SUN; FENG, ZHI-CHUN

    2016-01-01

    Patients with essential hypertension undergo endothelial dysfunction, particularly in the conduit arteries. Cilostazol, a type III phosphodiesterase inhibitor, serves a role in the inhibition of platelet aggregation and it is widely used in the treatment of peripheral vascular diseases. Previous studies have suggested that cilostazol suppresses endothelial dysfunction; however, it remains unknown whether cilostazol protects the endothelial function in essential hypertension. The aim of the present study was to investigate whether, and how, cilostazol suppresses angiotensin II (angII)-induced endothelial dysfunction. Human umbilical vein endothelial cells (HUVECs) and Sprague Dawley rats were exposed to angII and treated with cilostazol. Endothelial cell apoptosis and function, nitric oxide and superoxide production, phosphorylation (p) of Akt, and caspase-3 protein expression levels were investigated. AngII exposure resulted in the apoptosis of endothelial cells in vitro and in vivo. In vitro, cilostazol significantly suppressed the angII-induced apoptosis of HUVECs; however, this effect was reduced in the presence of LY294002, a phosphoinositide 3 kinase (PI3K) inhibitor. Furthermore, cilostazol suppressed the angII-induced p-Akt downregulation and cleaved caspase-3 upregulation. These effects were also alleviated by LY294002. In vivo, cilostazol suppressed the angII-induced endothelial cell apoptosis and dysfunction. Cilostazol was also demonstrated to partially reduced the angII-induced increase in superoxide production. The results of the present study suggested that cilostazol suppresses endothelial apoptosis and dysfunction by modulating the PI3K/Akt pathway. PMID:26862035

  11. 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.

  12. Endothelial metabolism of angiotensin II to angiotensin III, not angiotensin (1-7), augments the vasorelaxation response in adrenal cortical arteries.

    PubMed

    Kopf, Phillip G; Campbell, William B

    2013-12-01

    Hyperaldosteronism is linked to the development and progression of several different cardiovascular diseases. Angiotensin (Ang) II increases aldosterone secretion and adrenal blood flow. Ang II peptide fragments are produced by various peptidases, and these Angs have diverse and vital physiologic roles. Due to the uncharacteristic vasorelaxation of adrenal arteries by Ang II, we tested the hypothesis that Ang II metabolism contributes to its relaxant activity in adrenal arteries. Metabolism of Angs by bovine adrenal cortical arteries and isolated bovine adrenal vascular cells was measured by liquid chromatography-mass spectrometry. The primary Ang metabolites of adrenal arteries are Ang III and Ang (1-7), with Ang IV produced to a lesser extent. Bovine microvascular endothelial cells produced a similar metabolic profile to adrenal arteries, whereas bovine adrenal artery smooth muscle cells exhibited less metabolism. In preconstricted adrenal arteries, Ang II caused relaxation in picomolar concentrations and constrictions at 10nM. Ang-converting enzyme 2 inhibition augmented this relaxation response, whereas aminopeptidase inhibition did not. Ang III was equipotent to Ang II in relaxing adrenal arteries. Ang IV did not cause relaxation. Nitric oxide synthase inhibition enhanced Ang II-induced constriction of adrenal arteries. Aminopeptidase inhibition increased the concentration range for Ang II-induced constriction of adrenal arteries. Ang III and Ang IV did not change the basal tone but caused constriction of adrenal arteries with nitric oxide synthase inhibition. These data indicate that Ang II metabolism modulates the vascular effects of Ang II in the adrenal vasculature. PMID:24092640

  13. 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.

  14. miR-34a modulates angiotensin II-induced myocardial hypertrophy by direct inhibition of ATG9A expression and autophagic activity.

    PubMed

    Huang, Jionghua; Sun, Wen; Huang, He; Ye, Jing; Pan, Wei; Zhong, Yun; Cheng, Chuanfang; You, Xiangyu; Liu, Benrong; Xiong, Longgen; Liu, Shiming

    2014-01-01

    Cardiac hypertrophy is characterized by thickening myocardium and decreasing in heart chamber volume in response to mechanical or pathological stress, but the underlying molecular mechanisms remain to be defined. This study investigated altered miRNA expression and autophagic activity in pathogenesis of cardiac hypertrophy. A rat model of myocardial hypertrophy was used and confirmed by heart morphology, induction of cardiomyocyte autophagy, altered expression of autophagy-related ATG9A, LC3 II/I and p62 proteins, and decrease in miR-34a expression. The in vitro data showed that in hypertrophic cardiomyocytes induced by Ang II, miR-34a expression was downregulated, whereas ATG9A expression was up-regulated. Moreover, miR-34a was able to bind to ATG9A 3'-UTR, but not to the mutated 3'-UTR and inhibited ATG9A protein expression and autophagic activity. The latter was evaluated by autophagy-related LC3 II/I and p62 levels, TEM, and flow cytometry in rat cardiomyocytes. In addition, ATG9A expression induced either by treatment of rat cardiomyocytes with Ang II or ATG9A cDNA transfection upregulated autophagic activity and cardiomyocyte hypertrophy in both morphology and expression of hypertrophy-related genes (i.e., ANP and β-MHC), whereas knockdown of ATG9A expression downregulated autophagic activity and cardiomyocyte hypertrophy. However, miR-34a antagonized Ang II-stimulated myocardial hypertrophy, whereas inhibition of miR-34a expression aggravated Ang II-stimulated myocardial hypertrophy (such as cardiomyocyte hypertrophy-related ANP and β-MHC expression and cardiomyocyte morphology). This study indicates that miR-34a plays a role in regulation of Ang II-induced cardiomyocyte hypertrophy by inhibition of ATG9A expression and autophagic activity. PMID:24728149

  15. Transcriptional up-regulation of antioxidant genes by PPAR{delta} inhibits angiotensin II-induced premature senescence in vascular smooth muscle cells

    SciTech Connect

    Kim, Hyo Jung; Ham, Sun Ah; Paek, Kyung Shin; Hwang, Jung Seok; Jung, Si Young; Kim, Min Young; Jin, Hanna; Kang, Eun Sil; Woo, Im Sun; Kim, Hye Jung; Lee, Jae Heun; Chang, Ki Churl; Han, Chang Woo; Seo, Han Geuk

    2011-03-25

    Research highlights: {yields} Activation of PPAR{delta} by GW501516 significantly inhibited Ang II-induced premature senescence in hVSMCs. {yields} Agonist-activated PPAR{delta} suppressed generation of Ang II-triggered ROS with a concomitant reduction in DNA damage. {yields} GW501516 up-regulated expression of antioxidant genes, such as GPx1, Trx1, Mn-SOD and HO-1. {yields} Knock-down of these antioxidant genes abolished the effects of GW501516 on ROS production and premature senescence. -- Abstract: This study evaluated peroxisome proliferator-activated receptor (PPAR) {delta} as a potential target for therapeutic intervention in Ang II-induced senescence in human vascular smooth muscle cells (hVSMCs). Activation of PPAR{delta} by GW501516, a specific agonist of PPAR{delta}, significantly inhibited the Ang II-induced premature senescence of hVSMCs. Agonist-activated PPAR{delta} suppressed the generation of Ang II-triggered reactive oxygen species (ROS) with a concomitant reduction in DNA damage. Notably, GW501516 up-regulated the expression of antioxidant genes, such as glutathione peroxidase 1, thioredoxin 1, manganese superoxide dismutase and heme oxygenase 1. siRNA-mediated down-regulation of these antioxidant genes almost completely abolished the effects of GW501516 on ROS production and premature senescence in hVSMCs treated with Ang II. Taken together, the enhanced transcription of antioxidant genes is responsible for the PPAR{delta}-mediated inhibition of premature senescence through sequestration of ROS in hVSMCs treated with Ang II.

  16. Angiotensin II formation in the intact human heart. Predominance of the angiotensin-converting enzyme pathway.

    PubMed Central

    Zisman, L S; Abraham, W T; Meixell, G E; Vamvakias, B N; Quaife, R A; Lowes, B D; Roden, R L; Peacock, S J; Groves, B M; Raynolds, M V

    1995-01-01

    It has been proposed that the contribution of myocardial tissue angiotensin converting enzyme (ACE) to angiotensin II (Ang II) formation in the human heart is low compared with non-ACE pathways. However, little is known about the actual in vivo contribution of these pathways to Ang II formation in the human heart. To examine angiotensin II formation in the intact human heart, we administered intracoronary 123I-labeled angiotensin I (Ang I) with and without intracoronary enalaprilat to orthotopic heart transplant recipients. The fractional conversion of Ang I to Ang II, calculated after separation of angiotensin peptides by HPLC, was 0.415 +/- 0.104 (n = 5, mean +/- SD). Enalaprilat reduced fractional conversion by 89%, to a value of 0.044 +/- 0.053 (n = 4, P = 0.002). In a separate study of explanted hearts, a newly developed in vitro Ang II-forming assay was used to examine cardiac tissue ACE activity independent of circulating components. ACE activity in solubilized left ventricular membrane preparations from failing hearts was 49.6 +/- 5.3 fmol 125I-Ang II formed per minute per milligram of protein (n = 8, +/- SE), and 35.9 +/- 4.8 fmol/min/mg from nonfailing human hearts (n = 7, P = 0.08). In the presence of 1 microM enalaprilat, ACE activity was reduced by 85%, to 7.3 +/- 1.4 fmol/min/mg in the failing group and to 4.6 +/- 1.3 fmol/min/mg in the nonfailing group (P < 0.001). We conclude that the predominant pathway for angiotensin II formation in the human heart is through ACE. Images PMID:7657820

  17. The effect of HN-65021 on responses to angiotensin II in human forearm vasculature.

    PubMed Central

    Cockcroft, J R; Chowienczyk, P J; Brett, S E; Mant, T G; Durnin, C; Lynn, F; Stevenson, P; Ritter, J M

    1995-01-01

    We studied the effect of (2-butyl-4-chloro-1[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]methyl]-1H-imadazole-5-carboxylic acid,-1-(ethoxycarbonyloxy) ethyl-ester (HN-65021), on angiotensin II induced vasoconstriction in forearm vasculature of eight healthy men. Placebo and HN-65021 (5, 10 and 100 mg) were administered orally. Forearm blood flow was measured by venous occlusion plethysmography during rising dose brachial artery infusions of angiotensin II (0.3-1000 pmol min-1) 2 h after dosing. HN-65021 inhibited angiotensin II, causing a shift to the right of the dose-response curve. Angiotensin II (100 pmol min-1) decreased mean blood flow in the infused arm by 63.1 +/- 3.2% when infused following placebo and by 49.9 +/- 4.3%, 50.7 +/- 3.5% and 36.4 +/- 2.8% following HN-65021 doses of 5.10 and 100 mg respectively. These results demonstrate that HN-65021 antagonises angiotensin II receptor mediated vasoconstriction in human forearm resistance vessels. PMID:8703667

  18. Angiotensin II Receptor Blockers and Cancer Risk

    PubMed Central

    Zhao, Yun-Tao; Li, Peng-Yang; Zhang, Jian-Qiang; Wang, Lei; Yi, Zhong

    2016-01-01

    Abstract Angiotensin II receptor blockers (ARB) are widely used drugs that are proven to reduce cardiovascular disease events; however, several recent meta-analyses yielded conflicting conclusions regarding the relationship between ARB and cancer incidence, especially when ARB are combined with angiotensin-converting enzyme inhibitors (ACEI). We investigated the risk of cancer associated with ARB at different background ACEI levels. Search of PubMed and EMBASE (1966 to December 17, 2015) without language restriction. Randomized, controlled trials (RCTs) had at least 12 months of follow-up data and reported cancer incidence was included. Study characteristics, quality, and risk of bias were assessed by 2 reviewers independently. Nineteen RCTs including 148,334 patients were included in this study. Random-effects model meta-analyses were used to estimate the risk ratio (RR) of cancer risk. No excessive cancer risk was observed in our analyses of ARB alone versus placebo alone without background ACEI use (risk ratio [RR] 1.08, 95% confidence interval [CI] 1.00–1.18, P = 0.05); ARB alone versus ACEI alone (RR 1.03, 95%CI 0.94–1.14, P = 0.50); ARB plus partial use of ACEI versus placebo plus partial use of ACEI (RR 0.97, 95%CI 0.90–1.04, P = 0.33); and ARB plus ACEI versus ACEI (RR 0.99, 95%CI 0.79–1.24, P = 0.95). Lack of long-term data, inadequate reporting of safety data, significant heterogeneity in underlying study populations, and treatment regimens. ARB have a neutral effect on cancer incidence in randomized trials. We observed no significant differences in cancer incidence when we compared ARB alone with placebo alone, ARB alone with ACEI alone, ARB plus partial use of ACEI with placebo plus partial use of ACEI, or ARB plus ACEI combination with ACEI. PMID:27149494

  19. Central Rho kinase inhibition restores baroreflex sensitivity and angiotensin II type 1 receptor protein imbalance in conscious rabbits with chronic heart failure.

    PubMed

    Haack, Karla K V; Gao, Lie; Schiller, Alicia M; Curry, Pamela L; Pellegrino, Peter R; Zucker, Irving H

    2013-03-01

    The small GTPase RhoA and its associated kinase ROCKII are involved in vascular smooth muscle cell contraction and endothelial NO synthase mRNA destabilization. Overactivation of the RhoA/ROCKII pathway is implicated in several pathologies, including chronic heart failure (CHF), and may contribute to the enhanced sympathetic outflow seen in CHF as a result of decreased NO availability. Thus, we hypothesized that central ROCKII blockade would improve the sympathovagal imbalance in a pacing rabbit model of CHF in an NO-dependent manner. CHF was induced by rapid ventricular pacing and characterized by an ejection fraction of ≤45%. Animals were implanted with an intracerbroventricular cannula and osmotic minipump (rate, 1 μL/h) containing sterile saline, 1.5 µg/kg per day fasudil (Fas, a ROCKII inhibitor) for 4 days or Fas+100 µg/kg per day Nω-Nitro-l-arginine methyl ester hydrochloride, a NO synthase inhibitor. Arterial baroreflex control was assessed by intravenous infusion of sodium nitroprusside and phenylephrine. Fas infusion significantly lowered resting heart rate by decreasing sympathetic and increasing vagal tone. Furthermore, Fas improved baroreflex gain in CHF in an NO-dependent manner. In CHF Fas animals, the decrease in heart rate in response to intravenous metoprolol was similar to Sham and was reversed by Nω-Nitro-l-arginine methyl ester hydrochloride. Fas decreased angiotensin II type 1 receptor and phospho-ERM protein expression and increased endothelial NO synthase expression in the brain stem of CHF animals. These data strongly suggest that central ROCKII activation contributes to cardiac sympathoexcitation in the setting of CHF and that central Fas restores vagal and sympathetic tone in an NO-dependent manner. ROCKII may be a new central therapeutic target in the setting of CHF. PMID:23283363

  20. The Nox1/4 Dual Inhibitor GKT137831 or Nox4 Knockdown Inhibits Angiotensin-II-Induced Adult Mouse Cardiac Fibroblast Proliferation and Migration. AT1 Physically Associates With Nox4.

    PubMed

    Somanna, Naveen K; Valente, Anthony J; Krenz, Maike; Fay, William P; Delafontaine, Patrice; Chandrasekar, Bysani

    2016-05-01

    Both oxidative stress and inflammation contribute to chronic hypertension-induced myocardial fibrosis and adverse cardiac remodeling. Here we investigated whether angiotensin (Ang)-II-induced fibroblast proliferation and migration are NADPH oxidase (Nox) 4/ROS and IL-18 dependent. Our results show that the potent induction of mouse cardiac fibroblast (CF) proliferation and migration by Ang-II is markedly attenuated by Nox4 knockdown and the Nox inhibitor DPI. Further, Nox4 knockdown and DPI pre-treatment attenuated Ang-II-induced IL-18, IL-18Rα and collagen expression, and MMP9 and LOX activation. While neutralization of IL-18 blunted Ang-II-induced CF proliferation and migration, knockdown of MMP9 attenuated CF migration. The antioxidant NAC and the cell-permeable SOD mimetics Tempol, MnTBAP, and MnTMPyP attenuated oxidative stress and inhibited CF proliferation and migration. The Nox1/Nox4 dual inhibitor GKT137831 also blunted Ang-II-induced H2 O2 production and CF proliferation and migration. Further, AT1 bound Nox4, and Ang-II enhanced their physical association. Notably, GKT137831 attenuated the AT1/Nox4 interaction. These results indicate that Ang-II induces CF proliferation and migration in part via Nox4/ROS-dependent IL-18 induction and MMP9 activation, and may involve AT1/Nox4 physical association. Thus, either (i) neutralizing IL-18, (ii) blocking AT1/Nox4 interaction or (iii) use of the Nox1/Nox4 inhibitor GKT137831 may have therapeutic potential in chronic hypertension-induced adverse cardiac remodeling. PMID:26445208

  1. 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. PMID:26112903

  2. Immunosuppressive treatment protects against angiotensin II-induced renal damage.

    PubMed

    Muller, Dominik N; Shagdarsuren, Erdenechimeg; Park, Joon-Keun; Dechend, Ralf; Mervaala, Eero; Hampich, Franziska; Fiebeler, Anette; Ju, Xinsheng; Finckenberg, Piet; Theuer, Jürgen; Viedt, Christiane; Kreuzer, Joerg; Heidecke, Harald; Haller, Hermann; Zenke, Martin; Luft, Friedrich C

    2002-11-01

    Angiotensin (Ang) II promotes renal infiltration by immunocompetent cells in double-transgenic rats (dTGRs) harboring both human renin and angiotensinogen genes. To elucidate disease mechanisms, we investigated whether or not dexamethasone (DEXA) immunosuppression ameliorates renal damage. Untreated dTGRs developed hypertension, renal damage, and 50% mortality at 7 weeks. DEXA reduced albuminuria, renal fibrosis, vascular reactive oxygen stress, and prevented mortality, independent of blood pressure. In dTGR kidneys, p22phox immunostaining co-localized with macrophages and partially with T cells. dTGR dendritic cells expressed major histocompatibility complex II and CD86, indicating maturation. DEXA suppressed major histocompatibility complex II+, CD86+, dendritic, and T-cell infiltration. In additional experiments, we treated dTGRs with mycophenolate mofetil to inhibit T- and B-cell proliferation. Reno-protective actions of mycophenolate mofetil and its effect on dendritic and T cells were similar to those obtained with DEXA. We next investigated whether or not Ang II directly promotes dendritic cell maturation in vitro. Ang II did not alter CD80, CD83, and MHC II expression, but increased CCR7 expression and cell migration. To explore the role of tumor necrosis factor (TNF)-alpha on dendritic cell maturation in vivo, we treated dTGRs with the soluble TNF-alpha receptor etanercept. This treatment had no effect on blood pressure, but decreased albuminuria, nuclear factor-kappaB activation, and infiltration of all immunocompetent cells. These data suggest that immunosuppression prevents dendritic cell maturation and T-cell infiltration in a nonimmune model of Ang II-induced renal damage. Ang II induces dendritic migration directly, whereas in vivo TNF-alpha is involved in dendritic cell infiltration and maturation. Thus, Ang II may initiate events leading to innate and acquired immune response. PMID:12414515

  3. Immunosuppressive Treatment Protects Against Angiotensin II-Induced Renal Damage

    PubMed Central

    Muller, Dominik N.; Shagdarsuren, Erdenechimeg; Park, Joon-Keun; Dechend, Ralf; Mervaala, Eero; Hampich, Franziska; Fiebeler, Anette; Ju, Xinsheng; Finckenberg, Piet; Theuer, Jürgen; Viedt, Christiane; Kreuzer, Joerg; Heidecke, Harald; Haller, Hermann; Zenke, Martin; Luft, Friedrich C.

    2002-01-01

    Angiotensin (Ang) II promotes renal infiltration by immunocompetent cells in double-transgenic rats (dTGRs) harboring both human renin and angiotensinogen genes. To elucidate disease mechanisms, we investigated whether or not dexamethasone (DEXA) immunosuppression ameliorates renal damage. Untreated dTGRs developed hypertension, renal damage, and 50% mortality at 7 weeks. DEXA reduced albuminuria, renal fibrosis, vascular reactive oxygen stress, and prevented mortality, independent of blood pressure. In dTGR kidneys, p22phox immunostaining co-localized with macrophages and partially with T cells. dTGR dendritic cells expressed major histocompatibility complex II and CD86, indicating maturation. DEXA suppressed major histocompatibility complex II+, CD86+, dendritic, and T-cell infiltration. In additional experiments, we treated dTGRs with mycophenolate mofetil to inhibit T- and B-cell proliferation. Reno-protective actions of mycophenolate mofetil and its effect on dendritic and T cells were similar to those obtained with DEXA. We next investigated whether or not Ang II directly promotes dendritic cell maturation in vitro. Ang II did not alter CD80, CD83, and MHC II expression, but increased CCR7 expression and cell migration. To explore the role of tumor necrosis factor (TNF)-α on dendritic cell maturation in vivo, we treated dTGRs with the soluble TNF-α receptor etanercept. This treatment had no effect on blood pressure, but decreased albuminuria, nuclear factor-κB activation, and infiltration of all immunocompetent cells. These data suggest that immunosuppression prevents dendritic cell maturation and T-cell infiltration in a nonimmune model of Ang II-induced renal damage. Ang II induces dendritic migration directly, whereas in vivo TNF-α is involved in dendritic cell infiltration and maturation. Thus, Ang II may initiate events leading to innate and acquired immune response. PMID:12414515

  4. Angiotensin II induced release of prostaglandins from rat uterus.

    PubMed

    Campos, G A; Guerra, F A; Israel, E J

    1983-08-01

    The effect of Angiotensin II (A-II) on 6-keto-prostaglandin F1 (6-keto-PGF1 alpha) and prostaglandin F (PGF) production by the rat uterus was studied using a novel superfusion technique. The method of superfusion used allows prostaglandin synthesis in the myometrium and endometrium to be measured independently while their anatomical relationship is undisturbed. Prostaglandins were measured by radioimmunoassay. In uterine horns from castrated, estrogen treated rats, A-II (10(-6)M) stimulated the production rate of 6-keto-PGF1 alpha in the myometrium nd PGF in the endometrium. Sterile horns and pregnant horns coexisting in the same animals showed different responses when superfused with culture medium containing A-II (10(-6)M). In the sterile horns A-II failed to stimulate prostaglandin synthesis whereas in the pregnant horns there was a significant increase in the production rate of both 6-keto-PGF1 alpha and PGF in the decidua (endometrium) and of 6-keto-PGF1 alpha in the myometrium. Our results suggests that the effect of A-II on prostaglandin synthesis by the rat uterus appears to be dependent of the hormonal milieu of the experimental animal. Estrogen stimulated A-II induced PG synthesis. Progesterone inhibited the synthesis of PGs caused by A-II in non-decidualized uterus but stimulated the release of PG in the decidualized uterus. The apparent differential effect of A-II in stimulating prostaglandin synthesis in the whole uterus indicates that there are different pathways for prostaglandin production in both the endometrium and myometrium. PMID:6689628

  5. Angiotensin 1-7 Protects against Angiotensin II-Induced Endoplasmic Reticulum Stress and Endothelial Dysfunction via Mas Receptor

    PubMed Central

    Murugan, Dharmani; Lau, Yeh Siang; Lau, Wai Chi; Mustafa, Mohd Rais; Huang, Yu

    2015-01-01

    Angiotensin 1–7 (Ang 1–7) counter-regulates the cardiovascular actions of angiotensin II (Ang II). The present study investigated the protective effect of Ang 1–7 against Ang II-induced endoplasmic reticulum (ER) stress and endothelial dysfunction. Ex vivo treatment with Ang II (0.5 μM, 24 hours) impaired endothelium-dependent relaxation in mouse aortas; this harmful effect of Ang II was reversed by co-treatment with ER stress inhibitors, l4-phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) as well as Ang 1–7. The Mas receptor antagonist, A779, antagonized the effect of Ang 1–7. The elevated mRNA expression of CHOP, Grp78 and ATF4 or protein expression of p-eIF2α and ATF6 (ER stress markers) in Ang II-treated human umbilical vein endothelial cells (HUVECs) and mouse aortas were blunted by co-treatment with Ang 1–7 and the latter effect was reversed by A779. Furthermore, Ang II-induced reduction in both eNOS phosphorylation and NO production was inhibited by Ang 1–7. In addition, Ang 1–7 decreased the levels of ER stress markers and augmented NO production in HUVECs treated with ER stress inducer, tunicamycin. The present study provides new evidence for functional antagonism between the two arms of the renin-angiotensin system in endothelial cells by demonstrating that Ang 1–7 ameliorates Ang II-stimulated ER stress to raise NO bioavailability, and subsequently preserves endothelial function. PMID:26709511

  6. Angiotensin-converting enzyme inhibition by Brazilian plants.

    PubMed

    Braga, Fernão C; Serra, Carla P; Viana, Nilton S; Oliveira, Alaíde B; Côrtes, Steyner F; Lombardi, Júlio A

    2007-07-01

    The potential antihypertensive activity of Brazilian plants was evaluated in vitro by its ability to inhibit the angiotensin-converting enzyme (ACE). Forty-four plants belonging to 30 families were investigated. Plants were selected based on their popular use as antihypertensive and/or diuretics. The following plants presented significant ACE inhibition rates: Calophyllum brasiliense, Combretum fruticosum, Leea rubra, Phoenix roebelinii and Terminalia catappa. PMID:17513067

  7. Angiopoietin-like protein 2 expression is suppressed by angiotensin II via the angiotensin II type 1 receptor in rat cardiomyocytes

    PubMed Central

    Wang, Shuya; Li, Ying; Miao, Wei; Zhao, Hong; Zhang, Feng; Liu, Nan; Su, Guohai; Cai, Xiaojun

    2016-01-01

    The present study aimed to determine the inhibitory effects of angiotensin II (AngII) on angiopoietin-like protein 2 (Angptl2) in rat primary cardiomyocytes, and to investigate the potential association between angiotensin II type 1 receptor (AT1R) and these effects. Cardiomyocytes were isolated from 3-day-old Wistar rats, and were cultured and identified. Subsequently, the expression levels of Angptl2 were detected following incubation with various concentrations of AngII for various durations using western blotting, reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescence. Finally, under the most appropriate conditions (100 nmol/l AngII, 24 h), the cardiomyocytes were divided into six groups: Normal, AngII, AngII + losartan, normal + losartan, AngII + PD123319 and normal + PD123319 groups, in order to investigate the possible function of AT1R in Angptl2 suppression. Losartan and PD123319 are antagonists of AT1R and angiotensin II type 2 receptor, respectively. The statistical significance of the results was analyzed using Student's t-test or one-way analysis of variance. The results demonstrated that Angptl2 expression was evidently suppressed (P<0.05) following incubation with 100 nmol/l AngII for 24 h. Conversely, the expression levels of Angptl2 were significantly increased in the AngII + losartan group compared with the AngII group (P<0.01). However, no significant difference was detected between the AngII + PD123319, normal + losartan or normal + PD123319 groups and the normal group. The present in vitro study indicated that AngII was able to suppress Angptl2 expression, whereas losartan was able to significantly reverse this decrease by inhibiting AT1R. PMID:27483989

  8. Angiotensin II regulation of angiotensin-converting enzymes in spontaneously hypertensive rat primary astrocyte cultures.

    PubMed

    Gowrisankar, Yugandhar V; Clark, Michelle A

    2016-07-01

    Angiotensin (Ang) II plays a critical role in cardiovascular and blood pressure regulation. Ang II is produced by angiotensin-converting enzyme (ACE) and it interacts with the Ang AT1 receptor to cause much of its well-known cardiovascular effects. Ang-(1-7) is another active peptide produced by the rennin-angiotensin system. This peptide is produced from Ang I or Ang II by the catalytic activity of ACE2. Ang-(1-7) interacts with the Mas receptor to counteract many of the effects of Ang II. Thus, the ACE2/Ang-(1-7)/Mas axis acts opposite of the ACE/Ang II/AT1 axis. In this study we investigated how Ang II regulates the key enzymes of these axes, ACE and its homolog ACE2, and determined whether they are dysregulated in the hypertensive condition. Brainstem and cerebellum astrocytes isolated from the spontaneously hypertensive rat (SHR) were used in these studies. Ang II effect on the enzymes' mRNA and protein levels was measured using quantitative PCR and western blotting techniques, respectively. Results from this study showed that Ang II up-regulated ACE protein levels, but down-regulated ACE mRNA levels in brainstem and cerebellum astrocytes in both models. Ang II also reduced ACE2 mRNA expression in SHR and Wistar astrocytes isolated from both brain regions. Ang II effects on ACE2 protein were biphasic. In SHR astrocytes, Ang II-mediated ACE2 protein initially increased then decreased at later time points. In contrast, in Wistar astrocytes, Ang II initially decreased ACE2 protein expression, but up-regulated the protein at later time points. The findings of these studies suggest that Ang II has a differential effect on ACE and ACE2 expression. Furthermore, in the SHR model there may be alteration in the ACE/ACE2 balance in a manner that favors increased Ang II generation and decreased Ang-(1-7) production contributing to the hypertensive phenotype observed in this model. The levels of angiotensin (Ang) II depend on the actions of angiotensin-converting enzyme

  9. Angiotensin II (AT(1)) receptor blockade reduces vascular tissue factor in angiotensin II-induced cardiac vasculopathy.

    PubMed

    Müller, D N; Mervaala, E M; Dechend, R; Fiebeler, A; Park, J K; Schmidt, F; Theuer, J; Breu, V; Mackman, N; Luther, T; Schneider, W; Gulba, D; Ganten, D; Haller, H; Luft, F C

    2000-07-01

    Tissue factor (TF), a main initiator of clotting, is up-regulated in vasculopathy. We tested the hypothesis that chronic in vivo angiotensin (ANG) II receptor AT(1) receptor blockade inhibits TF expression in a model of ANG II-induced cardiac vasculopathy. Furthermore, we explored the mechanisms by examining transcription factor activation and analyzing the TF promoter. Untreated transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR) feature hypertension and severe left ventricular hypertrophy with focal areas of necrosis, and die at age 7 weeks. Plasma and cardiac ANG II was three- to fivefold increased compared to Sprague-Dawley rats. Chronic treatment with valsartan normalized blood pressure and coronary resistance completely, and ameliorated cardiac hypertrophy (P < 0.001). Valsartan prevented monocyte/macrophage infiltration, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) activation, and c-fos expression in dTGR hearts. NF-kappaB subunit p65 and TF expression was increased in the endothelium and media of cardiac vessels and markedly reduced by valsartan treatment. To analyze the mechanism of TF transcription, we then transfected human coronary artery smooth muscle cells and Chinese hamster ovary cells overexpressing the AT(1) receptor with plasmids containing the human TF promoter and the luciferase reporter gene. ANG II induced the full-length TF promoter in both transfected cell lines. TF transcription was abolished by AT(1) receptor blockade. Deletion of both AP-1 and NF-kappaB sites reduced ANG II-induced TF gene transcription completely, whereas the deletion of AP-1 sites reduced transcription. Thus, the present study clearly shows an aberrant TF expression in the endothelium and media in rats with ANG II-induced vasculopathy. The beneficial effects of AT(1) receptor blockade in this model are mediated via the inhibition of NF-kappaB and AP-1 activation, thereby preventing TF expression, cardiac vasculopathy, and

  10. Angiotensin II (AT1) Receptor Blockade Reduces Vascular Tissue Factor in Angiotensin II-Induced Cardiac Vasculopathy

    PubMed Central

    Müller, Dominik N.; Mervaala, Eero M. A.; Dechend, Ralf; Fiebeler, Anette; Park, Joon-Keun; Schmidt, Folke; Theuer, Jürgen; Breu, Volker; Mackman, Nigel; Luther, Thomas; Schneider, Wolfgang; Gulba, Dietrich; Ganten, Detlev; Haller, Hermann; Luft, Friedrich C.

    2000-01-01

    Tissue factor (TF), a main initiator of clotting, is up-regulated in vasculopathy. We tested the hypothesis that chronic in vivo angiotensin (ANG) II receptor AT1 receptor blockade inhibits TF expression in a model of ANG II-induced cardiac vasculopathy. Furthermore, we explored the mechanisms by examining transcription factor activation and analyzing the TF promoter. Untreated transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR) feature hypertension and severe left ventricular hypertrophy with focal areas of necrosis, and die at age 7 weeks. Plasma and cardiac ANG II was three- to fivefold increased compared to Sprague-Dawley rats. Chronic treatment with valsartan normalized blood pressure and coronary resistance completely, and ameliorated cardiac hypertrophy (P < 0.001). Valsartan prevented monocyte/macrophage infiltration, nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activation, and c-fos expression in dTGR hearts. NF-κB subunit p65 and TF expression was increased in the endothelium and media of cardiac vessels and markedly reduced by valsartan treatment. To analyze the mechanism of TF transcription, we then transfected human coronary artery smooth muscle cells and Chinese hamster ovary cells overexpressing the AT1 receptor with plasmids containing the human TF promoter and the luciferase reporter gene. ANG II induced the full-length TF promoter in both transfected cell lines. TF transcription was abolished by AT1 receptor blockade. Deletion of both AP-1 and NF-κB sites reduced ANG II-induced TF gene transcription completely, whereas the deletion of AP-1 sites reduced transcription. Thus, the present study clearly shows an aberrant TF expression in the endothelium and media in rats with ANG II-induced vasculopathy. The beneficial effects of AT1 receptor blockade in this model are mediated via the inhibition of NF-κB and AP-1 activation, thereby preventing TF expression, cardiac vasculopathy, and microinfarctions. PMID

  11. Platelet activation during angiotensin II infusion in healthy volunteers.

    PubMed

    Larsson, P T; Schwieler, J H; Wallén, N H

    2000-01-01

    The present study was undertaken to evaluate the effects of an intravenous infusion of angiotensin II (10 ng/kg per min) on platelet function and coagulation in vivo in 18 healthy males. The infusion increased mean arterial pressure by 23+/-2 mm Hg. Plasma beta-thromboglobulin levels, reflecting platelet secretion, increased by 66+/-24% during the infusion, as did also platelet surface expression of P-selectin as measured by flow cytometry. Platelet fibrinogen binding increased, whereas platelet aggregability, assessed by ex vivo filtragometry, was unaltered. Angiotensin II caused mild activation of the coagulation cascade with increases in plasma levels of thrombin-antithrombin complex and prothrombin fragment F1 + 2. In conclusion, angiotensin II has mild platelet-activating effects in vivo and also enhances coagulation. Markers of platelet secretion are significantly increased, whereas markers of platelet aggregability are less affected. The clinical relevance of these findings remains to be clarified. PMID:10691100

  12. PKC δ and βII regulate angiotensin II-mediated fibrosis through p38: a mechanism of RV fibrosis in pulmonary hypertension

    PubMed Central

    Chichger, Havovi; Vang, Alexander; O'Connell, Kelly A.; Zhang, Peng; Mende, Ulrike; Harrington, Elizabeth O.

    2015-01-01

    Pulmonary hypertension (PH) eventually leads to right ventricular (RV) fibrosis and dysfunction that is associated with increased morbidity and mortality. Although angiotensin II plays an important role in RV remodeling associated with hypoxic PH, the molecular mechanisms underlying RV fibrosis in PH largely remain unresolved. We hypothesized that PKC-p38 signaling is involved in RV collagen accumulation in PH and in response to angiotensin II stimulation. Adult male Sprague-Dawley rats were exposed to 3 wk of normoxia or hypoxia (10% FiO2) as a model of PH. Hypoxic rats developed RV hypertrophy and fibrosis associated with an increase in PKC βII and δ protein expression and p38 dephosphorylation in freshly isolated RV cardiac fibroblasts. Further mechanistic studies were performed in cultured primary cardiac fibroblasts stimulated with angiotensin II, a key activator of ventricular fibrosis in PH. Angiotensin II induced a reduction in p38 phosphorylation that was attenuated following chemical inhibition of PKC βII and δ. Molecular and chemical inhibition of PKC βII and δ abrogated angiotensin II-induced cardiac fibroblast proliferation and collagen deposition in vitro. The effects of PKC inhibition on proliferation and fibrosis were reversed by chemical inhibition of p38. Conversely, constitutive activation of p38 attenuated angiotensin II-induced increase of cardiac fibroblast proliferation and collagen accumulation. PKC βII- and δ-dependent inactivation of p38 regulates cardiac fibroblast proliferation and collagen deposition in response to angiotensin II, which suggests that the PKC-p38 signaling in cardiac fibroblasts may be involved and important in the pathophysiology of RV fibrosis in PH. PMID:25659900

  13. Angiotensin II inhibitor facilitates epidermal wound regeneration in diabetic mice

    PubMed Central

    Kamber, Maria; Papalazarou, Vasileios; Rouni, Georgia; Papageorgopoulou, Evagelia; Papalois, Apostolos; Kostourou, Vassiliki

    2015-01-01

    Tissue regeneration and wound healing are severely impaired in diabetes and are associated with poor circulation and dysfunctional blood vessels. Angiotensin II inhibitors are anti-hypertensive drugs used in clinical practice to regulate blood pressure and could affect tissue remodeling. We hypothesize that blocking angiotensin II, using Losartan, could facilitate tissue regeneration in diabetic mice. To this end, we established an experimental model of wound healing in streptozotocin-induced diabetic mice. Our data demonstrated that Losartan accelerates wound repair and normalizes wound stromal responses, having a beneficial role in wounds of diabetic individuals. Our findings highlight a potential therapeutic use of Losartan in improving wound repair in diabetic conditions. PMID:26106332

  14. Contractile effects of intracellularly administered angiotensin II are partially dependent on membrane receptors internalization in isolated rat aorta.

    PubMed

    Petrescu, G; Costuleanu, M; Slătineanu, S M; Foia, L; Costuleanu, N; Costuleanu, A

    2001-01-01

    In the present study we used the isolated rat aorta as a model to characterize the modulation of contractile effects of extra- and intracellularly administered angiotensin II by dithiothreitol (DTT) and hyperosmotic sucrose. DTT inactivation of AT1 receptor as well as disruption of the clathrin-coated pits by hyperosmotic sucrose significantly inhibited the contraction induced by intracellularly administered AII. We suggest that these intracellular effects of angiotensin peptides are associated with AT1 receptor activation/internalization and may thus be part of the mechanism of angiotensin peptides direct contractile effects in the vascular smooth muscle. PMID:12092224

  15. Recent Updates on the Proximal Tubule Renin-Angiotensin System in Angiotensin II-Dependent Hypertension.

    PubMed

    Li, Xiao C; Zhuo, Jia L

    2016-08-01

    It is well recognized that the renin-angiotensin system (RAS) exists not only as circulating, paracrine (cell to cell), but also intracrine (intracellular) system. In the kidney, however, it is difficult to dissect the respective contributions of circulating RAS versus intrarenal RAS to the physiological regulation of proximal tubular Na(+) reabsorption and hypertension. Here, we review recent studies to provide an update in this research field with a focus on the proximal tubular RAS in angiotensin II (ANG II)-induced hypertension. Careful analysis of available evidence supports the hypothesis that both local synthesis or formation and AT1 (AT1a) receptor- and/or megalin-mediated uptake of angiotensinogen (AGT), ANG I and ANG II contribute to high levels of ANG II in the proximal tubules of the kidney. Under physiological conditions, nearly all major components of the RAS including AGT, prorenin, renin, ANG I, and ANG II would be filtered by the glomerulus and taken up by the proximal tubules. In ANG II-dependent hypertension, the expression of AGT, prorenin, and (pro)renin receptors, and angiotensin-converting enzyme (ACE) is upregulated rather than downregulated in the kidney. Furthermore, hypertension damages the glomerular filtration barrier, which augments the filtration of circulating AGT, prorenin, renin, ANG I, and ANG II and their uptake in the proximal tubules. Together, increased local ANG II formation and augmented uptake of circulating ANG II in the proximal tubules, via activation of AT1 (AT1a) receptors and Na(+)/H(+) exchanger 3, may provide a powerful feedforward mechanism for promoting Na(+) retention and the development of ANG II-induced hypertension. PMID:27372447

  16. Addition of Angiotensin Receptor Blockade or Mineralocorticoid Antagonism to Maximal Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy

    PubMed Central

    Mehdi, Uzma F.; Adams-Huet, Beverley; Raskin, Philip; Vega, Gloria L.

    2009-01-01

    Aldosterone promotes glomerular and tubular sclerosis independent of angiotensin II in animal models of diabetic nephropathy. Most human studies testing the renoprotective benefit of adding an angiotensin receptor blocker or a mineralocorticoid receptor antagonist to a regimen based on inhibition of angiotensin-converting enzyme (ACE) used relatively low doses of ACE inhibitors. Furthermore, these studies did not determine whether antiproteinuric effects were independent of BP lowering. We conducted a double-blind, placebo-controlled trial in 81 patients with diabetes, hypertension, and albuminuria (urine albumin-to-creatinine ratio ≥300 mg/g) who all received lisinopril (80 mg once daily). We randomly assigned the patients to placebo, losartan (100 mg daily), or spironolactone (25 mg daily) for 48 wk. We obtained blood and urine albumin, urea, creatinine, electrolytes, A1c, and ambulatory BP at baseline, 24, and 48 wk. Compared with placebo, the urine albumin-to-creatinine ratio decreased by 34.0% (95% CI, −51.0%, −11.2%, P = 0.007) in the group assigned to spironolactone and by 16.8% (95% CI, −37.3%, +10.5%, P = 0.20) in the group assigned to losartan. Clinic and ambulatory BP, creatinine clearance, sodium and protein intake, and glycemic control did not differ between groups. Serum potassium level was significantly higher with the addition of either spironolactone or losartan. In conclusion, the addition of spironolactone, but not losartan, to a regimen including maximal ACE inhibition affords greater renoprotection in diabetic nephropathy despite a similar effect on BP. These results support the need to conduct a long-term, large-scale, renal failure outcomes trial. PMID:19926893

  17. Baicalin attenuates angiotensin II-induced endothelial dysfunction.

    PubMed

    Wei, Xiling; Zhu, Xingyu; Hu, Nan; Zhang, Xiuqin; Sun, Tianjiao; Xu, Jiyang; Bian, Xiaohong

    2015-09-11

    Angiotensin II (Ang II) has been shown to activate multiple downstream pathways resulting in endothelial dysfunction and oxidative stress. Baicalin, a natural flavone, exerts anti-oxidant and anti-apoptotic effects in cardiovascular diseases. In the present study, we hypothesized that baicalin has beneficial effects in Ang II-induced endothelial cells injury. Here, we shown that baicalin improved endothelial fuction impaired by Ang II through promoting endothelial-dependent vasodilation and suppressing the apoptosis of HUVECs in which baicalin decreased the expression of bax and cleaved caspase-3, and increased bcl-2 expression. Additionally, baicalin significantly conversed Ang II to angiotensin-1-7 [Ang-(1-7)] by activating angiotensin-converting enzyme 2 (ACE2) and Mas receptor mRNA expression and protein expression. Moreover, treatment with baicalin significantly reduced cell oxidative damage induced by Ang II through MDA/ROS decrease and NO/T-AOC increase. This antioxidant capacity was related to the increases of PI3K, phosphor-AKT (Ser-473) and phosphor-eNOS (Ser-1177). In conclusion, our results implicate that baicalin could protect endothelial cells from Ang II-induced endothelial dysfunction and oxidative stress via modulating the expression of bax, bcl-2 and cleaved caspase-3, activating ACE2/Ang-(1-7)/Mas axis and up-regulating PI3K/AKT/eNOS pathway. PMID:26239661

  18. Combined Sub-Optimal Doses of Rosuvastatin and Bexarotene Impair Angiotensin II-Induced Arterial Mononuclear Cell Adhesion Through Inhibition of Nox5 Signaling Pathways and Increased RXR/PPARα and RXR/PPARγ Interactions

    PubMed Central

    Escudero, Paula; Martinez de Marañón, Aranzazu; Collado, Aida; Gonzalez-Navarro, Herminia; Hermenegildo, Carlos; Peiró, Concepción

    2015-01-01

    Abstract Aim: Mononuclear cell (MC) infiltration into the arterial subendothelium is a key event in atherogenesis. Rosuvastatin (Rosu) and bexarotene (Bex) exert anti-inflammatory activity, but serious dose-related adverse effects have emerged. The need for safer and effective strategies to prevent and treat atherosclerosis led us to test the effect of combined use of both drugs on angiotensin II (Ang-II)-induced arterial MC recruitment. Results: Vehicle, Rosu (10–30 nM), Bex (0.3–1 μM), or a combination of both were administered to human umbilical arterial endothelial cells (HUAECs) 20 h before stimulation with 1 μM Ang-II (4 h). Surprisingly, a combination of Rosu (10 nM)+Bex (0.3 μM), which did not influence Ang-II-induced MC recruitment when either stimulus was studied alone, significantly reduced this response. This effect was accompanied by diminished Ang-II-induced ICAM-1, VCAM-1, and CX3CL1 endothelial expression and CXCL1, CXCL8, CCL2, and CCL5 production. Preincubation of HUAECs with Rosu+Bex inhibited Nox5 expression and Nox5-induced RhoA activation stimulated by Ang-II through increased RXRα, PPARα, and PPARγ expression in addition to RXRα/PPARα and RXRα/PPARγ interactions. In vivo, combined but not single administration of Rosu (1.25 mg/kg/day) and Bex (10 mg/kg/day) significantly diminished Ang-II-induced arteriolar leukocyte adhesion in the cremasteric microcirculation of C57BL/6 mice and atherosclerotic lesion formation in apoE−/− mice subjected to an atherogenic diet. Innovation and Conclusion: Combined administration of Bex+Rosu at suboptimal doses may constitute a new alternative and effective therapy in the control of the vascular inflammation associated to cardiometabolic disorders, since they synergize in their anti-inflammatory actions and may counteract their associated adverse effects. Antioxid. Redox Signal. 22, 901–920. PMID:25602514

  19. The inhibitory effect of angiotensin II on BKCa channels in podocytes via oxidative stress.

    PubMed

    Gao, Na; Wang, Hui; Zhang, Xiaochen; Yang, Zhuo

    2015-01-01

    Angiotensin II (Ang II) is an important active substance of the renin-angiotensin system (RAS). The present study has confirmed that abnormalities of Ang II may be related with cerebrovascular diseases, endocrine diseases, cardiovascular diseases, liver diseases, such as: cerebral hypoxia, diabetes, obesity, atrial fibrillation, and liver cirrhosis. However, understanding effects of Ang II on podocytes is not enough. This study was to investigate the effects of oxidative stress on the large conductance, Ca(2+)-activated K(+) channels (BKCa). Results from the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay showed that Ang II induced podocyte death in a concentration-dependent manner. The measurement of superoxide dismutase (SOD) generation demonstrated that Ang II decreased the total SOD of cellular levels. Meaningfully, pretreatment of a type of ROS scavenger formulations named N-(mercaptopropionyl)-glycine (N-MPG) could inhibit podocyte apoptosis induced by Ang II. Meanwhile, patch-clamp technique was used in this study to detect the effects of Ang II on currents of BKCa channel in podocytes. The results indicated that Ang II inhibited the current amplitude of BKCa channel and decreased the slope of I-V curve. Ang II also made the activation curves of BKCa channel shift to the left. These results may provide a theoretical basis for potential treatment of chronic glomerular disease in the future. PMID:25234195

  20. Expression of Angiotensin II Receptor-1 in Human Articular Chondrocytes

    PubMed Central

    Kawakami, Yuki; Matsuo, Kosuke; Murata, Minako; Yudoh, Kazuo; Nakamura, Hiroshi; Shimizu, Hiroyuki; Beppu, Moroe; Inaba, Yutaka; Saito, Tomoyuki; Kato, Tomohiro; Masuko, Kayo

    2012-01-01

    Background. Besides its involvement in the cardiovascular system, the renin-angiotensin-aldosterone (RAS) system has also been suggested to play an important role in inflammation. To explore the role of this system in cartilage damage in arthritis, we investigated the expression of angiotensin II receptors in chondrocytes. Methods. Articular cartilage was obtained from patients with osteoarthritis, rheumatoid arthritis, and traumatic fractures who were undergoing arthroplasty. Chondrocytes were isolated and cultured in vitro with or without interleukin (IL-1). The expression of angiotensin II receptor types 1 (AT1R) and 2 (AT2R) mRNA by the chondrocytes was analyzed using reverse transcription-polymerase chain reaction (RT-PCR). AT1R expression in cartilage tissue was analyzed using immunohistochemistry. The effect of IL-1 on AT1R/AT2R expression in the chondrocytes was analyzed by quantitative PCR and flow cytometry. Results. Chondrocytes from all patient types expressed AT1R/AT2R mRNA, though considerable variation was found between samples. Immunohistochemical analysis confirmed AT1R expression at the protein level. Stimulation with IL-1 enhanced the expression of AT1R/AT2R mRNA in OA and RA chondrocytes. Conclusions. Human articular chondrocytes, at least partially, express angiotensin II receptors, and IL-1 stimulation induced AT1R/AT2R mRNA expression significantly. PMID:23346400

  1. 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

  2. Angiotensin II modulates salty and sweet taste sensitivities.

    PubMed

    Shigemura, Noriatsu; Iwata, Shusuke; Yasumatsu, Keiko; Ohkuri, Tadahiro; Horio, Nao; Sanematsu, Keisuke; Yoshida, Ryusuke; Margolskee, Robert F; Ninomiya, Yuzo

    2013-04-10

    Understanding the mechanisms underlying gustatory detection of dietary sodium is important for the prevention and treatment of hypertension. Here, we show that Angiotensin II (AngII), a major mediator of body fluid and sodium homeostasis, modulates salty and sweet taste sensitivities, and that this modulation critically influences ingestive behaviors in mice. Gustatory nerve recording demonstrated that AngII suppressed amiloride-sensitive taste responses to NaCl. Surprisingly, AngII also enhanced nerve responses to sweeteners, but had no effect on responses to KCl, sour, bitter, or umami tastants. These effects of AngII on nerve responses were blocked by the angiotensin II type 1 receptor (AT1) antagonist CV11974. In behavioral tests, CV11974 treatment reduced the stimulated high licking rate to NaCl and sweeteners in water-restricted mice with elevated plasma AngII levels. In taste cells AT1 proteins were coexpressed with αENaC (epithelial sodium channel α-subunit, an amiloride-sensitive salt taste receptor) or T1r3 (a sweet taste receptor component). These results suggest that the taste organ is a peripheral target of AngII. The specific reduction of amiloride-sensitive salt taste sensitivity by AngII may contribute to increased sodium intake. Furthermore, AngII may contribute to increased energy intake by enhancing sweet responses. The linkage between salty and sweet preferences via AngII signaling may optimize sodium and calorie intakes. PMID:23575826

  3. 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

  4. 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.

  5. 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.

  6. Glial high-affinity binding site with specificity for angiotensin II not angiotensin III: a possible N-terminal-specific converting enzyme

    SciTech Connect

    Printz, M.P.; Jennings, C.; Healy, D.P.; Kalter, V.

    1986-01-01

    Anomalous binding properties of angiotensin II to fetal rat brain primary cultures suggested a possible contribution from contaminating glia. To investigate this possibility, cultures of C6 glioma, a clonal rat cell line, were examined for the presence of angiotensin II receptors. A specific high-affinity site for (/sup 125/I)angiotensin II was measured both by traditional methodology using whole cells and by autoradiography. This site shared properties similar to that found with the brain cells, namely low ligand internalization and markedly decreased affinity for N-terminal sarcosine or arginine-angiotensin analogs. The competition rank order was angiotensin II much greater than (Sar1,Ile8)angiotensin II greater than or equal to des(Asp1,Arg2)angiotensin II. Angiotensin III did not compete for binding to the site. High-pressure liquid chromatography analysis indicated that the ligand either in the incubation or bound to the site was stable at 15 degrees C, but there was very rapid and extensive degradation by the C6 glioma cells at 37 degrees C. It is concluded that the site exhibits unusual N-terminal specificity for angiotensin with nanomolar affinity for angiotensin II. If angiotensin III is an active ligand in the brain, the site may have a converting enzyme function. Alternatively, it may form the des-Asp derivatives of angiotensin for subsequent degradation by other enzymatic pathways. Either way, it is proposed that the site may modulate the brain-angiotensin system.

  7. Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: A mechanism by which angiotensin II antagonizes cGMP signaling

    PubMed Central

    Kim, Dongsoo; Aizawa, Toru; Wei, Heng; Pi, Xinchun; Rybalkin, Sergei D.; Berk, Bradford C.; Yan, Chen

    2014-01-01

    Angiotensin II (Ang II) and nitric oxide (NO)/natriuretic peptide (NP) signaling pathways mutually regulate each other. Imbalance of Ang II and NO/NP has been implicated in the pathophysiology of many vascular diseases. cGMP functions as a key mediator in the interaction between Ang II and NO/NP. Cyclic nucleotide phosphodiesterase 5A (PDE5A) is important in modulating cGMP signaling by hydrolyzing cGMP in vascular smooth muscle cells (VSMC). Therefore, we examined whether Ang II negatively modulates intracellular cGMP signaling in VSMC by regulating PDE5A. Ang II rapidly and transiently increased PDE5A mRNA levels in rat aortic VSMC. Upregulation of PDE5A mRNA was associated with a time-dependent increase of both PDE5 protein expression and activity. Increased PDE5A mRNA level was transcription-dependent and mediated by the Ang II type 1 receptor. Ang II-mediated activation of extracellular signal-regulated kinases 1/2 (ERK1/2) was essential for Ang II-induced PDE5A upregulation. Pretreatment of VSMC with Ang II inhibited C-type NP (CNP) stimulated cGMP signaling, such as cGMP dependent protein kinase (PKG)-mediated phosphorylation of vasodilator-stimulated-phosphoprotein (VASP). Ang II-mediated inhibition of PKG was blocked when PDE5 activity was decreased by selective PDE5 inhibitors, suggesting that upregulation of PDE5A expression is an important mechanism for Ang II to attenuate cGMP signaling. PDE5A may also play a critical role in the growth promoting effects of Ang II because inhibition of PDE5A activity significantly decreased Ang II-stimulated VSMC growth. These observations establish a new mechanism by which Ang II antagonizes cGMP signaling and stimulates VSMC growth. PMID:15623434

  8. Angiotensin and mineralocorticoid receptor antagonism attenuates cardiac oxidative stress in angiotensin II-infused rats.

    PubMed

    Minas, Jacqueline N; Thorwald, Max A; Conte, Debra; Vázquez-Medina, Jose-Pablo; Nishiyama, Akira; Ortiz, Rudy M

    2015-11-01

    Angiotensin II (Ang II) and aldosterone contribute to hypertension, oxidative stress and cardiovascular damage, but the contributions of aldosterone during Ang II-dependent hypertension are not well defined because of the difficulty to assess each independently. To test the hypothesis that during Ang II infusion, oxidative and nitrosative damage is mediated through both the mineralocorticoid receptor (MR) and angiotensin type 1 receptor (AT1), five groups of Sprague-Dawley rats were studied: (i) control; (ii) Ang II infused (80 ng/min × 28 days); (iii) Ang II + AT1 receptor blocker (ARB; 10 mg losartan/kg per day × 21 days); (iv) Ang II + mineralocorticoid receptor (MR) antagonist (Epl; 100 mg eplerenone/day × 21 days); and (v) Ang II + ARB + Epl (Combo; × 21 days). Both ARB and combination treatments completely alleviated the Ang II-induced hypertension, whereas eplerenone treatment only prolonged the onset of the hypertension. Eplerenone treatment exacerbated the Ang II-mediated increase in plasma and heart aldosterone 2.3- and 1.8-fold, respectively, while ARB treatment reduced both. Chronic MR blockade was sufficient to ameliorate the AT1-mediated increase in oxidative damage. All treatments normalized protein oxidation (nitrotyrosine) levels; however, only ARB and Combo treatments completely reduced lipid peroxidation (4-hydroxynonenal) to control levels. Collectively, these data suggest that receptor signalling, and not the elevated arterial blood pressure, is the principal culprit in the oxidative stress-associated cardiovascular damage in Ang II-dependent hypertension. PMID:26234762

  9. Pancreatic angiotensin-converting enzyme 2 improves glycemia in angiotensin II-infused mice

    PubMed Central

    Chhabra, Kavaljit H.; Xia, Huijing; Pedersen, Kim Brint; Speth, Robert C.

    2013-01-01

    An overactive renin-angiotensin system (RAS) is known to contribute to type 2 diabetes mellitus (T2DM). Although ACE2 overexpression has been shown to be protective against the overactive RAS, a role for pancreatic ACE2, particularly in the islets of Langerhans, in regulating glycemia in response to elevated angiotensin II (Ang II) levels remains to be elucidated. This study examined the role of endogenous pancreatic ACE2 and the impact of elevated Ang II levels on the enzyme's ability to alleviate hyperglycemia in an Ang II infusion mouse model. Male C57bl/6J mice were infused with Ang II or saline for a period of 14 days. On the 7th day of infusion, either an adenovirus encoding human ACE2 (Ad-hACE2) or a control adenovirus (Ad-eGFP) was injected into the mouse pancreas. After an additional 7–8 days, glycemia and plasma insulin levels as well as RAS components expression and oxidative stress were assessed. Ang II-infused mice exhibited hyperglycemia, hyperinsulinemia, and impaired glucose-stimulated insulin secretion from pancreatic islets compared with control mice. This phenotype was associated with decreased ACE2 expression and activity, increased Ang II type 1 receptor (AT1R) expression, and increased oxidative stress in the mouse pancreas. Ad-hACE2 treatment restored pancreatic ACE2 expression and compensatory activity against Ang II-mediated impaired glycemia, thus improving β-cell function. Our data suggest that decreased pancreatic ACE2 is a link between overactive RAS and impaired glycemia in T2DM. Moreover, maintenance of a normal endogenous ACE2 compensatory activity in the pancreas appears critical to avoid β-cell dysfunction, supporting a therapeutic potential for ACE2 in controlling diabetes resulting from an overactive RAS. PMID:23462816

  10. Angiotensin-II blockage, muscle strength, and exercise capacity in physically independent older adults

    PubMed Central

    Coelho, Vinícius A.; Probst, Vanessa S.; Nogari, Bruna M.; Teixeira, Denilson C.; Felcar, Josiane M.; Santos, Denis C.; Gomes, Marcus Vinícius M.; Andraus, Rodrigo A. C.; Fernandes, Karen B. P.

    2016-01-01

    [Purpose] This study aimed to assess the exercise capacity and muscle strength in elderly people using drugs for angiotensin-II blockage. [Subjects and Methods] Four hundred and seven older adults were recruited for this study. Data about comorbidities and medication use were recorded and the individuals were divided into three groups: control group- elderly people with normal exercise capacity (n=235); angiotensin-converting enzyme inhibitor group − individuals using angiotensin-converting enzyme inhibitors (n=140); and angiotensin-II receptor blocker group- patients using angiotensin-II receptor blockers (n= 32). Exercise capacity was evaluated by a 6-minute walking test and muscle strength was measured using a handgrip dynamometer. [Results] Patients from the angiotensin-converting enzyme inhibitor group (mean: 99 ± 12%) and the angiotensin-II receptor blocker group (mean: 101 ± 14%) showed higher predicted values in the 6-minute walking test than the control group patients (mean: 96 ± 10%). Patients from the angiotensin-converting enzyme inhibitor group (mean: 105 ± 19%) and the angiotensin-II receptor blocker group (mean: 105.1 ± 18.73%) showed higher predicted values of muscle strength than control group patients (mean: 98.15 ± 18.77%). [Conclusion] Older adults using angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers have better functional exercise capacity and muscle strength. PMID:27065543

  11. Angiotensin II receptors and peritoneal dialysis-induced peritoneal fibrosis.

    PubMed

    Morinelli, Thomas A; Luttrell, Louis M; Strungs, Erik G; Ullian, Michael E

    2016-08-01

    The vasoactive hormone angiotensin II initiates its major hemodynamic effects through interaction with AT1 receptors, a member of the class of G protein-coupled receptors. Acting through its AT1R, angiotensin II regulates blood pressure and renal salt and water balance. Recent evidence points to additional pathological influences of activation of AT1R, in particular inflammation, fibrosis and atherosclerosis. The transcription factor nuclear factor κB, a key mediator in inflammation and atherosclerosis, can be activated by angiotensin II through a mechanism that may involve arrestin-dependent AT1 receptor internalization. Peritoneal dialysis is a therapeutic modality for treating patients with end-stage kidney disease. The effectiveness of peritoneal dialysis at removing waste from the circulation is compromised over time as a consequence of peritoneal dialysis-induced peritoneal fibrosis. The non-physiological dialysis solution used in peritoneal dialysis, i.e. highly concentrated, hyperosmotic glucose, acidic pH as well as large volumes infused into the peritoneal cavity, contributes to the development of fibrosis. Numerous trials have been conducted altering certain components of the peritoneal dialysis fluid in hopes of preventing or delaying the fibrotic response with limited success. We hypothesize that structural activation of AT1R by hyperosmotic peritoneal dialysis fluid activates the internalization process and subsequent signaling through the transcription factor nuclear factor κB, resulting in the generation of pro-fibrotic/pro-inflammatory mediators producing peritoneal fibrosis. PMID:27167177

  12. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system and proinflammatory cytokines in hypertension

    SciTech Connect

    Su, Qing; Qin, Da-Nian; Wang, Fu-Xin; Ren, Jun; Li, Hong-Bao; Zhang, Meng; Yang, Qing; Miao, Yu-Wang; Yu, Xiao-Jing; Qi, Jie; Zhu, Zhiming; Zhu, Guo-Qing; Kang, Yu-Ming

    2014-04-15

    Aims: To explore whether reactive oxygen species (ROS) scavenger (tempol) in the hypothalamic paraventricular nucleus (PVN) attenuates renin–angiotensin system (RAS) and proinflammatory cytokines (PICs), and decreases the blood pressure and sympathetic activity in angiotensin II (ANG II)-induced hypertension. Methods and results: Male Sprague–Dawley rats were infused intravenously with ANG II (10 ng/kg per min) or normal saline (NS) for 4 weeks. These rats were treated with bilateral PVN infusion of oxygen free radical scavenger tempol (TEMP, 20 μg/h) or vehicle (artificial cerebrospinal fluid, aCSF) for 4 weeks. ANG II infusion resulted in increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). These ANG II-infused rats also had higher levels of gp91{sup phox} (a subunit of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), and interleukin-1beta (IL-1β) in the PVN than the control animals. Treatment with PVN infusion of TEMP attenuated the overexpression of gp91{sup phox}, ACE and IL-1β within the PVN, and decreased sympathetic activity and MAP in ANG II-infused rats. Conclusion: These findings suggest that ANG II infusion induces elevated PICs and oxidative stress in the PVN, which contribute to the sympathoexcitation in hypertension. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system, proinflammatory cytokines and oxidative stress in ANG II-induced hypertension. - Highlights: • The effect of chronic inhibiting PVN superoxide on hypertension was investigated. • ANG II infusion induced increased proinflammatory cytokines and superoxide in PVN. • ANG II infusion resulted in oxidative stress, sympathoexcitation and hypertension. • Chronic inhibiting PVN superoxide attenuates RAS and cytokines in hypertension.

  13. Aliskiren inhibits the renin-angiotensin system in retinal pigment epithelium cells.

    PubMed

    Simão, Sónia; Santos, Daniela F; Silva, Gabriela A

    2016-09-20

    Observations of increased angiotensin II levels and activation of the (pro)renin receptor in retinopathies support the role of ocular renin-angiotensin system (RAS) in the development of retinal diseases. While targeting RAS presents significant therapeutic potential, current RAS-based therapies are ineffective halting the progression of these diseases. A new class of drugs, the direct renin inhibitors such as aliskiren, is a potential therapeutic alternative. However, it is unclear how aliskiren acts in the retina, in particular in the retinal pigment epithelium (RPE), the structure responsible for the maintenance of retinal homeostasis whose role is deeply compromised in retinal diseases. We firstly analyzed the expression and activity of the main RAS components in RPE cells. Time- and concentration-dependent treatments with aliskiren were performed to modulate different pathways of the RAS in RPE cells. Our data demonstrate that RPE cells express the main RAS constituents. Exposure of RPE cells to aliskiren inhibited the activity of renin and consequently decreased the levels of angiotensin II. Additionally, aliskiren reduced the translocation of the (pro)renin receptor to the cellular membrane of RPE cells preventing the activation of ERK1/2. Our findings of the RPE well-defined RAS, together with the demonstration that aliskiren effectively blocks this system at different steps of the cascade, suggest that aliskiren might be an alternative and successful drug in preventing the deleterious effects derived from the overactivation of the RAS, known to contribute to the pathogenesis of different retinal diseases. PMID:27343695

  14. Angiotensin II centrally induces frequent detrusor contractility of the bladder by acting on brain angiotensin II type 1 receptors in rats

    PubMed Central

    Kawamoto, Bunya; Shimizu, Shogo; Shimizu, Takahiro; Higashi, Youichirou; Honda, Masashi; Sejima, Takehiro; Saito, Motoaki; Takenaka, Atsushi

    2016-01-01

    Angiotensin (Ang) II plays an important role in the brain as a neurotransmitter and is involved in psychological stress reactions, for example through activation of the sympatho-adrenomedullary system. We investigated the effects of centrally administered Ang II on the micturition reflex, which is potentially affected by the sympatho-adrenomedullary system, and brain Ang II receptors in urethane-anesthetized (1.0 g/kg, intraperitoneally) male rats. Central administration of Ang II (0.01, 0.02, and 0.07 nmol per rat, intracerebroventricularly, icv) but not vehicle rapidly and dose-dependently decreased the urinary bladder intercontraction interval, without altering the bladder detrusor pressure. Central administration of antagonists of Ang II type 1 but not type 2 receptors inhibited the Ang II-induced shortening of intercontraction intervals. Administration of the highest dose of Ang II (0.07 nmol per rat, icv) but not lower doses (0.01 and 0.02 nmol per rat, icv) elevated the plasma concentration of adrenaline. Bilateral adrenalectomy reduced Ang II-induced elevation in adrenaline, but had no effect on the Ang II-induced shortening of the intercontraction interval. These data suggest that central administration of Ang II increases urinary frequency by acting on brain Ang II type 1 receptors, independent of activation of the sympatho-adrenomedullary system. PMID:26908391

  15. Angiotensin II in inflammation, immunity and rheumatoid arthritis

    PubMed Central

    Chang, Y; Wei, W

    2015-01-01

    Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that is characterized by increased cardiovascular morbidity and mortality, independent of the traditional risk factors for cardiovascular disease. Although classically known for its role in the regulation of circulatory homeostasis, angiotensin II (Ang II) is recognized to act as a powerful proinflammatory mediator. Some research has showed that Ang II plays important roles in autoimmune diseases, including RA, systemic lupus erythematosus and multiple sclerosis. Ang II blockers prove effective in reducing inflammation and autoimmunity in rheumatic diseases and their relative safety, together with their effects for reducing the cardiovascular disease risk, suggest that Ang II blockers may at least act as effective adjunctive therapy for disease control in patients with RA. The present review focuses systematically on the potential impact of Ang II and its receptors on inflammation and immunomodulation in patients with RA. PMID:25302847

  16. Apoptosis after reperfused myocardial infarction: Role of angiotensin II

    PubMed Central

    Jugdutt, Bodh I

    2004-01-01

    Angiotensin II (Ang II) plays a significant role in apoptosis after myocardial infarction (MI) and reperfused MI. Cumulative evidence suggests that Ang II is a major contributor to cardiomyocyte (CM) apoptosis and left ventricular (LV) dysfunction after acute reperfused MI and that apoptosis mediates a major portion of early LV dysfunction. Importantly, blockade of the Ang II type 1 receptor (AT1R) limits CM apoptosis and LV dysfunction after acute reperfused MI. Ang II type 2 receptor activation during AT1R blockade contributes to these beneficial effects. The role of Ang II and apoptosis in chronic LV remodelling, healing and post-MI heart failure is more complex and involves effects on the CMs, fibroblasts and vascular cells. The long-term effects of agents targeting apoptosis after reperfused MI, including AT1R blockade, on apoptosis in different cell types, windows of enhanced apoptosis and the appropriate timing of therapy need to be considered. PMID:19641712

  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. Effect of angiotensin-(1-7) and angiotensin II on the proliferation and activation of human endometrial stromal cells in vitro

    PubMed Central

    Shan, Tieying; Shang, Wei; Zhang, Lei; Zhao, Chunfang; Chen, Wei; Zhang, Yanan; Li, Guiying

    2015-01-01

    Recent studies have shown that angiotensin II (Ang II) or angiotensin-(1-7) [Ang-(1-7)] has effect on the proliferation and activation of a variety of cells, however, the exact mechanisms that the role of Ang II or Ang-(1-7) in human endometrial stromal cell (ESCs) remains elusive. Here we demonstrated that Ang II could promote proliferation and activation of ESCs, up-regulated the expression of a-SMA, TGF-β1 and IGF-I, increased the secretion of extracellular matrix [Type I collagen (Col I) and fibronectin (FN)] of ESCs; Ang-(1-7) could inhibit Ang II induced the proliferation and activation of ESCs, down-regulated the expression of a-SMA, TGF-β1 and IGF-I, decreased the secretion of extracellular matrix (Col I and FN) of ESCs. These findings suggest that Ang-(1-7) can inhibits Ang II induced the proliferation of ESCs, Ang-(1-7) can inhibits the Ang II induced activation of ESCs and decreases secretion of Col I and FN by suppressing TGF-β1 and IGF-I expression. PMID:26464636

  19. Angiotensin II prevents hypoxic pulmonary hypertension and vascular changes in rat

    SciTech Connect

    Rabinovitch, M.; Mullen, M.; Rosenberg, H.C.; Maruyama, K.; O'Brodovich, H.; Olley, P.M. )

    1988-03-01

    Angiotensin II, a vasoconstrictor, has been previously demonstrated to produce a secondary vasodilatation due to release of prostaglandins. Because of this effect, the authors investigated whether infusion of exogenous angiotensin II via miniosmopumps in rats during a 1-wk exposure to chronic hypobaric hypoxia might prevent pulmonary hypertension, right ventricular hypertrophy, and vascular changes. They instrumented the rats with indwelling cardiovascular catheters and compared the hemodynamic and structural response in animals given angiotensin II, indomethacin in addition to angiotensin II (to block prostaglandin production), or saline with or without indomethacin. They then determine whether angiotensin II infusion also prevents acute hypoxic pulmonary vasoconstriction. They observed that exogenous angiotensin II infusion abolished the rise in pulmonary artery pressure, the right ventricular hypertrophy, and the vascular changes induced during chronic hypoxia in control saline-infused rats with or without indomethacin. The protective effects of angiotensin II was lost when indomethacin was given to block prostaglandin synthesis. During acute hypoxia, both antiotensin II and prostacyclin infusion similarly prevented the rise in pulmonary artery pressure observed in saline-infused rats and in rats given indomethacin or saralasin in addition to angiotensin II. Thus exogenous angiotensin II infusion prevents chronic hypoxic pulmonary hypertension, associated right ventricular hypertrophy, and vascular changes and blocks acute hypoxic pulmonary hypertension, and this is likely related to its ability to release vasodilator prostaglandins.

  20. [Inhibition of renin-angiotensin-aldosterone system in heart failure, or from CONSENSUS to PARADIGM-HF].

    PubMed

    Vítovec, Jiří; Špinar, Jindřich; Špinarová, Lenka

    2015-05-01

    An historical survey is presented of mortality trials on angiotensin-aldosteron system inhibition in patients with chronic heart failure. From the CONSENSUS trial up to the PARADIGM-HF trial, ACE inhibitors/angiotensin II receptor antagonists (AT1-blockers, ARBs, sartans), along with mineralocorticoid receptor blockers, have been the gold standard of treatment. Both direct renin blocker aliskiren and dual blocker enalapril + neprilysin proved ineffective; on the other hand, the new dual inhibitor valsartan + neprilysin LCZ 696 is a new and promising therapeutic agent for future treatment of chronic heart failure. PMID:26075858

  1. Angiotensin II receptor blockade in normotensive subjects: A direct comparison of three AT1 receptor antagonists.

    PubMed

    Mazzolai, L; Maillard, M; Rossat, J; Nussberger, J; Brunner, H R; Burnier, M

    1999-03-01

    Use of angiotensin (Ang) II AT1 receptor antagonists for treatment of hypertension is rapidly increasing, yet direct comparisons of the relative efficacy of antagonists to block the renin-angiotensin system in humans are lacking. In this study, the Ang II receptor blockade induced by the recommended starting dose of 3 antagonists was evaluated in normotensive subjects in a double-blind, placebo-controlled, randomized, 4-way crossover study. At 1-week intervals, 12 subjects received a single dose of losartan (50 mg), valsartan (80 mg), irbesartan (150 mg), or placebo. Blockade of the renin-angiotensin system was assessed before and 4, 24, and 30 hours after drug intake by 3 independent methods: inhibition of the blood pressure response to exogenous Ang II, in vitro Ang II receptor assay, and reactive changes in plasma Ang II levels. At 4 hours, losartan blocked 43% of the Ang II-induced systolic blood pressure increase; valsartan, 51%; and irbesartan, 88% (P<0.01 between drugs). The effect of each drug declined with time. At 24 hours, a residual effect was found with all 3 drugs, but at 30 hours, only irbesartan induced a marked, significant blockade versus placebo. Similar results were obtained when Ang II receptor blockade was assessed with an in vitro receptor assay and by the reactive rise in plasma Ang II levels. This study thus demonstrates that the first administration of the recommended starting dose of irbesartan induces a greater and longer lasting Ang II receptor blockade than that of valsartan and losartan in normotensive subjects. PMID:10082498

  2. 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.

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

    PubMed

    Sheppard, Richard J; Schiffrin, Ernesto L

    2013-04-01

    The renin-angiotensin system when activated exerts proliferative and pro-inflammatory actions and thereby contributes to progression of atherosclerosis, including that occurring in the coronary arteries. It thus contributes as well to coronary artery disease (CAD). Several clinical trials have examined effects of renin-angiotensin system inhibition for primary and secondary prevention of coronary heart disease. These include important trials such as HOPE, EUROPA and PEACE using angiotensin converting enzyme inhibitors, VALIANT, OPTIMAAL and TRANSCEND using angiotensin receptor blockers, and the ongoing TOPCAT study in patients with preserved ejection fraction heart failure, many of who also have coronary artery disease. Data are unavailable as yet of effects of either direct renin inhibitors or the new angiotensin receptor/neprilysin inhibitor agents. Today, inhibition of the renin-angiotensin system is standard-of-care therapy for lowering cardiovascular risk in secondary prevention in high cardiovascular risk subjects. PMID:23523606

  4. Telmisartan Induced Inhibition of Vascular Cell Proliferation beyond Angiotensin Receptor Blockade and PPARγ Activation

    PubMed Central

    Yamamoto, Koichi; Ohishi, Mitsuru; Ho, Christopher; Kurtz, Theodore W; Rakugi, Hiromi

    2010-01-01

    We investigated the ability of ARBs with PPARγ agonist activity (telmisartan and irbesartan), and ARBs devoid of PPARγ agonist activity (eprosartan and valsartan), to inhibit vascular cell proliferation studied in the absence of angiotensin II stimulation. Telmisartan and to a lesser extent irbesartan, inhibited proliferation of human aortic vascular smooth muscle cells in a dose dependent fashion whereas eprosartan and valsartan did not. To investigate the role of PPARγ in the antiproliferative effects of telmisartan, we studied genetically engineered NIH3T3 cells that express PPARγ. Pioglitazone inhibited proliferation of NIH3T3 cells expressing PPARγ, but had little effect on control NIH3T3 cells that lack PPARγ. In contrast, telmisartan inhibited proliferation equally in NIH3T3 with and without PPARγ. Valsartan failed to inhibit proliferation of either cell line. In addition, telmisartan inhibited proliferation equally in aortic smooth muscle cells derived from mice with targeted knockout of PPARγ in smooth muscle and from control mice whereas valsartan had no effect on cell proliferation. Telmisartan but not valsartan, reduced phosphorylation of AKT but not ERK otherwise induced by exposure to serum of either quiescent human smooth muscle cells, quiescent mice smooth muscle cells lacking PPARγ or quiescent CHO-K1 cells lacking AT1 receptor. In summary, the antiproliferative effect of telmisartan in the absence of exogenously supplemented angiotensin II involve more than just AT1 receptor blockade and do not require activation of PPARγ. It might be postulated that inhibition of AKT activation is a mechanism mediating the antiproliferative effects of telmisartan including in cells lacking AT1 receptors or PPARγ. PMID:19822796

  5. Angiopoietin-like protein 2 expression is suppressed by angiotensin II via the angiotensin II type 1 receptor in rat cardiomyocytes.

    PubMed

    Wang, Shuya; Li, Ying; Miao, Wei; Zhao, Hong; Zhang, Feng; Liu, Nan; Su, Guohai; Cai, Xiaojun

    2016-09-01

    The present study aimed to determine the inhibitory effects of angiotensin II (AngII) on angiopoietin‑like protein 2 (Angptl2) in rat primary cardiomyocytes, and to investigate the potential association between angiotensin II type 1 receptor (AT1R) and these effects. Cardiomyocytes were isolated from 3-day-old Wistar rats, and were cultured and identified. Subsequently, the expression levels of Angptl2 were detected following incubation with various concentrations of AngII for various durations using western blotting, reverse transcription‑quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescence. Finally, under the most appropriate conditions (100 nmol/l AngII, 24 h), the cardiomyocytes were divided into six groups: Normal, AngII, AngII + losartan, normal + losartan, AngII + PD123319 and normal + PD123319 groups, in order to investigate the possible function of AT1R in Angptl2 suppression. Losartan and PD123319 are antagonists of AT1R and angiotensin II type 2 receptor, respectively. The statistical significance of the results was analyzed using Student's t‑test or one‑way analysis of variance. The results demonstrated that Angptl2 expression was evidently suppressed (P<0.05) following incubation with 100 nmol/l AngII for 24 h. Conversely, the expression levels of Angptl2 were significantly increased in the AngII + losartan group compared with the AngII group (P<0.01). However, no significant difference was detected between the AngII + PD123319, normal + losartan or normal + PD123319 groups and the normal group. The present in vitro study indicated that AngII was able to suppress Angptl2 expression, whereas losartan was able to significantly reverse this decrease by inhibiting AT1R. PMID:27483989

  6. Improving vagal activity ameliorates cardiac fibrosis induced by angiotensin II: in vivo and in vitro

    PubMed Central

    Liu, Jin-Jun; Huang, Ning; Lu, Yi; Zhao, Mei; Yu, Xiao-Jiang; Yang, Yang; Yang, Yong-hua; Zang, Wei-Jin

    2015-01-01

    Cardiac remodeling is characterized by overactivity of the renin–angiotensin system (RAS) and withdrawal of vagal activity. We hypothesized that improving vagal activity could attenuate cardiac fibrosis induced by angiotensin II (Ang II) in vivo and in vitro. Rats were subjected to abdominal aorta constriction (AAC) with or without pyridostigmine (PYR) (31 mg/kg/d). After 8 weeks, PYR significantly decreased Ang II level, AT1 protein expression, and collagen deposition in cardiac tissue and improved heart rate variability, baroreflex sensitivity and cardiac function, which were abolished by atropine. In vitro, treatment of cardiac fibroblasts (CFs) with Ang II (10−7 M) increased cell proliferation, migration, transformation, and secretory properties, which were significantly diminished by acetylcholine (ACh, 10−6 M). Subsequently, Ang II significantly increased collagen type I expression as well as metalloproteinase (MMP)-2 expression and activity. Transforming growth factor (TGF)-β1 expression and Smad3 phosphorylation presented a similar trend. Notably, the knockdown of the acetylcholine M2 receptor by siRNA could abolish ACh anti-fibrotic action. These data implicated cholinesterase inhibitor can increase vagal activity and reduce local Ang II level, and ACh inhibit Ang II pro-fibrotic effects. Our findings suggested that the parasympathetic nervous system can serve as a promising target for cardiac remodeling treatment. PMID:26596640

  7. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels

    PubMed Central

    Chauhan, Vikash P.; Martin, John D.; Liu, Hao; Lacorre, Delphine A.; Jain, Saloni R.; Kozin, Sergey V.; Stylianopoulos, Triantafyllos; Mousa, Ahmed S.; Han, Xiaoxing; Adstamongkonkul, Pichet; Popović, Zoran; Huang, Peigen; Bawendi, Moungi G.; Boucher, Yves; Jain, Rakesh K.

    2013-01-01

    Cancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because of its swelling behaviour. Here we show, unexpectedly, that hyaluronan compresses vessels only in collagen-rich tumours, suggesting that collagen and hyaluronan together are critical targets for decompressing tumour vessels. We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-β1, CCN2 and ET-1, downstream of angiotensin-II-receptor-1 inhibition. Consequently, losartan reduces solid stress in tumours resulting in increased vascular perfusion. Through this physical mechanism, losartan improves drug and oxygen delivery to tumours, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Thus, angiotensin inhibitors —inexpensive drugs with decades of safe use — could be rapidly repurposed as cancer therapeutics. PMID:24084631

  8. 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

  9. Angiotensin II revisited: new roles in inflammation, immunology and aging

    PubMed Central

    Benigni, Ariela; Cassis, Paola; Remuzzi, Giuseppe

    2010-01-01

    That the renin–angiotensin system (RAS) is involved in regulation of blood pressure, vasoconstriction, sodium intake and potassium excretion is well established. Studies in the last few years have however documented new roles for this molecule as a pro-inflammatory molecule and more recently as a possible pro-fibrotic agent that contributes to progressive deterioration of organ function in disease. Binding of Ang II to its receptors (in particular AT1) mediates intracellular free radical generation that contributes to tissue damage by promoting mitochondrial dysfunction. Blocking Ang II signalling protects against neurodegenerative processes and promotes longevity in rodents. Altogether these findings open the unanticipated perspective for exploring Ang II signalling in therapeutic interventions in inflammatory diseases and aging-related tissue injury. This review extends from the discovery of Ang II and its implications in renal and cardiovascular physiology to cover the roles of the system in inflammation, tissue injury, autoimmunity, oxidative stress and aging. PMID:20597104

  10. 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. PMID:26781276

  11. Inhibition of tissue angiotensin converting enzyme. Quantitation by autoradiography

    SciTech Connect

    Sakaguchi, K.; Chai, S.Y.; Jackson, B.; Johnston, C.I.; Mendelsohn, F.A.

    1988-03-01

    Inhibition of angiotensin converting enzyme (ACE) in serum and tissues of rats was studied after administration of lisinopril, an ACE inhibitor. Tissue ACE was assessed by quantitative in vitro autoradiography using the ACE inhibitor (/sup 125/I)351A, as a ligand, and serum ACE was measured by a fluorimetric method. Following oral administration of lisinopril (10 mg/kg), serum ACE activity was acutely reduced but recovered gradually over 24 hours. Four hours after lisinopril administration, ACE activity was markedly inhibited in kidney (11% of control level), adrenal (8%), duodenum (8%), and lung (33%; p less than 0.05). In contrast, ACE in testis was little altered by lisinopril (96%). In brain, ACE activity was markedly reduced 4 hours after lisinopril administration in the circumventricular organs, including the subfornical organ (16-22%) and organum vasculosum of the lamina terminalis (7%; p less than 0.05). In other areas of the brain, including the choroid plexus and caudate putamen, ACE activity was unchanged. Twenty-four hours after administration, ACE activity in peripheral tissues and the circumventricular organs of the brain had only partially recovered toward control levels, as it was still below 50% of control activity levels. These results establish that lisinopril has differential effects on inhibiting ACE in different tissues and suggest that the prolonged tissue ACE inhibition after a single oral dose of lisinopril may reflect targets involved in the hypotensive action of ACE inhibitors.

  12. [Effect of safflor yellow B on vascular endothelial cells injury induced by angiotensin-II].

    PubMed

    Wang, Chao-Yun; Zhang, Shu-Ping; Xu, Yong; Yang, Ming; Jiang, Wen-Guo; Luan, Hai-Yun

    2012-06-01

    This study is to investigate protective effect of safflor yellow B (SYB) against vascular endothelial cells (VECs) injury induced by angiotensin-II (Ang-II). VECs were cultured and divided into six groups: control group, Ang-II group, Ang-II + SYB (1 micromolL(-1)) group, Ang-II + SYB (10 micromolL(-1)) group, Ang-II + SYB (100 micromolL(-1)) group and Ang- II + verapamil (10 micromolL(-1)) group. Except control group, all of VECs in other groups were treated with Ang- II at the final concentration of 0.1 micromolL(-1). Mitochondria membrane potential (MMP) and free calcium concentration ([Ca2+]i) were measured by laser scanning confocal microscopy, and mitochondria complex IV activity was detected by BCA method. The levels of reactive oxygen species (ROS) in VECs were analyzed by fluorescence detector and apoptosis of VECs was observed by flow cytometer. Caspase 3 was determined by Western blotting method. Comparing with control group, Ang-II was able to increase [Ca2+]i and ROS level, decrease MMP level, inhibit complex IV activity and enhance caspase 3 activity in VECs, as a result, enhance apoptosis of VECs. But SYB could significantly reduce the result induced by Ang- II relying on different dosages (P < 0.05 or P < 0.01). SYB was able to eliminate the effect of Ang-II on VECs via regulating [Ca2+]i, mitochondrial structure and function and inhibiting apoptosis. PMID:22919732

  13. Histone-deacetylase Inhibition Reverses Atrial Arrhythmia Inducibility and Fibrosis in Cardiac Hypertrophy Independent of Angiotensin

    PubMed Central

    Liu, Fang; Levin, Mark D.; Petrenko, Nataliya B.; Lu, Min Min; Wang, Tao; Yuan, Li Jun; Stout, Andrea L.; Epstein, Jonathan A.; Patel, Vickas V.

    2008-01-01

    Atrial fibrosis influences the development of atrial fibrillation (AF), particularly in the setting of structural heart disease where angiotensin-inhibition is partially effective for reducing atrial fibrosis and AF. Histone-deacetylase inhibition reduces cardiac hypertrophy and fibrosis, so we sought to determine if the HDAC inhibitor trichostatin A (TSA) could reduce atrial fibrosis and arrhythmias. Mice over-expressing homeodomain-only protein (HopXTg), which recruits HDAC activity to induce cardiac hypertrophy were investigated in 4 groups (aged 14-18 weeks): wild-type (WT), HopXTg, HopXTg mice treated with TSA for 2 weeks (HopX-TSA) and wild-type mice treated with TSA for 2 weeks (WT-TSA). These groups were characterized using invasive electrophysiology, atrial fibrosis measurements, atrial connexin immunocytochemistry and myocardial angiotensin II measurements. Invasive electrophysiologic stimulation, using the same attempts in each group, induced more atrial arrhythmias in HopXTg mice (48 episodes in 13 of 15 HopXTg mice versus 5 episodes in 2 of 15 HopX-TSA mice, P<0.001; versus 9 episodes in 2 of 15 WT mice, P<0.001; versus no episodes in any WT-TSA mice, P<0.001). TSA reduced atrial arrhythmia duration in HopXTg mice (1307±289 milliseconds versus 148±110 milliseconds, P<0.01) and atrial fibrosis (8.1±1.5% versus 3.9±0.4%, P<0.001). Atrial connexin40 was lower in HopXTg compared to WT mice, and TSA normalized the expression and size distribution of connexin40 gap junctions. Myocardial angiotensin II levels were similar between WT and HopXTg mice (76.3±26.0 versus 69.7±16.6 pg/mg protein, P=NS). Therefore, it appears HDAC inhibition reverses atrial fibrosis, connexin40 remodeling and atrial arrhythmia vulnerability independent of angiotensin II in cardiac hypertrophy. PMID:18926829

  14. Role of angiotensin II in renal wrap hypertension.

    PubMed

    Denton, K M; Anderson, W P

    1985-01-01

    The role of angiotensin II in the development of renal wrap hypertension was studied in rabbits that underwent either bilateral renal cellophane wrap or sham operation. In half the rabbits, angiotensin II production was blocked by continuous administration of enalapril. Four weeks after renal wrapping, mean arterial pressure had risen by 48 +/- 5 mm Hg in untreated rabbits, but by only 25 +/- 4 mm Hg in enalapril-treated rabbits (p less than 0.01). Similar differences were also measured 6 weeks after wrapping. In untreated rabbits, plasma renin activity had increased fourfold 4 and 6 weeks after renal wrapping. There were no significant changes in blood pressure or plasma renin activity following sham operation. Compared with that in sham-operated rabbits, renal blood flow was reduced by 60% in the untreated rabbits 4 weeks after wrapping but by only 30% in the enalapril-treated wrapped rabbits (p less than 0.05). Renal vascular resistances were 5.5 +/- 1.7 mm Hg . ml-1 . min-1 and 1.2 +/- 0.1 mm Hg . min . ml-1 in the untreated wrapped and sham-operated rabbits respectively and 1.9 +/- 0.4 mm Hg . min . ml-1 and 0.8 +/- 1 mm Hg . min . ml-1 in the enalapril-treated wrapped and sham-operated rabbits. Renal wrapping did not alter filtration fraction in untreated rabbits, but markedly reduced it in enalapril-treated rabbits. These results suggest that angiotensin II had two major effects in rabbits after bilateral renal wrapping: it contributed substantially to the increase in blood pressure and caused renal vasoconstriction, primarily at a postglomerular site. PMID:3000937

  15. A Study of Angiotensin II Pressor Response throughout Primigravid Pregnancy

    PubMed Central

    Gant, Norman F.; Daley, Gilroy L.; Chand, Santosh; Whalley, Peggy J.; MacDonald, Paul C.

    1973-01-01

    The present study was designed to ascertain sequentially the pressor response to angiotensin II in young primigravid patients throughout pregnancy in order a) to define when in pregnancy resistance to the pressor effects of angiotensin II develops; b) to define the physiologic sequence of events leading to this resistance; and c) to ascertain whether sensitivity to infused angiotensin II could be detected before the onset of clinical signs of pregnancy-induced hypertension. With this prospective approach, two separate groups of patients were defined. The first group of patients remained normal throughout pregnancy. The second group consisted of those patients who, while clinically normotensive during the initial phase of the study, ultimately developed hypertension of pregnancy. 192 patients were studied; of these, 120 patients remained normotensive and 72 developed pregnancy-induced hypertension. In both groups, vascular resistance to infused angiotensin II (more than 8 ng/kg/min required to elicit a pressor response of 20 mm Hg in diastolic pressure) was demonstrated as early as the 10th wk of pregnancy. In the group that remained normotensive, maximum mean vascular resistance occurred at 18-30 wk of pregnancy, (mean pressor dose required being 13.5 to 14.9 ng/kg/min). In those subjects who developed pregnancy-induced hypertension, the mean maximum dose required was 12.9 ng/kg/min, which was observed at the 18th wk of pregnancy. By the 22nd wk there was a clear separation of the two groups, with the mean dose requirement of the subjects destined to develop hypertension being progressively less than that of those who remained normal. The difference between the two groups became significant (P < 0.01) by 23-26 wk of pregnancy. Among patients requiring more than 8 ng/kg/min on one or more tests done between wk 28-32, 91% remained normotensive. Conversely, during the same time period among patients requiring less than 8 ng/kg/min, on at least one occasion, 90

  16. Angiotensin II and Oxidative Stress in the Failing Heart

    PubMed Central

    Zablocki, Daniela

    2013-01-01

    Abstract Significance: Despite recent medical advances, cardiovascular disease and heart failure (HF) continue to be major health concerns, and related mortality remains high. As a result, investigation of the mechanisms involved in the development of HF continues to be an active field of study. Recent Advances: The renin–angiotensin system (RAS) and its effector molecule, angiotensin (Ang) II, affect cardiac function through both systemic and local actions, and have been shown to play a major role in cardiac remodeling and dysfunction in the failing heart. Many of the downstream effects of AngII signaling are mediated by elevated levels of reactive oxygen species (ROS) and oxidative stress, which have also been implicated in the pathology of HF. Critical Issues: Inhibitors of the RAS have proven beneficial in the treatment of patients at risk for and suffering from HF, but remain only partially effective. ROS can be generated from several different sources, and the oxidative state is normally tightly regulated in the heart. How AngII increases ROS levels and causes dysregulation of the cardiac oxidative state has been the subject of considerable interest in recent years. Future Directions: A better understanding of this process and the mechanisms involved should lead to the development of more effective HF therapies and improved outcomes. Antioxid. Redox Signal. 19, 1095–1109. PMID:22429089

  17. Angiotensin II stimulates melanogenesis via the protein kinase C pathway

    PubMed Central

    LIU, LI-HONG; FAN, XIN; XIA, ZHI-KUAN; AN, XU-XI; YANG, RONG-YA

    2015-01-01

    Melanogenesis is a physiological process that results in the synthesis of melanin pigments, which serve a crucial function in hyperpigmentation. The aim of the present study was to determine the effects of angiotensin II (Ang II) on melanogenesis and to elucidate the molecular events of Ang II-induced melanogenesis. Experiments were performed on human melanocytes to elucidate the pigmenting effect of Ang II and the underlying mechanisms. The elements involved in melanogenesis, including melanin content, tyrosinase (TYR) activity, and microphthalmia-associated transcription factor (MITF) and TYR expression at the mRNA and protein levels were evaluated. Melanin content and TYR activity increased in response to Ang II treatment in a concentration-dependent manner. MITF and TYR mRNA and protein expression levels were increased significantly in response to Ang II in a concentration-dependent manner. The Ang II-induced increase in melanin synthesis was reduced significantly in response to co-treatment with Ro-32-0432, a protein kinase C (PKC) inhibitor, whereas co-treatment with H-89, a PKA inhibitor, did not attenuate the Ang II-induced increase in melanin levels. These results suggest that PKC is required for Ang II-induced pigmentation in human melanocytes and that the mechanism involves the PKC pathway and MITF upregulation. PMID:26622519

  18. Csk regulates angiotensin II-induced podocyte apoptosis.

    PubMed

    Zhang, Lu; Ren, Zhilong; Yang, Qian; Ding, Guohua

    2016-07-01

    Increasing data have shown that angiotensin II (Ang II) perpetuates podocyte injury and promotes progression to end-stage kidney disease. The mechanism underlying Ang II-induced podocyte apoptosis has not been established. C-terminal Src kinase (Csk) is a cytoplasmic kinase that interacts with scaffolding proteins involved in cell growth, adhesion, and polarization, and the role of Csk in regulating cellular apoptosis has gradually attracted attention. This study evaluates the role of Csk in Ang II-induced podocyte apoptosis. In vivo, Wistar rats were randomly subjected to a normal saline or Ang II infusion. In vitro, we exposed differentiated mouse podocytes to Ang II. Ang II increased Csk expression and induced podocyte apoptosis, stimulated Csk translocation and binding to Caveolin-1, and stimulated decreased Fyn pY416, increased Fyn pY529, and nephrin dephosphorylation. Csk knockdown prevented Ang II-induced podocyte apoptosis, reduced Fyn kinase inactivation, and increased the interaction between nephrin and the activated form of Fyn, accompanied by a reduced interaction between Csk and Caveolin-1. These findings indicate that Ang II induces podocyte injury via a Csk-dependent pathway. PMID:27225249

  19. 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.

  20. Dual renin-angiotensin system inhibition for prevention of renal and cardiovascular events: do the latest trials challenge existing evidence?

    PubMed Central

    2013-01-01

    Circulatory and tissue renin-angiotensin systems (RAS) play a central role in cardiovascular (CV) and renal pathophysiology, making RAS inhibition a logical therapeutic approach in the prevention of CV and renal disease in patients with hypertension. The cardio- and renoprotective effects observed with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) monotherapy, together with the availability of a direct renin inhibitor (DRI), led to the investigation of the potential benefits of dual RAS inhibition. In small studies, ARB and ACE inhibitor combinations were shown to be beneficial in patients with CV or renal disease, with improvement in surrogate markers. However, in larger outcome trials, involving combinations of ACE inhibitors, ARBs or DRIs, dual RAS inhibition did not show reduction in mortality in patients with diabetes, heart failure, coronary heart disease or after myocardial infarction, and was in fact, associated with increased harm. A recent meta-analysis of all major trials conducted over the past 22 years involving dual RAS inhibition has clearly shown that the risk-benefit ratio argues against the use of dual RAS inhibition. Hence, the recent evidence clearly advocates against the use of dual RAS inhibition, and single RAS inhibition appears to be the most suitable approach to controlling blood pressure and improving patient outcomes. PMID:23866091

  1. [Polyamines antagonizing angiotensin II contractile effects in isolated rat aorta].

    PubMed

    Costuleanu, Natalia; Foia, Liliana; Slătineanu, Simona Mihaela; Indrei, L L; Costuleanu, M; Petrescu, Gh

    2003-01-01

    Our study showed that the administration in pre-treatment of some polyamines (especially spermine and spermidine and almost null agmatine, putrescine and cadaverine) reduced the contractile effects of angiotensin II (Ang II) in isolated rat aorta. These effects might not be associated to the interference of clathrin coated vesicles (coated pits) formation or caveolae interaction (and thus to Ang II internalization through AT1 receptors). In contrast, these effects seem to be due to the interaction with voltage-gated membrane Ca2+ channels. Therefore, the alteration of transmembrane Ca2+ fluxes does not exclude the involvement of internalization process through coated pits or caveolae, since the endocytosis mediated by these phenomena essentially needs Ca2+. In addition, the inhibitory effects are dependent on the number of positive charges of the polyamine molecules. PMID:14755941

  2. Effect of boldine, secoboldine, and boldine methine on angiotensin II-induced neutrophil recruitment in vivo.

    PubMed

    Estellés, Rossana; Milian, Lara; Nabah, Yafa Naim Abu; Mateo, Teresa; Cerdá-Nicolás, Miguel; Losada, Mercedes; Ivorra, María Dolores; Issekutz, Andrew C; Cortijo, Julio; Morcillo, Esteban J; Blázquez, María Amparo; Sanz, María-Jesús

    2005-09-01

    Angiotensin-II (Ang-II) has inflammatory activity and is involved in different diseases associated with the cardiovascular system. This study has evaluated the effect of boldine (B), and two phenanthrene alkaloids semisynthesized by us, secoboldine (SB) and boldine methine (BM), on Ang-II-induced neutrophil recruitment. Intraperitoneal administration of 1 nM Ang-II induced significant neutrophil accumulation, which was maximal at 4-8 h. BM inhibited neutrophil infiltration into the peritoneal cavity at 4 h and 8 h by 73% and 77%, respectively, SB at 8 h by 55%, and B had no effect on this response. Although BM inhibited the release of cytokine-inducible neutrophil chemoattractant/keratinocyte-derived chemokine, macrophage inflammatory protein-2 (MIP-2), and platelet-activating factor (PAF) elicited by Ang-II, SB only reduced the release of MIP-2 after 4 h of its administration. Sixty-minute superfusion of the rat mesentery with 1 nM Ang-II induced a significant increase in the leukocyte-endothelial cell interactions and P-selectin up-regulation, which were inhibited by 1 microM BM and SB. The generation of reactive oxygen species (ROS) in endothelial cells stimulated with Ang-II was inhibited significantly by the three alkaloids tested. BM also diminished Ang-II-induced interleukin-8 release from endothelial cells and blocked the PAF receptor on human neutrophils (concentration of the compound needed to produce 50% inhibition value: 28.2 microM). Therefore, BM is a potent inhibitor of Ang-II-induced neutrophil accumulation in vivo. This effect appears to be mediated through inhibition of CXC chemokine and PAF release, ROS scavenging activity, and blockade of the PAF receptor. Thus, it may have potential therapeutic interest for the control of neutrophil recruitment that occurs in inflammation associated with elevated levels of Ang-II. PMID:15944212

  3. Angiotensin II Stimulates Sympathetic Neurotransmission to Adipose Tissue.

    PubMed

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

    2013-08-01

    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 [(3)H]nisoxetine (NIS). At doses that lowered body weight, AngII significantly increased ISBAT [(3)H]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

  4. Cardiac steatosis potentiates angiotensin II effects in the heart.

    PubMed

    Glenn, Denis J; Cardema, Michelle C; Ni, Wei; Zhang, Yan; Yeghiazarians, Yerem; Grapov, Dmitry; Fiehn, Oliver; Gardner, David G

    2015-02-15

    Lipid accumulation in the heart is associated with obesity and diabetes and may play an important role in the pathogenesis of heart failure. The renin-angiotensin system is also thought to contribute to cardiovascular morbidity in obese and diabetic patients. We hypothesized that the presence of lipid within the myocyte might potentiate the cardiomyopathic effects of ANG II in the cardiac diacylglycerol acyl transferase 1 (DGAT1) transgenic mouse model of myocyte steatosis. Treatment with ANG II resulted in a similar increase in blood pressure in both nontransgenic and DGAT1 transgenic mice. However, ANG II in DGAT1 transgenic mice resulted in a marked increase in interstitial fibrosis and a reduction in systolic function compared with nontransgenic littermates. Lipidomic analysis revealed that >20% of lipid species were significantly altered between nontransgenic and DGAT1 transgenic animals, whereas 3% were responsive to ANG II administration. ROS were also increased by ANG II in DGAT1 transgenic hearts. ANG II treatment resulted in increased expression of transforming growth factor (TGF)-β2 and the type I TGF-β receptor as well as increased phosphorylation of Smad2 in DGAT1 transgenic hearts. Injection of neutralizing antibodies to TGF-β resulted in a reduction in fibrosis in DGAT1 transgenic hearts treated with ANG II. These results suggest that myocyte steatosis amplifies the fibrotic effects of ANG II through mechanisms that involve activation of TGF-β signaling and increased production of ROS. PMID:25485904

  5. Angiotensin II Contributes to Diabetic Renal Dysfunction in Rodents and Humans via Notch1/Snail Pathway

    PubMed Central

    Gagliardini, Elena; Perico, Norberto; Rizzo, Paola; Buelli, Simona; Longaretti, Lorena; Perico, Luca; Tomasoni, Susanna; Zoja, Carla; Macconi, Daniela; Morigi, Marina; Remuzzi, Giuseppe; Benigni, Ariela

    2014-01-01

    In nondiabetic rat models of renal disease, angiotensin II (Ang II) perpetuates podocyte injury and promotes progression to end-stage kidney disease. Herein, we wanted to explore the role of Ang II in diabetic nephropathy by a translational approach spanning from in vitro to in vivo rat and human studies, and to dissect the intracellular pathways involved. In isolated perfused rat kidneys and in cultured human podocytes, Ang II down-regulated nephrin expression via Notch1 activation and nuclear translocation of Snail. Hairy enhancer of split-1 was a Notch1-downstream gene effector that activated Snail in cultured podocytes. In vitro changes of the Snail/nephrin axis were similar to those in renal biopsy specimens of Zucker diabetic fatty rats and patients with advanced diabetic nephropathy, and were normalized by pharmacological inhibition of the renin-angiotensin system. Collectively, the present studies provide evidence that Ang II plays a relevant role in perpetuating glomerular injury in experimental and human diabetic nephropathy via persistent activation of Notch1 and Snail signaling in podocytes, eventually resulting in down-regulation of nephrin expression, the integrity of which is crucial for the glomerular filtration barrier. PMID:23707238

  6. 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.

  7. Cytoplasmic translocation of HuR contributes to angiotensin II induced cardiac fibrosis.

    PubMed

    Bai, Danna; Ge, Lan; Gao, Yan; Lu, Xiaozhao; Wang, Haichang; Yang, Guodong

    2015-08-01

    Cardiac fibrosis is one of the key structural changes of the hypertrophied left ventricle in hypertensive heart disease. Increased angiotensin II was found to be important in the hypertension related fibrosis, while the underlying mechanism is unknown. In this study, we found that angiotensin II dose-dependently increased the expression of Col1a1, Col3a1 and α-smooth muscle actin, which were blocked by ROS (reactive oxygen species) scavenger N-acetyl cysteine (NAC). Mechanistically, angiotensin II induced robust ROS generation, which in turn induced cytoplasmic translocation of RNA binding protein HuR. Cytoplasmic translocated HuR increased TGFβ pathway activity and subsequent collagen synthesis. In contrast, knockdown of HuR nearly blocked angiotensin II induced TGFβ activation and collagen synthesis. Taken together, we here identified that angiotensin II promotes collagen synthesis in cardiac fibroblast through ROS-HuR-TGFβ pathway. PMID:26093296

  8. 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.

  9. 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

  10. Nitric oxide up-regulates endothelial expression of angiotensin II type 2 receptors.

    PubMed

    Dao, Vu Thao-Vi; Medini, Sawsan; Bisha, Marion; Balz, Vera; Suvorava, Tatsiana; Bas, Murat; Kojda, Georg

    2016-07-15

    Increasing vascular NO levels following up-regulation of endothelial nitric oxide synthase (eNOS) is considered beneficial in cardiovascular disease. Whether such beneficial effects exerted by increased NO-levels include the vascular renin-angiotensin system remains elucidated. Exposure of endothelial cells originated from porcine aorta, mouse brain and human umbilical veins to different NO-donors showed that expression of the angiotensin-II-type-2-receptor (AT2) mRNA and protein is up-regulated by activation of soluble guanylyl cyclase, protein kinase G and p38 mitogen-activated protein kinase without changing AT2 mRNA stability. In mice, endothelial-specific overexpression of eNOS stimulated, while chronic treatment with the NOS-blocker l-nitroarginine inhibited AT2 expression. The NO-induced AT2 up-regulation was associated with a profound inhibition of angiotensin-converting enzyme (ACE)-activity. In endothelial cells this reduction of ACE-activity was reversed by either the AT2 antagonist PD 123119 or by inhibition of transcription with actinomycin D. Furthermore, in C57Bl/6 mice an acute i.v. bolus of l-nitroarginine did not change AT2-expression and ACE-activity suggesting that inhibition of ACE-activity by endogenous NO is crucially dependent on AT2 protein level. Likewise, three weeks of either voluntary or forced exercise training increased AT2 expression and reduced ACE-activity in C57Bl/6 but not in mice lacking eNOS suggesting significance of this signaling interaction for vascular physiology. Finally, aortic AT2 expression is about 5 times greater in female as compared to male C57Bl/6 and at the same time aortic ACE activity is reduced in females by more than 50%. Together these findings imply that endothelial NO regulates AT2 expression and that AT2 may regulate ACE-activity. PMID:27235748

  11. Angiotensin II activates different calcium signaling pathways in adipocytes.

    PubMed

    Dolgacheva, Lyudmila P; Turovskaya, Maria V; Dynnik, Vladimir V; Zinchenko, Valery P; Goncharov, Nikolay V; Davletov, Bazbek; Turovsky, Egor A

    2016-03-01

    Angiotensin II (Ang II) is an important mammalian neurohormone involved in reninangiotensin system. Ang II is produced both constitutively and locally by RAS systems, including white fat adipocytes. The influence of Ang II on adipocytes is complex, affecting different systems of signal transduction from early Са(2+) responses to cell proliferation and differentiation, triglyceride accumulation, expression of adipokine-encoding genes and adipokine secretion. It is known that white fat adipocytes express all RAS components and Ang II receptors (АТ1 and АТ2). The current work was carried out with the primary white adipocytes culture, and Са(2+) signaling pathways activated by Ang II were investigated using fluorescent microscopy. Са(2+)-oscillations and transient responses of differentiated adipocytes to Ang II were registered in cells with both small and multiple lipid inclusions. Using inhibitory analysis and selective antagonists, we now show that Ang II initiates periodic Са(2+)-oscillations and transient responses by activating АТ1 and АТ2 receptors and involving branched signaling cascades: 1) Ang II → Gq → PLC → IP3 → IP3Rs → Ca(2+) 2) Gβγ → PI3Kγ → PKB 3) PKB → eNOS → NO → PKG 4) CD38 → cADPR → RyRs → Ca(2+) In these cascades, AT1 receptors play the leading role. The results of the present work open a perspective of using Ang II for correction of signal resistance of adipocytes often observed during obesity and type 2 diabetes. PMID:26850364

  12. Renovascular remodeling and renal injury after extended angiotensin II infusion.

    PubMed

    Casare, Fernando Augusto Malavazzi; Thieme, Karina; Costa-Pessoa, Juliana Martins; Rossoni, Luciana Venturini; Couto, Gisele Kruger; Fernandes, Fernanda Barrinha; Casarini, Dulce Elena; Oliveira-Souza, Maria

    2016-06-01

    Chronic angiotensin II (ANG II) infusion for 1 or 2 wk leads to progressive hypertension and induces inward hypertrophic remodeling in preglomerular vessels, which is associated with increased renal vascular resistance (RVR) and decreased glomerular perfusion. Considering the ability of preglomerular vessels to exhibit adaptive responses, the present study was performed to evaluate glomerular perfusion and renal function after 6 wk of ANG II infusion. To address this study, male Wistar rats were submitted to sham surgery (control) or osmotic minipump insertion (ANG II 200 ng·kg(-1)·min(-1), 42 days). A group of animals was treated or cotreated with losartan (10 mg·kg(-1)·day(-1)), an AT1 receptor antagonist, between days 28 and 42 Chronic ANG II infusion increased systolic blood pressure to 185 ± 4 compared with 108 ± 2 mmHg in control rats. Concomitantly, ANG II-induced hypertension increased intrarenal ANG II level and consequently, preglomerular and glomerular injury. Under this condition, ANG II enhanced the total renal plasma flow (RPF), glomerular filtration rate (GFR), urine flow and induced pressure natriuresis. These changes were accompanied by lower RVR and enlargement of the lumen of interlobular arteries and afferent arterioles, consistent with impairment of renal autoregulatory capability and outward preglomerular remodeling. The glomerular injury culminated with podocyte effacement, albuminuria, tubulointerstitial macrophage infiltration and intrarenal extracellular matrix accumulation. Losartan attenuated most of the effects of ANG II. Our findings provide new information regarding the contribution of ANG II infusion over 2 wk to renal hemodynamics and function via the AT1 receptor. PMID:26962104

  13. Mechanism of pulmonary conversion of angiotensin I to angiotensin II in the dog.

    NASA Technical Reports Server (NTRS)

    Oparil, S.; Tregear, G. W.; Koerner, T.; Barnes, B. A.; Haber, E.

    1971-01-01

    The conversion mechanism was studied in vivo in the pulmonary circulation of the intact anesthetized dog and in vitro in plasma by using L-Leu-angiotensin I, D-Leu-angiotensin I, and des-Leu-angiotensin I which had been synthesized by the solid-phase technique. The results obtained indicate that pulmonary conversion in vivo and plasma conversion in vitro occur via a dipeptidylcarboxypeptidase and that a D-amino acid at the C-terminus prevents conversion.

  14. Nitric oxide mediates the inhibitory action of platelet-activating factor on angiotensin II-induced renal vasoconstriction, in vivo.

    PubMed

    Handa, R K; Strandhoy, J W

    1996-06-01

    The objective of our study was to determine the mechanism(s) involved in the inhibitory effect of platelet-activating factor on renal vascular reactivity, in vivo. Bolus injections of vasoconstrictor agonists were administered into the renal circulation of pentobarbital anesthetized male Wistar rats at a dose to cause a transient 45 to 50% decrease in renal blood flow. Intrarenal infusion of platelet-activating factor (PAF) at 2.5 ng/min/kg attenuated the vasoconstrictor response to angiotensin II by 66%, a significantly smaller reduction of 35% for norepinephrine-mediated vasoconstriction, 22% for vasopressin-mediated vasoconstriction and no alteration of KCl-mediated vasoconstriction. The preferential inhibitory effect of platelet-activating factor on angiotensin II-mediated renal vasoconstriction was mimicked by the intrarenal infusion of either 0.2 to 5 micrograms/min/kg methacholine (endothelium-dependent vasodilator) or 2 micrograms/min/kg sodium nitroprusside (nitric oxide donor). After inhibition of nitric oxide synthesis with NG-monomethyl-L-arginine, intrarenal infusion of PAF or methacholine reduced angiotensin II-mediated renal vasoconstriction significantly less than that observed in the absence of NG-monomethyl-L-arginine. Therefore, this study provides evidence that the shared ability of platelet-activating factor and methacholine to selectively reduce angiotensin II-mediated renal vasoconstriction involves endothelium-derived nitric oxide. PMID:8667214

  15. Involvement of Spinal Angiotensin II System in Streptozotocin-Induced Diabetic Neuropathic Pain in Mice.

    PubMed

    Ogata, Yoshiki; Nemoto, Wataru; Nakagawasai, Osamu; Yamagata, Ryota; Tadano, Takeshi; Tan-No, Koichi

    2016-09-01

    Renin-angiotensin system (RAS) activity increases under hyperglycemic states, and is thought to be involved in diabetic complications. We previously demonstrated that angiotensin (Ang) II, a main bioactive component of the RAS, might act as a neurotransmitter and/or neuromodulator in the transmission of nociceptive information in the spinal cord. Here, we examined whether the spinal Ang II system is responsible for diabetic neuropathic pain induced by streptozotocin (STZ). Tactile allodynia was observed concurrently with an increase in blood glucose levels the day after mice received STZ (200 mg/kg, i.v.) injections. Tactile allodynia on day 14 was dose-dependently inhibited by intrathecal administration of losartan, an Ang II type 1 (AT1) receptor antagonist, but not by PD123319, an AT2 receptor antagonist. In the lumbar dorsal spinal cord, the expression of Ang II, Ang converting enzyme (ACE), and phospho-p38 mitogen-activated protein kinase (MAPK) were all significantly increased on day 14 after STZ injection compared with vehicle-treated controls, whereas no differences were observed among AT1 receptors or angiotensinogen levels. Moreover, the increase in phospho-p38 MAPK was significantly inhibited by intrathecal administration of losartan. These results indicate that the expression of spinal ACE increased in STZ-induced diabetic mice, which in turn led to an increase in Ang II levels and tactile allodynia. This increase in spinal Ang II was accompanied by the phosphorylation of p38 MAPK, which was shown to be mediated by AT1 receptors. PMID:27401876

  16. Interleukin-2/Anti-Interleukin-2 Immune Complex Expands Regulatory T Cells and Reduces Angiotensin II-Induced Aortic Stiffening.

    PubMed

    Majeed, Beenish; Tawinwung, Supannikar; 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, [Val(5)]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

  17. Angiotensin-Converting-Enzyme Inhibition in Stable Coronary Artery Disease

    PubMed Central

    2008-01-01

    BACKGROUND Angiotensin-converting-enzyme (ACE) inhibitors are effective in reducing the risk of heart failure, myocardial infarction, and death from cardiovascular causes in patients with left ventricular systolic dysfunction or heart failure. ACE inhibitors have also been shown to reduce atherosclerotic complications in patients who have vascular disease without heart failure. METHODS In the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial, we tested the hypothesis that patients with stable coronary artery disease and normal or slightly reduced left ventricular function derive therapeutic benefit from the addition of ACE inhibitors to modern conventional therapy. The trial was a double-blind, placebo-controlled study in which 8290 patients were randomly assigned to receive either trandolapril at a target dose of 4 mg per day (4158 patients) or matching placebo (4132 patients). RESULTS The mean (±SD) age of the patients was 64±8 years, the mean blood pressure 133±17/78±10 mm Hg, and the mean left ventricular ejection fraction 58±9 percent. The patients received intensive treatment, with 72 percent having previously undergone coronary revascularization and 70 percent receiving lipid-lowering drugs. The incidence of the primary end point — death from cardiovascular causes, myocardial infarction, or coronary revascularization — was 21.9 percent in the trandolapril group, as compared with 22.5 percent in the placebo group (hazard ratio in the trandolapril group, 0.96; 95 percent confidence interval, 0.88 to 1.06; P=0.43) over a median follow-up period of 4.8 years. CONCLUSIONS In patients with stable coronary heart disease and preserved left ventricular function who are receiving “current standard” therapy and in whom the rate of cardiovascular events is lower than in previous trials of ACE inhibitors in patients with vascular disease, there is no evidence that the addition of an ACE inhibitor provides further benefit in

  18. 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.

  19. 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

  20. 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

  1. The effect of angiotensin II receptor blockers on hyperuricemia

    PubMed Central

    Wolff, Marissa L.; Cruz, Jennifer L.; Vanderman, Adam J.; Brown, Jamie N.

    2015-01-01

    The objective of this review was to explore the efficacy of angiotensin II receptor blockers (ARBs) for the treatment of hyperuricemia in individuals diagnosed with gout or hyperuricemia defined as ⩾7 mg/dl at baseline. A literature search of MEDLINE (1946 to June 2015) and EMBASE (1947 to June 2015) was conducted. The following search terms were used: ‘uric acid’, ‘urate transporter’, ‘gout’, ‘angiotensin II receptor blockers’, ‘hyperuricemia’ and the names for individual ARBs, as well as any combinations of these terms. Studies were excluded that did not explore fractional excretion or serum uric acid as an endpoint, if patients did not have a diagnosis of gout or hyperuricemia at baseline, or if they were non-English language. A total of eight studies met the inclusion criteria. Of the eight studies identified, six explored ARB monotherapy and two studies investigated ARBs as adjunct therapy. Losartan demonstrated statistically significant reductions in serum uric acid levels or increases in fractional excretion of uric acid in all studies, whereas no other ARB reached statistical benefit. The effect of ARBs on the occurrence of gout attacks or other clinical outcomes were not represented. Four studies evaluated safety effects of these agents indicating abnormalities such as minor changes in lab values. In conclusion, losartan is the only ARB that has consistently demonstrated a significant reduction in serum uric acid levels, although the significance of impacting clinical outcomes remains unknown. Losartan appears to be a safe and efficacious agent to lower serum uric acid levels in patients with hyperuricemia. PMID:26568810

  2. 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.

  3. Baicalein protects against the development of angiotensin II-induced abdominal aortic aneurysms by blocking JNK and p38 MAPK signaling.

    PubMed

    Wang, Fang; Chen, Houzao; Yan, Yunfei; Liu, Yue; Zhang, Shuyang; Liu, Depei

    2016-09-01

    An abdominal aortic aneurysm (AAA) is a permanent, localized dilatation of the abdominal aorta. In western countries, the morbidity of AAA is approximately 8%. Currently, pharmacotherapies for AAA are limited. Here, we demonstrate that baicalein (BAI), the main component of the Chinese traditional drug "Huang Qin", attenuates the incidence and severity of AAA in Apoe (-/-) mice infused with angiotensin II (AngII). Mechanically, BAI treatment decreases AngII-induced reactive oxygen species (ROS) production in the aortic wall. Moreover, BAI inhibits inflammatory cell accumulation in the aortas of mice infused with AngII. It also inhibits AngII-induced activation of matrix metalloproteinase 2 (MMP-2) and MMP-9 to maintain elastin content in vivo. In addition, it blocks AngII cascade by downregulating angiotensin type 1 receptor (AT1R) and inhibiting mitogen-activated protein kinases (MAPKs). Taken together, our findings show that BAI is an effective agent for AAA prevention. PMID:27333787

  4. 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. PMID:23769949

  5. Enkephalin inhibition of angiotensin-stimulated release of oxytocin and vasopressin

    NASA Technical Reports Server (NTRS)

    Keil, L. C.; Chee, O.; Rosella-Dampman, L. M.; Emmert, S.; Summy-Long, J. Y.

    1984-01-01

    The effect of intracerebroventricular (ICV) pretreatment with 100 ng/5 microliter leucine(5)-enkephalin (LE) on the increase in plasma oxytocin (OT) and vasopressin (VP) caused by ICV injection of 10, 50, or 100 ng/5 microliter of angiotensin II (AII) is investigated experimentally in conscious adult male Sprague-Dawley rats; the effects of water-deprivation dehydration and lactation/suckling (in female rats) are also studied. An OT radioimmunoassay (RIA) with a sensitivity of 800 fg/ml (described in detail) and the VP RIA technique of Keil and Severs (1977) are employed. Administration of AII or dehydration for 48 or 72 h cause a significant increase in OT and VP without affecting the ratio, while lactation and suckling increase OT only. LE pretreatment inhibits significantly but does not suppress the AII-stimulated OT-VP response.

  6. Intracrine angiotensin II functions originate from noncanonical pathways in the human heart.

    PubMed

    Ferrario, Carlos M; Ahmad, Sarfaraz; Varagic, Jasmina; Cheng, Che Ping; Groban, Leanne; Wang, Hao; Collawn, James F; Dell Italia, Louis J

    2016-08-01

    Although it is well-known that excess renin angiotensin system (RAS) activity contributes to the pathophysiology of cardiac and vascular disease, tissue-based expression of RAS genes has given rise to the possibility that intracellularly produced angiotensin II (Ang II) may be a critical contributor to disease processes. An extended form of angiotensin I (Ang I), the dodecapeptide angiotensin-(1-12) [Ang-(1-12)], that generates Ang II directly from chymase, particularly in the human heart, reinforces the possibility that an alternative noncanonical renin independent pathway for Ang II formation may be important in explaining the mechanisms by which the hormone contributes to adverse cardiac and vascular remodeling. This review summarizes the work that has been done in evaluating the functional significance of Ang-(1-12) and how this substrate generated from angiotensinogen by a yet to be identified enzyme enhances knowledge about Ang II pathological actions. PMID:27233763

  7. Assessment of angiotensin II receptor blockade in humans using a standardized angiotensin II receptor-binding assay.

    PubMed

    Maillard, M P; Mazzolai, L; Daven, V; Centeno, C; Nussberger, J; Brunner, H R; Burnier, M

    1999-12-01

    An in vitro angiotensin II (AngII) receptor-binding assay was developed to monitor the degree of receptor blockade in standardized conditions. This in vitro method was validated by comparing its results with those obtained in vivo with the injection of exogenous AngII and the measurement of the AngII-induced changes in systolic blood pressure. For this purpose, 12 normotensive subjects were enrolled in a double-blind, four-way cross-over study comparing the AngII receptor blockade induced by a single oral dose of losartan (50 mg), valsartan (80 mg), irbesartan (150 mg), and placebo. A significant linear relationship between the two methods was found (r = 0.723, n = 191, P<.001). However, there exists a wide scatter of the in vivo data in the absence of active AngII receptor blockade. Thus, the relationship between the two methods is markedly improved (r = 0.87, n = 47, P<.001) when only measurements done 4 h after administration of the drugs are considered (maximal antagonist activity observed in vivo) suggesting that the two methods are equally effective in assessing the degree of AT-1 receptor blockade, but with a greatly reduced variability in the in vitro assay. In addition, the pharmacokinetic/pharmacodynamic analysis performed with the three antagonists suggest that the AT-1 receptor-binding assay works as a bioassay that integrates the antagonistic property of all active drug components of the plasma. This standardized in vitro-binding assay represents a simple, reproducible, and precise tool to characterize the pharmacodynamic profile of AngII receptor antagonists in humans. PMID:10619583

  8. 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

  9. Differentiation in the angiotensin II receptor 1 blocker class on autonomic function.

    PubMed

    Krum, H

    2001-09-01

    Autonomic function is disordered in cardiovascular disease states such as chronic heart failure (CHF) and hypertension. Interactions between the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS) may potentially occur at a number of sites. These include central sites (eg, rostral ventrolateral medulla), at the level of baroreflex control, and at the sympathetic prejunctional angiotensin II receptor 1 (AT(1)) receptor, which is facilitatory for norepinephrine release from the sympathetic nerve terminal. Therefore, drugs that block the RAAS may be expected to improve autonomic dysfunction in cardiovascular disease states. In order to test the hypothesis that RAAS inhibition directly reduces SNS activity, a pithed rat model of sympathetic stimulation has been established. In this model, an increase in frequency of stimulation results in a pressor response that is sympathetically mediated and highly reproducible. This pressor response is enhanced in the presence of angiotensin II and is reduced in the presence of nonselective AIIRAs that block both AT(1) and AT(2) receptor subtypes (eg, saralasin). AT(1)-selective antagonists have also been studied in this model, at pharmacologically relevant doses. In one such study, only the AT(1) blocker eprosartan reduced sympathetically stimulated increases in blood pressure, whereas comparable doses of losartan, valsartan, and irbesartan did not. The reason(s) for the differences between eprosartan and other agents of this class on sympathetic modulation are not clear, but may relate to the chemical structure of the drug (a non- biphenyl tetrazole structure that is chemically distinct from the structure of other AIIRAs), receptor binding characteristics (competitive), or unique effects on presynaptic AT(1) receptors. PMID:11580884

  10. Angiotensin-induced EGF receptor transactivation inhibits insulin signaling in C9 hepatic cells

    PubMed Central

    Arellano-Plancarte, Araceli; Hernandez-Aranda, Judith; Catt, Kevin J.; Olivares-Reyes, J. Alberto

    2014-01-01

    To investigate the potential interactions between the angiotensin II (Ang II) and insulin signaling systems, regulation of IRS-1 phosphorylation and insulin-induced Akt activation by Ang II were examined in clone 9 (C9) hepatocytes. In these cells, Ang II specifically inhibited activation of insulin-induced Akt Thr308 and its immediate downstream substrate GSK-3α/β in a time-dependent fashion, with ∼70% reduction at 15min. These inhibitory actions were associated with increased IRS-1 phosphorylation of Ser636/Ser639 that was prevented by selective blockade of EGFR tyrosine kinase activity with AG1478. Previous studies have shown that insulin-induced phosphorylation of IRS-1 on Ser636/Ser639 is mediated mainly by the PI3K/mTOR/S6K-1 sequence. Studies with specific inhibitors of PI3K (wortmannin) and mTOR (rapamycin) revealed that Ang II stimulates IRS-1 phosphorylation of Ser636/Ser639 via the PI3K/mTOR/S6K-1 pathway. Both inhibitors blocked the effect of Ang II on insulin-induced activation of Akt. Studies using the specific MEK inhibitor, PD98059, revealed that ERK1/2 activation also mediates Ang II-induced S6K-1 and IRS-1 phosphorylation, and the impairment of Akt Thr308 and GSK-3α/β phosphorylation. Further studies with selective inhibitors showed that PI3K activation was upstream of ERK, suggesting a new mechanism for Ang II-induced impairment of insulin signaling. These findings indicate that Ang II has a significant role in the development of insulin resistance by a mechanism that involves EGFR transactivation and the PI3K/ERK1/2/mTOR-S6K-1 pathway. PMID:19879250

  11. 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

  12. 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. PMID:26101342

  13. Nerve-mediated antidiuresis and antinatriuresis after air-jet stress is modulated by angiotensin II.

    PubMed

    Veelken, R; Hilgers, K F; Stetter, A; Siebert, H G; Schmieder, R E; Mann, J F

    1996-11-01

    A putative interaction between angiotensin II (Ang II) and the sympathetic nervous system within the kidney has been reported. We tested the hypothesis in conscious rats that endogenous Ang II modulates the renal effects of a stress-induced increase in sympathetic nerve activity. We recorded mean arterial blood pressure, heart rate, renal sympathetic nerve activity, renal hemodynamics, urine volume, and urinary sodium content in conscious rats. We used the Ang II type 1 receptor blocker ZD 7155 to inhibit the effects of endogenous Ang II. Ten minutes of air-jet stress increased renal sympathetic nerve activity by 98 +/- 4% (n = 6) without changing systemic hemodynamics. Air-jet stress reduced urine volume (from 31 +/- 3 to 8 +/- 4 microL/min per gram kidney weight, P < .05, n = 12) and sodium excretion (from 4.3 +/- 0.9 to 1.2 +/- 0.3 mumol/min per gram kidney weight, P < .05, n = 12). After renal denervation, air-jet stress had no effect on either parameter. Six micrograms of the Ang II type 1 receptor inhibitor ZD 7155 blunted the decrease in urine volume and sodium excretion in response to air-jet stress, although the increase in renal sympathetic nerve activity during air-jet stress and the pressor response to exogenous Ang II were not affected. Glomerular filtration rate and renal plasma flow were also not affected. Higher doses of 30 and 60 micrograms ZD 7155 inhibited the pressor response to exogenous Ang II and abolished the changes in urine volume and sodium excretion in response to air-jet stress. None of the ZD 7155 doses affected urinary sodium excretion permanently. Hence, the Ang II type 1 receptor antagonist ZD 7155 impaired or abolished the renal nerve-mediated antinatriuresis and anitidiuresis in response to air-jet stress. We conclude that endogenous Ang II modulates the renal effects of centrally mediated changes of sympathetic nerve activity in conscious rats. PMID:8901830

  14. ACE inhibition, ACE2 and angiotensin-(1-7) axis in kidney and cardiac inflammation and fibrosis.

    PubMed

    Simões E Silva, Ana Cristina; Teixeira, Mauro Martins

    2016-05-01

    The Renin Angiotensin System (RAS) is a pivotal physiological regulator of heart and kidney homeostasis, but also plays an important role in the pathophysiology of heart and kidney diseases. Recently, new components of the RAS have been discovered, including angiotensin converting enzyme 2 (ACE2), Angiotensin(Ang)-(1-7), Mas receptor, Ang-(1-9) and Alamandine. These new components of RAS are formed by the hydrolysis of Ang I and Ang II and, in general, counteract the effects of Ang II. In experimental models of heart and renal diseases, Ang-(1-7), Ang-(1-9) and Alamandine produced vasodilation, inhibition of cell growth, anti-thrombotic, anti-inflammatory and anti-fibrotic effects. Recent pharmacological strategies have been proposed to potentiate the effects or to enhance the formation of Ang-(1-7) and Ang-(1-9), including ACE2 activators, Ang-(1-7) in hydroxypropyl β-cyclodextrin, cyclized form of Ang-(1-7) and nonpeptide synthetic Mas receptor agonists. Here, we review the role and effects of ACE2, ACE2 activators, Ang-(1-7) and synthetic Mas receptor agonists in the control of inflammation and fibrosis in cardiovascular and renal diseases and as counter-regulators of the ACE-Ang II-AT1 axis. We briefly comment on the therapeutic potential of the novel members of RAS, Ang-(1-9) and alamandine, and the interactions between classical RAS inhibitors and new players in heart and kidney diseases. PMID:26995300

  15. 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

  16. 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. PMID:25767030

  17. Effects of Angiotensin II Receptor Signaling during Skin Wound Healing

    PubMed Central

    Takeda, Hikaru; Katagata, Yohtaro; Hozumi, Yutaka; Kondo, Shigeo

    2004-01-01

    The tissue angiotensin (Ang) system, which acts independently of the circulating renin Ang system, is supposed to play an important role in tissue repair in the heart and kidney. In the skin, the role of the system for wound healing has remained to be ascertained. Our study demonstrated that oral administration of selective AngII type-1 receptor (AT1) blocker suppressed keratinocyte re-epithelization and angiogenesis during skin wound healing in rats. Immunoprecipitation and Western blot analysis indicated the existence of AT1 and AngII type-2 receptor (AT2) in cultured keratinocytes and myofibroblasts. In a bromodeoxyuridine incorporation study, induction of AT1 signaling enhanced the incorporation into keratinocytes and myofibroblasts. Wound healing migration assays revealed that induction of AT1 signaling accelerated keratinocyte re-epithelization and myofibroblasts recovering. In these experiments, induction of AT2 signaling acted vice versa. Taken together, our study suggests that skin wound healing is regulated by balance of opposing signals between AT1 and AT2. PMID:15509535

  18. Quantitative distribution of angiotensin II binding sites in rat brain by autoradiography

    SciTech Connect

    Saavedra, J.M.; Israel, A.; Plunkett, L.M.; Kurihara, M.; Shigematsu, K.; Correa, F.M.

    1986-07-01

    Angiotensin II binding sites were localized and quantified in individual brain nuclei from single rats by incubation of tissue sections with 1 nM /sup 125/I-(Sar1)-angiotensin II, (/sup 3/H)-Ultrofilm autoradiography, computerized microdensitometry and comparison with /sup 125/I-standards. High angiotensin II binding was present in the circumventricular organs (organon vasculosum laminae terminalis, organon subfornicalis and area postrema), in selected hypothalamic nuclei (nuclei suprachiasmatis, periventricularis and paraventricularis) and in the nucleus tractus olfactorii lateralis, the nucleus preopticus medianus, the dorsal motor nucleus of the vagus and the nucleus tractus solitarii. High affinity (KA from 0.3 to 1.5 X 10(9) M-1) angiotensin II binding sites were demonstrated in the organon subfornicalis, the nucleus tractus solitarii and the area postrema after incubation of consecutive sections from single rat brains with /sup 125/I-(Sar1)-angiotensin II in concentrations from 100 pM to 5 nM. These results demonstrate and characterize brain binding sites for angiotensin II of variable high affinity binding both inside and outside the blood-brain barrier.

  19. Angiotensin II type 1 receptor antibodies in childhood kidney transplantation.

    PubMed

    Bjerre, Anna; Tangeraas, Trine; Heidecke, Harald; Dragun, Duska; Dechend, Ralf; Staff, Anne Cathrine

    2016-08-01

    Angiotensin II type 1 receptor antibodies (AT1 RAb) have emerged as non-HLA Ab present in patients with acute AMR and risk of graft loss. Furthermore, AT1 RAb have been shown to increase angiotensin II sensitivity which may play a role in the development of CVD and hypertension. Data on AT1 RAb in stable transplant recipients are lacking. The aim of this study was to analyze the levels of AT1 RAb in a cohort of stable patients after kidney transplantation (tx) in childhood. A cross-sectional study of 30 children (median age 14, range 3-19 yr, median time since tx five yr) and 28 adults who were transplanted in childhood (median age 26, range 20-40 yr, median time since tx 18 yr) transplanted between 1993-2006 and 1983-2002, respectively, was performed. Healthy controls were 51 healthy children (5-8 yr) and 199 healthy donors (median age 56.5 yr, range 42-83 yr). Plasma AT1 RAb were analyzed by immunoassay. Median total AT1 RAb IgG concentration was significantly higher in the pediatric-tx group as compared to the adult-tx group (40.0 and 10.95 U/mL, p < 0.0001). For both groups, the tx group showed higher levels: the pediatric-tx group vs. control group (40.0 vs. 13.3 U/mL, p = 0.0006) and the adult-tx group vs. adult control group (10.95 vs. 6.5 U/mL, p < 0.0001). Age was the strongest indicator of high levels of AT1 RAb IgG (p = 0.0003). AT1 RAb total IgG levels are significantly higher in a stable pediatric-tx cohort as compared to adult-tx patients and healthy controls of comparable age groups. The relevance of our findings in relation to age, time since tx, previous or future rejection, and CVD risk merits future studies. PMID:27251358

  20. The Role of Angiotensin II and Cyclic AMP in Alveolar Active Sodium Transport

    PubMed Central

    Ismael-Badarneh, Reem; Guetta, Julia; Klorin, Geula; Berger, Gidon; Abu-saleh, Niroz; Abassi, Zaid; Azzam, Zaher S.

    2015-01-01

    Active alveolar fluid clearance is important in keeping airspaces free of edema. Angiotensin II plays a role in the pathogenesis of hypertension, heart failure and others. However, little is known about its contribution to alveolar fluid clearance. Angiotensin II effects are mediated by two specific receptors; AT1 and AT2. The localization of these two receptors in the lung, specifically in alveolar epithelial cells type II, was recently reported. We hypothesize that Angiotensin II may have a role in the regulation of alveolar fluid clearance. We investigated the effect of Angiotensin II on alveolar fluid clearance in rats using the isolated perfused lung model and isolated rat alveolar epithelial cells. The rate of alveolar fluid clearance in control rats was 8.6% ± 0.1 clearance of the initial volume and decreased by 22.5%, 28.6%, 41.6%, 48.7% and 39% in rats treated with 10-10 M, 10-9 M, 10-8 M, 10-7 M or 10-6 M of Ang II respectively (P < 0.003). The inhibitory effect of Angiotensin II was restored in losartan, an AT1 specific antagonist, pretreated rats, indicating an AT1 mediated effect of Ang II on alveolar fluid clearance. The expression of Na,K-ATPase proteins and cAMP levels in alveolar epithelial cells were down-regulated following the administration of Angiotensin II; suggesting that cAMP may be involved in AngII-induced reduced Na,K-ATPase expression, though the contribution of additional factors could not be excluded. We herein suggest a novel mechanism of clinical relevance by which angiotensin adversely impairs the ability of the lungs to clear edema. PMID:26230832

  1. Reactive oxygen species mediate angiotensin II-induced leukocyte-endothelial cell interactions in vivo.

    PubMed

    Alvarez, A; Sanz, M J

    2001-08-01

    Chronically elevated angiotensin II (Ang-II)-induced hypertension is partly mediated by superoxide production. In this study, we have investigated whether the leukocyte-endothelial cell interactions elicited by Ang-II involve reactive oxygen species (ROS) generation. Intravital microscopy within the rat mesenteric microvessels was used. Superfusion (60 min) with Ang-II (1 nM) induced significant increases in leukocyte rolling flux, adhesion, and emigration, which were inhibited by pretreatment with superoxide dismutase or catalase. Dihydrorhodamine-123 oxidation indicated that ROS are primarily produced by the vessel wall. Administration of dimethylthiourea, desferrioxamine, or N-acetylcysteine provoked significant reductions in Ang-II-induced leukocyte-endothelial cell interactions. In addition, a blockade of platelet-activating factor or leukotrienes also attenuated such responses significantly. The results presented indicate that in vivo Ang-II-induced leukocyte recruitment is dependent on the generation of intra- and extracellular ROS. Therefore, the use of anti-oxidants might constitute an alternative therapy for the control of the subendothelial leukocyte infiltration associated with hypertension and atherosclerosis. PMID:11493611

  2. BLOCKADE OF BRAIN ANGIOTENSIN II AT1 RECEPTORS AMELIORATES STRESS, ANXIETY, BRAIN INFLAMMATION AND ISCHEMIA: THERAPEUTIC IMPLICATIONS

    PubMed Central

    SAAVEDRA, Juan M.; SÁNCHEZ-LEMUS, Enrique; BENICKY, Julius

    2010-01-01

    SUMMARY Poor adaptation to stress, alterations in cerebrovascular function and excessive brain inflammation play critical roles in the pathophysiology of many psychiatric and neurological disorders such as major depression, schizophrenia, post traumatic stress disorder, Parkinson's and Alzheimer's diseases and traumatic brain injury. Treatment for these highly prevalent and devastating conditions is at present very limited and many times inefficient, and the search for novel therapeutic options is of major importance. Recently, attention has been focused on the role of a brain regulatory peptide, Angiotensin II, and in the translational value of the blockade of its physiological AT1 receptors. In addition to its well-known cardiovascular effects, Angiotensin II, through AT1 receptor stimulation, is a pleiotropic brain modulatory factor involved in the control of the reaction to stress, in the regulation of cerebrovascular flow and the response to inflammation. Excessive brain AT1 receptor activity is associated with exaggerated sympathetic and hormonal response to stress, vulnerability to cerebrovascular ischemia and brain inflammation, processes leading to neuronal injury. In animal models, inhibition of brain AT1 receptor activity with systemically administered Angiotensin II receptor blockers is neuroprotective; it reduces exaggerated stress responses and anxiety, prevents stress-induced gastric ulcerations, decreases vulnerability to ischemia and stroke, reverses chronic cerebrovascular inflammation, and reduces acute inflammatory responses produced by bacterial endotoxin. These effects protect neurons from injury and contribute to increase the lifespan. Angiotensin II receptor blockers are compounds with a good margin of safety widely used in the treatment of hypertension and their anti-inflammatory and vascular protective effects contribute to reduce renal and cardiovascular failure. Inhibition of brain AT1 receptors in humans is also neuroprotective

  3. Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: Therapeutic implications.

    PubMed

    Saavedra, Juan M; Sánchez-Lemus, Enrique; Benicky, Julius

    2011-01-01

    Poor adaptation to stress, alterations in cerebrovascular function and excessive brain inflammation play critical roles in the pathophysiology of many psychiatric and neurological disorders such as major depression, schizophrenia, post traumatic stress disorder, Parkinson's and Alzheimer's diseases and traumatic brain injury. Treatment for these highly prevalent and devastating conditions is at present very limited and many times inefficient, and the search for novel therapeutic options is of major importance. Recently, attention has been focused on the role of a brain regulatory peptide, Angiotensin II, and in the translational value of the blockade of its physiological AT(1) receptors. In addition to its well-known cardiovascular effects, Angiotensin II, through AT(1) receptor stimulation, is a pleiotropic brain modulatory factor involved in the control of the reaction to stress, in the regulation of cerebrovascular flow and the response to inflammation. Excessive brain AT(1) receptor activity is associated with exaggerated sympathetic and hormonal response to stress, vulnerability to cerebrovascular ischemia and brain inflammation, processes leading to neuronal injury. In animal models, inhibition of brain AT(1) receptor activity with systemically administered Angiotensin II receptor blockers is neuroprotective; it reduces exaggerated stress responses and anxiety, prevents stress-induced gastric ulcerations, decreases vulnerability to ischemia and stroke, reverses chronic cerebrovascular inflammation, and reduces acute inflammatory responses produced by bacterial endotoxin. These effects protect neurons from injury and contribute to increase the lifespan. Angiotensin II receptor blockers are compounds with a good margin of safety widely used in the treatment of hypertension and their anti-inflammatory and vascular protective effects contribute to reduce renal and cardiovascular failure. Inhibition of brain AT(1) receptors in humans is also neuroprotective

  4. Mechanisms underlying angiotensin II-induced calcium oscillations

    PubMed Central

    Edwards, Aurélie; Pallone, Thomas L.

    2008-01-01

    To gain insight into the mechanisms that underlie angiotensin II (ANG II)-induced cytoplasmic Ca2+ concentration ([Ca]cyt) oscillations in medullary pericytes, we expanded a prior model of ion fluxes. ANG II stimulation was simulated by doubling maximal inositol trisphosphate (IP3) production and imposing a 90% blockade of K+ channels. We investigated two configurations, one in which ryanodine receptors (RyR) and IP3 receptors (IP3R) occupy a common store and a second in which they reside on separate stores. Our results suggest that Ca2+ release from stores and import from the extracellular space are key determinants of oscillations because both raise [Ca] in subplasmalemmal spaces near RyR. When the Ca2+-induced Ca2+ release (CICR) threshold of RyR is exceeded, the ensuing Ca2+ release is limited by Ca2+ reuptake into stores and export across the plasmalemma. If sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) pumps do not remain saturated and sarcoplasmic reticulum Ca2+ stores are replenished, that phase is followed by a resumption of leak from internal stores that leads either to [Ca]cyt elevation below the CICR threshold (no oscillations) or to elevation above it (oscillations). Our model predicts that oscillations are more prone to occur when IP3R and RyR stores are separate because, in that case, Ca2+ released by RyR during CICR can enhance filling of adjacent IP3 stores to favor a high subsequent leak that generates further CICR events. Moreover, the existence or absence of oscillations depends on the set points of several parameters, so that biological variation might well explain the presence or absence of oscillations in individual pericytes. PMID:18562632

  5. Angiotensin II Stimulation of DPP4 Activity Regulates Megalin in the Proximal Tubules

    PubMed Central

    Aroor, Annayya; Zuberek, Marcin; Duta, Cornel; Meuth, Alex; Sowers, James R.; Whaley-Connell, Adam; Nistala, Ravi

    2016-01-01

    Proteinuria is a marker of incipient kidney injury in many disorders, including obesity. Previously, we demonstrated that megalin, a receptor endocytotic protein in the proximal tubule, is downregulated in obese mice, which was prevented by inhibition of dipeptidyl protease 4 (DPP4). Obesity is thought to be associated with upregulation of intra-renal angiotensin II (Ang II) signaling via the Ang II Type 1 receptor (AT1R) and Ang II suppresses megalin expression in proximal tubule cells in vitro. Therefore, we tested the hypothesis that Ang II will suppress megalin protein via activation of DPP4. We used Ang II (200 ng/kg/min) infusion in mice and Ang II (10−8 M) treatment of T35OK-AT1R proximal tubule cells to test our hypothesis. Ang II-infused mouse kidneys displayed increases in DPP4 activity and decreases in megalin. In proximal tubule cells, Ang II stimulated DPP4 activity concurrent with suppression of megalin. MK0626, a DPP4 inhibitor, partially restored megalin expression similar to U0126, a mitogen activated protein kinase (MAPK)/extracellular regulated kinase (ERK) kinase kinase (MEK) 1/2 inhibitor and AG1478, an epidermal growth factor receptor (EGFR) inhibitor. Similarly, Ang II-induced ERK phosphorylation was suppressed with MK0626 and Ang II-induced DPP4 activity was suppressed by U0126. Therefore, our study reveals a cross talk between AT1R signaling and DPP4 activation in the regulation of megalin and underscores the significance of targeting DPP4 in the prevention of obesity related kidney injury progression. PMID:27213360

  6. Angiotensin II Stimulation of DPP4 Activity Regulates Megalin in the Proximal Tubules.

    PubMed

    Aroor, Annayya; Zuberek, Marcin; Duta, Cornel; Meuth, Alex; Sowers, James R; Whaley-Connell, Adam; Nistala, Ravi

    2016-01-01

    Proteinuria is a marker of incipient kidney injury in many disorders, including obesity. Previously, we demonstrated that megalin, a receptor endocytotic protein in the proximal tubule, is downregulated in obese mice, which was prevented by inhibition of dipeptidyl protease 4 (DPP4). Obesity is thought to be associated with upregulation of intra-renal angiotensin II (Ang II) signaling via the Ang II Type 1 receptor (AT₁R) and Ang II suppresses megalin expression in proximal tubule cells in vitro. Therefore, we tested the hypothesis that Ang II will suppress megalin protein via activation of DPP4. We used Ang II (200 ng/kg/min) infusion in mice and Ang II (10(-8) M) treatment of T35OK-AT₁R proximal tubule cells to test our hypothesis. Ang II-infused mouse kidneys displayed increases in DPP4 activity and decreases in megalin. In proximal tubule cells, Ang II stimulated DPP4 activity concurrent with suppression of megalin. MK0626, a DPP4 inhibitor, partially restored megalin expression similar to U0126, a mitogen activated protein kinase (MAPK)/extracellular regulated kinase (ERK) kinase kinase (MEK) 1/2 inhibitor and AG1478, an epidermal growth factor receptor (EGFR) inhibitor. Similarly, Ang II-induced ERK phosphorylation was suppressed with MK0626 and Ang II-induced DPP4 activity was suppressed by U0126. Therefore, our study reveals a cross talk between AT₁R signaling and DPP4 activation in the regulation of megalin and underscores the significance of targeting DPP4 in the prevention of obesity related kidney injury progression. PMID:27213360

  7. 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.

  8. The Notch pathway mediates the angiotensin II-induced synthesis of extracellular matrix components in podocytes.

    PubMed

    Yao, Min; Wang, Xiaomei; Wang, Xiaomeng; Zhang, Tao; Chi, Yanqing; Gao, Feng

    2015-07-01

    The Notch pathway is known to contribute to the development of glomerular disease. Angiotensin II (Ang II), an important member of the renin-angiotensin system, stimulates the accumulation of extracellular matrix components in glomerular disease; however, the exact mechanisms involved remain to be elucidated. In the present study, we aimed to investigate the effects of the Notch pathway on the synthesis of extracellular matrix components in Ang II-stimulated podocytes. Mouse podocytes were stimulated with Ang II (10-6 mol/l). The activation of the Notch pathway was inhibited by a vector carrying short hairpin RNA (shRNA) targeting Notch1 (sh-Notch1) or by γ-secretase inhibitor (GSI). The protein levels of Notch1, Notch intracellular domain 1 (NICD1), hairy and enhancer of split-1 (Hes1), matrix metalloproteinase (MMP)-2, MMP-9, transforming growth factor-β1 (TGF-β1), type IV collagen and laminin were determined by western blot analysis. The Notch1, Hes1, MMP-2, MMP-9, TGF-β1, type IV collagen and laminin mRNA levels were detected by RT-PCR. The MMP-2 and MMP-9 activity was measured using a cell active fluorescence assay kit. The levels of TGF-β1, type IV collagen and laminin were determined in the culture medium of the podocytes by enzyme-linked immunosorbent assay (ELISA). Our results revealed that Ang II upregulated Notch1, NICD1, Hes1, TGF-β1, type IV collagen and laminin expression and downregulated MMP-2 and MMP-9 expression in the cultured podocytes. The inhibition of the Notch pathway by sh-Notch1 or GSI increased MMP-2 and MMP-9 expression, decreased the TGF-β1 level and suppressed type IV collagen and laminin expression. The inhibition of the Notch pathway by sh-Notch1 or GSI also increased MMP-2 and MMP-9 activity, and decreased TGF-β1 levels, type IV collagen levels and laminin secretion. These findings indicate that the Notch pathway potentially mediates the Ang II-induced synthesis of extracellular matrix components in podocytes through the

  9. 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

  10. Chromatographic resolution of angiotensin II receptor antagonists (sartans).

    PubMed

    Tahir, Muhammad Saqlain; Adnan, Ahmad; Syed, Quratulain

    2016-08-01

    First time a simple, sensitive and unified quantification method has been developed to analyze the complete class of angiotensin II receptor antagonists which are used in the treatment of hypertension either alone or in combination with some other drugs. The most important advantage of developed method was that the eight separate drugs can be determined on a single chromatographic system without modifications in detection wavelength and mobile phase. The drugs were separated on a Purospher Star 4.6mm×25cm, 5μm, C18 column maintained at 40°C with 1mLmin(-1) flow rate using ultra violet detection at 254nm. Good separation (Rs>2.0) was achieved in a short analysis allowing simultaneous determination of all eight sartans. The effect of variation in flow rate, detection wavelength and column oven temperature was also studied. The proposed method was statistically validated in terms of precision, accuracy, linearity, specificity and robustness. The newly developed method proved to be specific, robust and accurate for the quantification of eight sartans in commercial pharmaceutical formulations. PMID:27258943

  11. 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.

  12. Deletion of the angiotensin II type 1 receptor–associated protein enhances renal sodium reabsorption and exacerbates angiotensin II–mediated hypertension

    PubMed Central

    Ohsawa, Masato; Tamura, Kouichi; Wakui, Hiromichi; Maeda, Akinobu; Dejima, Toru; Kanaoka, Tomohiko; Azushima, Kengo; Uneda, Kazushi; Tsurumi-Ikeya, Yuko; Kobayashi, Ryu; Matsuda, Miyuki; Uchida, Shinichi; Toya, Yoshiyuki; Kobori, Hiroyuki; Nishiyama, Akira; Yamashita, Akio; Ishikawa, Yoshihiro; Umemura, Satoshi

    2014-01-01

    Angiotensin II type 1 receptor (AT1R)–associated protein (ATRAP) promotes AT1R internalization along with suppression of pathological activation of tissue AT1R signaling. However, the functional significance of ATRAP in renal sodium handling and blood pressure regulation under pathological stimuli is not fully resolved. Here we show the blood pressure of mice with a gene-targeted disruption of ATRAP was comparable to that of wild-type mice at baseline. However, in ATRAP-knockout mice, angiotensin II–induced hypertension was exacerbated and the extent of positive sodium balance was increased by angiotensin II. Renal expression of the sodium-proton antiporter 3, a major sodium transporter in the proximal tubules, urinary pH, renal angiotensinogen production, and angiotensin II content was unaffected. Stimulation of the renal expression and activity of the epithelial sodium channel (ENaC), a major sodium transporter in the distal tubules, was significantly enhanced by chronic angiotensin II infusion. The circulating and urinary aldosterone levels were comparable. The blood pressure response and renal ENaC expression by aldosterone were not affected. Thus, ATRAP deficiency exacerbated angiotensin II–mediated hypertension by pathological activation of renal tubular AT1R by angiotensin II. This directly stimulates ENaC in the distal tubules and enhances sodium retention in an aldosterone-independent manner. PMID:24694992

  13. Regional suppression by lesions in the anterior third ventricle of c-fos expression induced by either angiotensin II or hypertonic saline.

    PubMed

    Xu, Z; Herbert, J

    1995-07-01

    Angiotensin II (250 pmol) infused into the cerebral ventricles of male rats induces the expression of c-fos in the subfornical organ, supraoptic and paraventricular nuclei of the hypothalamus, as well as in the lateral parabrachial nucleus, locus coeruleus and the nucleus of the solitary tract in the brainstem. Electrolytic lesions of the anteroventral third ventricle, principally the subcommissural (ventral) median preoptic nucleus, inhibited the dipsogenic response to i.c.v. angiotensin II and also suppressed c-fos expression in supraoptic nucleus, paraventricular nucleus, lateral parabrachial nucleus, locus coeruleus and nucleus of the solitary tract but not in the subfornical organ or dorsal median preoptic nucleus. The stimulating effect of i.c.v. angiotensin II on corticosterone was also reduced. Median preoptic nucleus lesions also suppressed the expression of c-fos following i.v. infusions of 6 micrograms angiotensin II in supraoptic nucleus and paraventricular nucleus but not in subfornical organ, dorsal median preoptic nucleus, lateral parabrachial nucleus, locus coeruleus and nucleus of the solitary tract. Median preoptic nucleus lesions reduced the dipsogenic effects of an intragastric infusion of hypertonic (1.5 M) saline and suppressed c-fos expression in supraoptic nucleus and paraventricular nucleus compared to sham-lesioned rats. However, c-fos expression was unaltered in subfornical organ, dorsal median preoptic nucleus lesions had no effect on the increased corticosterone induced by hypertonic saline. Subfornical organ lesions did not alter dipsogenic responses to i.c.v. angiotensin II, nor was the i.c.v. angiotensin II-induced expression of c-fos suppressed in the basal forebrain. These experiments show that the ventral median preoptic nucleus (but not the subfornical organ), part of the anteroventral third ventricle, is critical for the expression of c-fos in more caudal areas of the brain following i.c.v. angiotensin II. c-fos expression in

  14. 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.

  15. Sirtuin3 Dysfunction Is the Key Determinant of Skeletal Muscle Insulin Resistance by Angiotensin II

    PubMed Central

    Macconi, Daniela; Perico, Luca; Longaretti, Lorena; Morigi, Marina; Cassis, Paola; Buelli, Simona; Perico, Norberto; Remuzzi, Giuseppe; Benigni, Ariela

    2015-01-01

    Background Angiotensin II promotes insulin resistance. The mechanism underlying this abnormality, however, is still poorly defined. In a different setting, skeletal muscle metabolism and insulin signaling are regulated by Sirtuin3. Objective Here, we investigate whether angiotensin II-induced insulin resistance in skeletal muscle is associated with Sirtuin3 dysregulation and whether pharmacological manipulation of Sirtuin3 confers protection. Study Design Parental and GLUT4-myc L6 rat skeletal muscle cells exposed to angiotensin II are used as in vitro models of insulin resistance. GLUT4 translocation, glucose uptake, intracellular molecular signals such as mitochondrial reactive oxygen species, Sirtuin3 protein expression and activity, along with its downstream targets and upstream regulators, are analyzed both in the absence and presence of acetyl-L-carnitine. The role of Sirtuin3 in GLUT4 translocation and intracellular molecular signaling is also studied in Sirtuin3-silenced as well as over-expressing cells. Results Angiotensin II promotes insulin resistance in skeletal muscle cells via mitochondrial oxidative stress, resulting in a two-fold increase in superoxide generation. In this context, reactive oxygen species open the mitochondrial permeability transition pore and significantly lower Sirtuin3 levels and activity impairing the cell antioxidant defense. Angiotensin II-induced Sirtuin3 dysfunction leads to the impairment of AMP-activated protein kinase/nicotinamide phosphoribosyltransferase signaling. Acetyl-L-carnitine, by lowering angiotensin II-induced mitochondrial superoxide formation, prevents Sirtuin3 dysfunction. This phenomenon implies the restoration of manganese superoxide dismutase antioxidant activity and AMP-activated protein kinase activation. Acetyl-L-carnitine protection is abrogated by specific Sirtuin3 siRNA. Conclusions Our data demonstrate that angiotensin II-induced insulin resistance fosters mitochondrial superoxide generation, in

  16. 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. PMID:27246933

  17. Interleukin-17A Regulates Renal Sodium Transporters and Renal Injury in Angiotensin II-Induced Hypertension.

    PubMed

    Norlander, Allison E; Saleh, Mohamed A; Kamat, Nikhil V; Ko, Benjamin; Gnecco, Juan; Zhu, Linjue; Dale, Bethany L; Iwakura, Yoichiro; Hoover, Robert S; McDonough, Alicia A; Madhur, Meena S

    2016-07-01

    Angiotensin II-induced hypertension is associated with an increase in T-cell production of interleukin-17A (IL-17A). Recently, we reported that IL-17A(-/-) mice exhibit blunted hypertension, preserved natriuresis in response to a saline challenge, and decreased renal sodium hydrogen exchanger 3 expression after 2 weeks of angiotensin II infusion compared with wild-type mice. In the current study, we performed renal transporter profiling in mice deficient in IL-17A or the related isoform, IL-17F, after 4 weeks of Ang II infusion, the time when the blood pressure reduction in IL-17A(-/-) mice is most prominent. Deficiency of IL-17A abolished the activation of distal tubule transporters, specifically the sodium-chloride cotransporter and the epithelial sodium channel and protected mice from glomerular and tubular injury. In human proximal tubule (HK-2) cells, IL-17A increased sodium hydrogen exchanger 3 expression through a serum and glucocorticoid-regulated kinase 1-dependent pathway. In mouse distal convoluted tubule cells, IL-17A increased sodium-chloride cotransporter activity in a serum and glucocorticoid-regulated kinase 1/Nedd4-2-dependent pathway. In both cell types, acute treatment with IL-17A induced phosphorylation of serum and glucocorticoid-regulated kinase 1 at serine 78, and treatment with a serum and glucocorticoid-regulated kinase 1 inhibitor blocked the effects of IL-17A on sodium hydrogen exchanger 3 and sodium-chloride cotransporter. Interestingly, both HK-2 and mouse distal convoluted tubule 15 cells produce endogenous IL-17A. IL17F had little or no effect on blood pressure or renal sodium transporter abundance. These studies provide a mechanistic link by which IL-17A modulates renal sodium transport and suggest that IL-17A inhibition may improve renal function in hypertension and other autoimmune disorders. PMID:27141060

  18. GLUTATHIONE PEROXIDASE-1 PLAYS A MAJOR ROLE IN PROTECTING AGAINST ANGIOTENSIN II-INDUCED VASCULAR DYSFUNCTION

    PubMed Central

    Chrissobolis, Sophocles; Didion, Sean P.; Kinzenbaw, Dale A.; Schrader, Laura I.; Dayal, Sanjana; Lentz, Steven R.; Faraci, Frank M.

    2011-01-01

    Levels of reactive oxygen species, including hydrogen peroxide (H2O2), increase in blood vessels during hypertension and in response to angiotensin II (Ang II). Although glutathione peroxidases (GPx) are known to metabolize H2O2, the role of GPx during hypertension is poorly defined. We tested the hypothesis that GPx-1 protects against Ang II-induced endothelial dysfunction. Responses of carotid arteries from Gpx1-deficient (Gpx1 +/− and Gpx1 −/−) and Gpx1 transgenic (Tg) mice, and their respective littermate controls, were examined in vitro following overnight incubation with either vehicle or Ang II. Under control conditions, relaxation to acetylcholine (ACh, an endothelium-dependent agonist) was similar in control, Gpx1 +/−, and Gpx1 Tg mice, whereas in Gpx1 −/− mice, responses to ACh were impaired. In control mice, ACh-induced vasorelaxation was not affected by 1 nmol/L Ang II. In contrast, relaxation to ACh in arteries from Gpx1 +/− mice was inhibited by ~60% following treatment with 1 nmol/L Ang II, indicating Gpx1 haploinsufficiency markedly enhances Ang II-induced endothelial dysfunction. A higher concentration of Ang II (10 nmol/L) selectively impaired relaxation to ACh in arteries from control mice, and this effect was prevented in arteries from Gpx1 Tg mice, or arteries from control mice treated with PEG-catalase (which degrades H2O2). Thus, genetic and pharmacological evidence suggests a major role for GPx-1 and H2O2 in Ang II-induced effects on vascular function. PMID:18299484

  19. Novel Roles for Peroxynitrite in Angiotensin II and CaMKII Signaling

    PubMed Central

    Zhou, Chaoming; Ramaswamy, Swarna S.; Johnson, Derrick E.; Vitturi, Dario A.; Schopfer, Franciso J.; Freeman, Bruce A.; Hudmon, Andy; Levitan, Edwin S.

    2016-01-01

    Ca2+/calmodulin-dependent protein kinase II (CaMKII) oxidation controls excitability and viability. While hydrogen peroxide (H2O2) affects Ca2+-activated CaMKII in vitro, Angiotensin II (Ang II)-induced CaMKIIδ signaling in cardiomyocytes is Ca2+ independent and requires NADPH oxidase-derived superoxide, but not its dismutation product H2O2. To better define the biological regulation of CaMKII activation and signaling by Ang II, we evaluated the potential for peroxynitrite (ONOO−) to mediate CaMKII activation and downstream Kv4.3 channel mRNA destabilization by Ang II. In vitro experiments show that ONOO− oxidizes and modestly activates pure CaMKII in the absence of Ca2+/CaM. Remarkably, this apokinase stimulation persists after mutating known oxidation targets (M281, M282, C290), suggesting a novel mechanism for increasing baseline Ca2+-independent CaMKII activity. The role of ONOO− in cardiac and neuronal responses to Ang II was then tested by scavenging ONOO− and preventing its formation by inhibiting nitric oxide synthase. Both treatments blocked Ang II effects on Kv4.3, tyrosine nitration and CaMKIIδ oxidation and activation. Together, these data show that ONOO− participates in Ang II-CaMKII signaling. The requirement for ONOO− in transducing Ang II signaling identifies ONOO−, which has been viewed as a reactive damaging byproduct of superoxide and nitric oxide, as a mediator of GPCR-CaMKII signaling. PMID:27079272

  20. Novel Roles for Peroxynitrite in Angiotensin II and CaMKII Signaling.

    PubMed

    Zhou, Chaoming; Ramaswamy, Swarna S; Johnson, Derrick E; Vitturi, Dario A; Schopfer, Franciso J; Freeman, Bruce A; Hudmon, Andy; Levitan, Edwin S

    2016-01-01

    Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) oxidation controls excitability and viability. While hydrogen peroxide (H2O2) affects Ca(2+)-activated CaMKII in vitro, Angiotensin II (Ang II)-induced CaMKIIδ signaling in cardiomyocytes is Ca(2+) independent and requires NADPH oxidase-derived superoxide, but not its dismutation product H2O2. To better define the biological regulation of CaMKII activation and signaling by Ang II, we evaluated the potential for peroxynitrite (ONOO(-)) to mediate CaMKII activation and downstream Kv4.3 channel mRNA destabilization by Ang II. In vitro experiments show that ONOO(-) oxidizes and modestly activates pure CaMKII in the absence of Ca(2+)/CaM. Remarkably, this apokinase stimulation persists after mutating known oxidation targets (M281, M282, C290), suggesting a novel mechanism for increasing baseline Ca(2+)-independent CaMKII activity. The role of ONOO(-) in cardiac and neuronal responses to Ang II was then tested by scavenging ONOO(-) and preventing its formation by inhibiting nitric oxide synthase. Both treatments blocked Ang II effects on Kv4.3, tyrosine nitration and CaMKIIδ oxidation and activation. Together, these data show that ONOO(-) participates in Ang II-CaMKII signaling. The requirement for ONOO(-) in transducing Ang II signaling identifies ONOO(-), which has been viewed as a reactive damaging byproduct of superoxide and nitric oxide, as a mediator of GPCR-CaMKII signaling. PMID:27079272

  1. 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.

  2. Direct positive chronotropic action by angiotensin II in the isolated mouse atrium.

    PubMed

    Mori, Toyoki; Hashimoto, Ayako

    2006-07-10

    We observed the direct positive chronotropic effect of angiotensin II in mouse atria and characterized its pharmacological property. C57BL/6J mice were anesthetized with pentobarbital and hearts were quickly excised. Atrial preparations including right and left atrium were isolated and suspended in the organ bath filled with Krebs-Henseleit solution gassed with 95% O2 and 5% CO2. Angiotensin II at concentrations of 10(-10) to 10(-6) M caused concentration-dependent increase in heart rate, and the maximal response was about 13% of that by isoproterenol. The effect was blocked by the selective AT1-receptor antagonist, losartan at concentrations of 10(-6) M, but not by the selective beta-blocker, nadolol at concentration of 10(-5) M. Furthermore, angiotensin I also caused concentration-dependent increase in heart rate, and the effect was blocked by angiotensin converting enzyme (ACE) inhibitor, captopril at concentrations of 10(-6) M. These results suggested that angiotensin I is converted to angiotensin II via ACE system in mice atria, and regulate heart rate through AT1-receptor stimulation, not by beta-adrenergic receptor. PMID:16564555

  3. [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.

  4. Angiotensin II and vasopressin are involved in the defense system against anaphylactic hypotension in anesthetized rats.

    PubMed

    Wang, Mofei; Shibamoto, Toshishige; Kuda, Yuhichi; Sun, Lingling; Tanida, Mamoru; Kurata, Yasutaka

    2014-05-15

    Anaphylactic shock is sometimes life-threatening, but the defense system against this circulatory failure was not fully understood. Ameliorating roles of angiotensin (ANG) II and vasopressin in anaphylactic hypotension were investigated in anesthetized ovalbumin-sensitized Sprague-Dawley rats. The sensitized rats were randomly allocated to the following pretreatment groups (n=7/group): (1) control (non-pretreatment), (2) ANG II synthesis inhibitor captopril, (3) ANG II receptor antagonist losartan, and (4) V1a vasopressin receptor antagonist. Anaphylactic shock was induced by an intravenous injection of the antigen. The systemic arterial pressure (SAP), central venous pressure (CVP), portal venous pressure (PVP) and portal venous blood flow (PBF) were measured, and splanchnic vascular resistance (Rspl: (SAP-PVP)/PBF) was determined. In the control group, SAP markedly decreased, followed by a gradual recovery toward baseline. Rspl transiently decreased immediately after antigen, and then increased 1.5-fold at 15 min and thereafter. The pretreatment with either losartan, captopril or V1a receptor antagonist augmented the initial fall of SAP and attenuated the SAP recovery along with augmentation of the late increase in Rspl. The 2-h survival rate was significantly smaller in either pretreatment group than in the control group (100%). Plasma levels of ANG II and vasopressin increased to 3.8- and 9.8-fold, respectively, at 30 min after antigen in the control group, whereas captopril pretreatment inhibited the increase in ANG II. In conclusion, inhibition of ANG II or vasopressin exacerbates anaphylaxis-induced hypotension in anesthetized rats. PMID:24650734

  5. Gene and MicroRNA Transcriptional Signatures of Angiotensin II in Endothelial Cells

    PubMed Central

    Mehta, Jawahar L.; Mercanti, Federico; Stone, Annjannette; Wang, Xianwei; Ding, Zufeng; Romeo, Francesco

    2015-01-01

    Abstract: Growth of atherosclerotic plaque requires neovascularization (angiogenesis). To elucidate the involvement of angiotensin II (Ang II) in angiogenesis, we performed gene microarray and microRNA (miRNA) polymerase chain reaction array analyses on human coronary artery endothelial cells exposed to moderate concentration of Ang II for 2 and 12 hours. At 12, but not 2, hours, cultures treated with Ang II exhibited shifts in transcriptional activity involving 267 genes (>1.5-fold difference; P < 0.05). Resulting transcriptome was most significantly enriched for genes associated with blood vessel development, angiogenesis, and regulation of proliferation. Majority of upregulated genes implicated in angiogenesis shared a commonality of being either regulators (HES1, IL-18, and CXCR4) or targets (ADM, ANPEP, HES1, KIT, NOTCH4, PGF, and SOX18) of STAT3. In line with these findings, STAT3 inhibition attenuated Ang II–dependent stimulation of tube formation in Matrigel assay. Expression analysis of miRNAs transcripts revealed that the pattern of differential expression for miRNAs was largely consistent with proangiogenic response with a prominent theme of upregulation of miRs targeting PTEN (miR-19b-3p, miR-21-5p, 23b-3p, and 24-3p), many of which are directly or indirectly STAT3 dependent. We conclude that STAT3 signaling may be an intrinsic part of Ang II–mediated proangiogenic response in human endothelial cells. PMID:24853489

  6. 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

  7. Hydrosmotic effect of angiotensin II in the toad skin: role of cyclic AMP.

    PubMed

    Coviello, A; Brauckmann, E S; de Atenor, M S; Apud, J A; Causarano, J

    1975-01-01

    The mechanism of action of the hydrosmotic response of the isolated skin of the toad Bufo arenarum Hensel to angiotensin II was studied by means of an indirect pharmacological approach. Angiotensin II (2.10(-10) M), vasopressin (2.10(-13) M) and theophylline (10(-4) and 10(-3) M) in subliminal doses produced a significant increase on water permeability when added in different paired combinations. Angiotensin II (2.10(-7) M) and vasopressin (2.10(-8) M) in doses producing significant effects on water permeability increased the response to submaximal doses of epinephrine (10(-6) M) but not to higher doses (10(-5) M). Acid pH (6.4) and prostaglandin E1 (2.10(-7) M) reduced significantly the hydrosmotic response to angiotensin II, but in contrast with the toad bladder, the effect was not completely abolished. Present results support the view that the hydrosmotic effect of angiotensin II in toad skin is mediated by the adenylate cyclase - cyclic AMP system. PMID:189568

  8. 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.

  9. [Duality of angiotensin II receptors and risk for stroke and cancer: what is the connection?].

    PubMed

    Fournier, A; Ghitu, A; Darabont, R; Mazouz, H; Makdassi, R; Canaple, S; Rosa, A; Fernandez, L A

    Angiotensin II (AII) acts by 2 types of receptors: the ATI receptor which mediates its actions on vasoconstriction, renin (inhibition) and aldosterone (stimulation) secretions, cellular proliferation and angiogenesis and the non-AT1 (often called AT2) receptors. Mainly expressed in the embryon these latter may favor cellular differentiation and recruitment of collateral circulation. Angiotensin converting enzyme inhibitors (ACEI) decrease the synthesis of All and therefore the stimulation of both receptor types whereas AT1-receptor antagonists (AT1RA) block only the stimulation of these latter and increase the stimulation of AT2 receptor since they increase the production of All secondarily to the inhibition of the feedback of renin secretion by All. Experimentally ACEI and AT1RA decrease angiogenesis and cellular proliferation and favor cellular differentiation which could explain the protective effect of ACEI against cancer suggested recently in a Scotish study. Despite of their common suppressive effect on angiogenesis AT1RA may better than ACEI protect against ischemic events specially the cerebral ones because they favor the rapid recruitment of collateral circulation. This has been demonstrated for losartan in case of abrupt ligation of the carotid in the gerbil since its previous administration protects against fatal cerebral ischemia whereas its previous administration with enalapril abolishes this protection. These data may explain why, in the CAPP trial, captopril which has prevented more effectively diabetes occurrence could not be proved superior to diuretics and/or betablocker in the prevention of myocardial infarction and specially of strokes for which exist on the contrary a suspicion of a lower protection. Therefore a comparative trial between AT1RA and ACEI in the prevention of stroke recurrence should appear as a priority for Public Health and Pharmaceutical Industry Authorities. PMID:10360191

  10. Oxidative stress-mediated effects of angiotensin II in the cardiovascular system

    PubMed Central

    Wen, Hairuo; Gwathmey, Judith K; Xie, Lai-Hua

    2014-01-01

    Angiotensin II (Ang II), an endogenous peptide hormone, plays critical roles in the pathophysiological modulation of cardiovascular functions. Ang II is the principle effector of the renin-angiotensin system for maintaining homeostasis in the cardiovascular system, as well as a potent stimulator of NAD(P)H oxidase, which is the major source and primary trigger for reactive oxygen species (ROS) generation in various tissues. Recent accumulating evidence has demonstrated the importance of oxidative stress in Ang II-induced heart diseases. Here, we review the recent progress in the study on oxidative stress-mediated effects of Ang II in the cardiovascular system. In particular, the involvement of Ang II-induced ROS generation in arrhythmias, cell death/heart failure, ischemia/reperfusion injury, cardiac hypertrophy and hypertension are discussed. Ca2+/calmodulin-dependent protein kinase II is an important molecule linking Ang II, ROS and cardiovascular pathological conditions. PMID:24587981

  11. 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.

  12. Association of the Serum Angiotensin II Level with Disease Severity in Severe Fever with Thrombocytopenia Syndrome Patients.

    PubMed

    Cheng, Jiamei; Li, Huiyu; Jie, Shenghua

    2016-01-01

    Objective Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a novel Bunyavirus. Recent data suggest that the physiological balance of multiple proinflammatory cytokines is substantially changed in cases of severe fever with thrombocytopenia syndrome virus (SFTSV) infection, and the inflammatory response probably plays an important role in disease progression. Angiotensin II is an important active substance of the renin-angiotensin system, and studies have demonstrated that angiotensin II is involved in key events in the inflammatory process and can regulate inflammatory cell responses. Methods In order to elucidate the role of angiotensin II in the pathogenesis of SFTS, we collected serum samples from SFTS patients in the acute or convalescent phase and tested the angiotensin II levels using an enzyme-linked immunosorbent assay as well as SFTSV viral RNA with real-time reverse-transcriptase polymerase chain reaction. Furthermore, we explored possible correlations between the angiotensin II levels and clinical parameters in SFTS patients. Results Our data showed that the serum level of angiotensin II was significantly increased in the acute phase compared with that seen in the convalescent phase and the healthy controls, while there were no significant differences between the convalescent cases and healthy controls (p>0.05). A correlation analysis demonstrated that the level of angiotensin II positively correlated with the SFTS viral RNA load. The angiotensin II levels were also found to be correlated with clinical parameters indicating impairments in organ functions. Moreover, we also found that the angiotensin II levels were significantly increased in the severe cases versus the non-severe cases (p<0.001). Conclusion The serum angiotensin II levels in SFTS patients may be used to stratify the disease severity and are possibly predictive of disease outcomes. PMID:27086801

  13. LCZ696 (angiotensin-neprilysin inhibition): the new kid on the heart failure block?

    PubMed

    Pham, Antony Q; Patel, Yesha; Gallagher, Brittany

    2015-04-01

    Angiotensin-converting enzyme inhibitors (ACEIs) have been the cornerstone in systolic heart failure (HF) regimens over the past 25 years. Their ability to block the renin-angiotensin-aldosterone system and their vasodilatory properties has repeatedly been shown to lower morbidity and mortality in patients with HF having reduced ejection fractions. In August 2014, the New England Journal of Medicine published a large trial studying a novel LCZ696 (angiotensin-neprilysin inhibition) agent against enalapril, an ACEI. In the phase III trial, LCZ696 demonstrated superiority to enalapril in composite death from cardiovascular causes and hospitalization for HF. The trial was stopped early due to overwhelming benefit of the study agent. This article provides an extensive review of the mechanism of action, pharmacokinetic properties, clinical efficacy, safety, and tolerability of LCZ696. PMID:25864789

  14. Role of EGFR transactivation in angiotensin II signaling to extracellular regulated kinase in preglomerular smooth muscle cells.

    PubMed

    Andresen, Bradley T; Linnoila, Jenny J; Jackson, Edwin K; Romero, Guillermo G

    2003-03-01

    Angiotensin (Ang) II promotes the phosphorylation of extracellular regulated kinase (ERK); however, the mechanisms leading to Ang II-induced ERK phosphorylation are debated. The currently accepted theory involves transactivation of epidermal growth factor receptor (EGFR). We have shown that generation of phosphatidic acid (PA) is required for the recruitment of Raf to membranes and the activation of ERK by multiple agonists, including Ang II. In the present report, we confirm that phospholipase D-dependent generation of PA is required for Ang II-mediated phosphorylation of ERK in Wistar-Kyoto and spontaneously hypertensive rat preglomerular smooth muscle cells (PGSMCs). However, EGF stimulation does not activate phospholipase D or generate PA. These observations indicate that EGF recruits Raf to membranes via a mechanism that does not involve PA, and thus, Ang II-mediated phosphorylation of ERK is partially independent of EGFR-mediated signaling cascades. We hypothesized that phosphoinositide-3-kinase (PI3K) can also act to recruit Raf to membranes; therefore, inhibition of PI3K should inhibit EGF signaling to ERK. Wortmannin, a PI3K inhibitor, inhibited EGF-mediated phosphorylation of ERK (IC50, approximately 14 nmol/L). To examine the role of the EGFR in Ang II-mediated phosphorylation of ERK we utilized 100 nmol/L wortmannin to inhibit EGFR signaling to ERK and T19N RhoA to block Ang II-mediated ERK phosphorylation. Wortmannin treatment inhibited EGF-mediated but not Ang II-mediated phosphorylation of ERK. Furthermore, T19N RhoA inhibited Ang II-mediated ERK phosphorylation, whereas T19N RhoA had significantly less effect on EGF-mediated ERK phosphorylation. We conclude that transactivation of the EGFR is not primarily responsible for Ang II-mediated activation of ERK in PGSMCs. PMID:12623996

  15. Activation of the retinoid X receptor modulates angiotensin II-induced smooth muscle gene expression and inflammation in vascular smooth muscle cells.

    PubMed

    Lehman, Allison M B; Montford, John R; Horita, Henrick; Ostriker, Allison C; Weiser-Evans, Mary C M; Nemenoff, Raphael A; Furgeson, Seth B

    2014-11-01

    The retinoid X receptor (RXR) partners with numerous nuclear receptors, such as the peroxisome proliferator activated receptor (PPAR) family, liver X receptors (LXRs), and farnesoid X receptor (FXR). Although each heterodimer can be activated by specific ligands, a subset of these receptors, defined as permissive nuclear receptors, can also be activated by RXR agonists known as rexinoids. Many individual RXR heterodimers have beneficial effects in vascular smooth muscle cells (SMCs). Because rexinoids can potently activate multiple RXR pathways, we hypothesized that treating SMCs with rexinoids would more effectively reverse the pathophysiologic effects of angiotensin II than an individual heterodimer agonist. Cultured rat aortic SMCs were pretreated with either an RXR agonist (bexarotene or 9-cis retinoic acid) or vehicle (dimethylsulfoxide) for 24 hours before stimulation with angiotensin II. Compared with dimethylsulfoxide, bexarotene blocked angiotensin II-induced SM contractile gene induction (calponin and smooth muscle-α-actin) and protein synthesis ([(3)H]leucine incorporation). Bexarotene also decreased angiotensin II-mediated inflammation, as measured by decreased expression of monocyte chemoattractant protein-1 (MCP-1). Activation of p38 mitogen-activated protein (MAP) kinase but not extracellular signal-related kinase (ERK) or protein kinase B (Akt) was also blunted by bexarotene. We compared bexarotene to five agonists of nuclear receptors (PPARα, PPARγ, PPARδ, LXR, and FXR). Bexarotene had a greater effect on calponin reduction, MCP-1 inhibition, and p38 MAP kinase inhibition than any individual agonist. PPARγ knockout cells demonstrated blunted responses to bexarotene, indicating that PPARγ is necessary for the effects of bexarotene. These data demonstrate that RXR is a potent modulator of angiotensin II-mediated responses in the vasculature, partially through inhibition of p38. PMID:25169989

  16. 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

  17. Conundrum of angiotensin II and TGF-β interactions in aortic aneurysms.

    PubMed

    Chen, Xiaofeng; Lu, Hong; Rateri, Debra L; Cassis, Lisa A; Daugherty, Alan

    2013-04-01

    Angiotensin II (AngII) has been invoked as a principal mediator for the development and progression of both thoracic and abdominal aortic aneurysms. While there is consistency in experimental and clinical studies that overactivation of the renin angiotensin system promotes aortic aneurysm development, there are many unknowns regarding the mechanistic basis underlying AngII-induced aneurysms. Interactions of AngII with TGF-β in both thoracic and abdominal aortic aneurysms have been the focus of recent studies. While these studies have demonstrated profound effects of manipulating TGF-β activity on AngII-induced aortic aneurysms, they have also led to more questions regarding the interactions between AngII and this multifunctional cytokine. This review compiled the recent literature to provide insights into understanding the potentially complex interactions between AngII and TGF-β in the development of aortic aneurysms. PMID:23395156

  18. The angiotensin II type 1 receptor blocker candesartan suppresses proliferation and fibrosis in gastric cancer.

    PubMed

    Okazaki, Mitsuyoshi; Fushida, Sachio; Harada, Shinichi; Tsukada, Tomoya; Kinoshita, Jun; Oyama, Katsunobu; Tajima, Hidehiro; Ninomiya, Itasu; Fujimura, Takashi; Ohta, Tetsuo

    2014-12-01

    Gastric cancer with peritoneal dissemination has poor clinical prognosis because of the presence of rich stromal fibrosis and acquired drug resistance. Recently, Angiotensin II type I receptor blockers such as candesartan have attracted attention for their potential anti-fibrotic activity. We examined whether candesartan could attenuate tumor proliferation and fibrosis through the interaction between gastric cancer cell line (MKN45) cells and human peritoneal mesothelial cells. Candesartan significantly reduced TGF-β1 expression and epithelial-to-mesenchymal transition-like change, while tumor proliferation and stromal fibrosis were impaired. Targeting the Angiotensin II signaling pathway may therefore be an efficient strategy for treatment of tumor proliferation and fibrosis. PMID:25224569

  19. Inhibition of phosphatidylcholine synthesis by vasopressin and angiotensin in rat hepatocytes.

    PubMed Central

    Alemany, S; Varela, I; Mato, J M

    1982-01-01

    The addition of 1 microM-vasopressin or -angiotensin to isolated rat hepatocytes induced a fast transient inhibition of the rate of incorporation of [Me-3H]choline into phosphatidylcholine. The cationophore A23187 induced a similar inhibition of phosphatidylcholine synthesis. The addition of micromolar Ca2+ to rat liver microsomes inhibited the activity of CDP-choline: 1,2-diacylglycerol cholinephosphotransferase. This inhibition is due a decrease in the Vmax. of the enzyme without affecting the Km for CDP-choline. It is concluded that Ca2+ regulates phosphatidylcholine synthesis in rat liver. PMID:6818955

  20. Angiotensin II Stimulation of Cardiac Hypertrophy and Functional Decompensation in Osteoprotegerin-Deficient Mice.

    PubMed

    Tsuruda, Toshihiro; Sekita-Hatakeyama, Yoko; Hao, Yilin; Sakamoto, Sumiharu; Kurogi, Syuji; Nakamura, Midori; Udagawa, Nobuyuki; Funamoto, Taro; Sekimoto, Tomohisa; Hatakeyama, Kinta; Chosa, Etsuo; Kato, Johji; Asada, Yujiro; Kitamura, Kazuo

    2016-05-01

    Circulating and myocardial expressions of receptor activator of nuclear factor-κb ligand and osteoprotegerin are activated in heart failure; however, it remains to be determined their pathophysiological roles on left ventricular structure and function in interaction with renin-angiotensin system. We conducted experiments using 8-week-old osteoprotegerin(-/-)mice and receptor activator of nuclear factor-κb ligand-transgenic mice to assess whether they affect the angiotensin II-induced left ventricular remodeling. Subcutaneous infusion of angiotensin II to osteoprotegerin(-/-)mice progressed the eccentric hypertrophy, resulting in left ventricular systolic dysfunction for 28 days, and this was comparable with wild-type mice, showing concentric hypertrophy, irrespective of equivalent elevation of systolic blood pressure. The structural alteration was associated with reduced interstitial fibrosis, decreased procollagen α1 and syndecan-1 expressions, and the increased number of apoptotic cells in the left ventricle, compared with wild-type mice. In contrast, angiotensin II infusion to the receptor activator of nuclear factor-κb ligand-transgenic mice revealed the concentric hypertrophy with preserved systolic contractile function. Intraperitoneal administration of human recombinant osteoprotegerin, but not subcutaneous injection of anti-receptor activator of nuclear factor-κb ligand antibody, to the angiotensin II-infused osteoprotegerin(-/-)mice for 28 days ameliorated the progression of heart failure without affecting systolic blood pressure. These results underscore the biological activity of osteoprotegerin in preserving myocardial structure and function during the angiotensin II-induced cardiac hypertrophy, independent of receptor activator of nuclear factor-κb ligand activity. In addition, the antiapoptotic and profibrotic actions of osteoprotegerin that emerged from our data might be involved in the mechanisms. PMID:27001297

  1. The Novel Angiotensin II Receptor Blocker Azilsartan Medoxomil Ameliorates Insulin Resistance Induced by Chronic Angiotensin II Treatment in Rat Skeletal Muscle

    PubMed Central

    Lastra, Guido; Santos, Fernando R.; Hooshmand, Payam; Hooshmand, Paria; Mugerfeld, Irina; Aroor, Annayya R.; DeMarco, Vincent G.; Sowers, James R.; Henriksen, Erik J.

    2013-01-01

    Angiotensin receptor (type 1) blockers (ARBs) can reduce both hypertension and insulin resistance induced by local and systemic activation of the renin-angiotensin-aldosterone system. The effectiveness of azilsartan medoxomil (AZIL-M), a novel imidazole-based ARB, to facilitate metabolic improvements in conditions of angiotensin II (Ang II)-associated insulin resistance is currently unknown. The aim of this study was to determine the impact of chronic AZIL-M treatment on glucose transport activity and key insulin signaling elements in red skeletal muscle of Ang II-treated rats. Male Sprague-Dawley rats were treated for 8 weeks with or without Ang II (200 ng/kg/min) combined with either vehicle or AZIL-M (1 mg/kg/day). Ang II induced significant (p < 0.05) increases in blood pressure, which were completely prevented by AZIL-M. Furthermore, Ang II reduced insulin-mediated glucose transport activity in incubated soleus muscle, and AZIL-M co-treatment increased this parameter. Moreover, AZIL-M treatment of Ang II-infused animals increased the absolute phosphorylation of insulin signaling molecules, including Akt [both Ser473 (81%) and Thr308 (23%)] and AS160 Thr642 (42%), in red gastrocnemius muscle frozen in situ. Absolute AMPKα (Thr172) phosphorylation increased (98%) by AZIL-M treatment, and relative Thr389 phosphorylation of p70 S6K1, a negative regulator of insulin signaling, decreased (51%) with AZIL-M treatment. These results indicate that ARB AZIL-M improves the in vitro insulin action on glucose transport in red soleus muscle and the functionality of the Akt/AS160 axis in red gastrocnemius muscle in situ in Ang II-induced insulin-resistant rats, with the latter modification possibly associated with enhanced AMPKα and suppressed p70 S6K1 activation. PMID:23922555

  2. Direct angiotensin II type 2 receptor stimulation decreases dopamine synthesis in the rat striatum.

    PubMed

    Mertens, Birgit; Vanderheyden, Patrick; Michotte, Yvette; Sarre, Sophie

    2010-06-01

    A relationship between the central renin angiotensin system and the dopaminergic system has been described in the striatum. However, the role of the angiotensin II type 2 (AT(2)) receptor in this interaction has not yet been established. The present study examined the outcome of direct AT(2) receptor stimulation on dopamine (DA) release and synthesis by means of the recently developed nonpeptide AT(2) receptor agonist, compound 21 (C21). The effects of AT(2) receptor agonism on the release of DA and its major metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and on the activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in the catecholamine biosynthesis, were investigated using in vivo microdialysis. Local administration of C21 (0.1 and 1 microM) resulted in a decrease of the extracellular DOPAC levels, whereas extracellular DA concentrations remained unaltered, suggesting a reduced synthesis of DA. This effect was mediated by the AT(2) receptor since it could be blocked by the AT(2) receptor antagonist PD123319 (1 microM). A similar effect was observed after local striatal (10 nM) as well as systemic (0.3 and 3 mg/kg i.p.) administration of the AT(1) receptor antagonist, candesartan. TH activity as assessed by accumulation of extracellular levels of L-DOPA after inhibition of amino acid decarboxylase with NSD1015, was also reduced after local administration of C21 (0.1 and 1 microM) and candesartan (10 nM). Together, these data suggest that AT(1) and AT(2) receptors in the striatum exert an opposite effect on the modulation of DA synthesis rather than DA release. PMID:20097214

  3. Angiotensin II receptor subtypes in rat renal preglomerular vessels.

    PubMed

    De León, H; Garcia, R

    1992-01-01

    A simple technique to isolate rat renal preglomerular vessels is described. Kidneys were pressed against a 0.3 mm stainless steel grid. The whole vascular tree, including the interlobar, arcuate, and interlobular arteries, as well as the afferent arterioles, remained on the grid surface from where they were recovered. Extensive washing yielded a highly pure preparation of renal microvessels. Radioligand binding experiments were performed to characterize 125I-[Sar1,Ile8]-ANG II binding sites in preglomerular microvessel membranes. Equilibrium saturation binding experiments revealed the presence of one group of high affinity receptors (Kd = 1.22 +/- 0.171 nM; Bmax = 209 +/- 14 fmol/mg protein). Competitive inhibition experiments with two highly specific nonpeptide ANG II antagonists, losartan (DuP 753), which is specific for the AT1 receptor subtype, and PD123319, which is specific for the AT2 subtype, demonstrated that the large majority of, if not all, ANG II receptors in rat renal preglomerular vessels correspond to the AT1 subtype. PMID:1299411

  4. 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. PMID:26661654

  5. Effects of Angiotensin II Receptor Blockers on Metabolism of Arachidonic Acid via CYP2C8.

    PubMed

    Senda, Asuna; Mukai, Yuji; Toda, Takaki; Hayakawa, Toru; Yamashita, Miki; Eliasson, Erik; Rane, Anders; Inotsume, Nobuo

    2015-01-01

    Arachidonic acid (AA) is metabolized to epoxyeicosatrienoic acids (EETs) via cytochrome enzymes such as CYP 2C9, 2C8 and 2J2. EETs play a role in cardioprotection and regulation of blood pressure. Recently, adverse reactions such as sudden heart attack and fatal myocardial infarction were reported among patients taking angiotensin II receptor blockers (ARBs). As some ARBs have affinity for these CYP enzymes, metabolic inhibition of AA by ARBs is a possible cause for the increase in cardiovascular events. In this study, we quantitatively investigated the inhibitory effects of ARBs on the formation of EETs and further metabolites, dihydroxyeicosatrienoic acids (DHETs), from AA via CYP2C8. In incubations with recombinant CYP2C8 in vitro, the inhibitory effects were compared by measuring EETs and DHETs by HPLC-MS/MS. Inhibition of AA metabolism by ARBs was detected in a concentration-dependent manner with IC50 values of losartan (42.7 µM), telmisartan (49.5 µM), irbesartan (55.6 µM), olmesartan (66.2 µM), candesartan (108 µM), and valsartan (279 µM). Losartan, telmisartan and irbesartan, which reportedly accumulate in the liver and kidneys, have stronger inhibitory effects than other ARBs. The lower concentration of EETs leads to less protective action on the cardiovascular system and a higher incidence of adverse effects such as sudden heart attack and myocardial infarction in patients taking ARBs. PMID:26632190

  6. Comparison of the hypertrophic effect of phorbol ester, norepinephrine, angiotensin II and contraction on cultured cardiomyocytes

    SciTech Connect

    Allo, S.N.; Carl, L.L.; Morgan, H.E. )

    1991-03-15

    Phorbol 12-myristate 13-acetate (PMA), norepinephrine (NE), angiotensin II (AII) and contraction stimulate cardiomyocyte growth. Differences exist in the time course and extent of protein and RNA accumulation. Cells plated at 4 {times} 10{sup 6} cells/60mm dish and arrested with 50 mM KCl demonstrated no significant growth. Treatment with PMA stimulated growth to a maximum of 17% at 48 h. In contrast, maximal stimulation of growth was 36% at 48 h and 31% at 72 h for contracting and NE treated cells, respectively. Maximal stimulation of the capacity for protein synthesis was 32% for PMA treated cells at 24 h as compared to 59% and 77% for NE treated and contracting cells respectively at 72 h. In support of a primary role for altered capacity in the regulation of protein synthesis, there was a significant correlation between RNA and protein content independent of the stimulus used. AII increased RNA content by 28% at 48h, but had no effect on growth up to 72h. Treatment with staurosporine blocked the stimulation of growth, suggestive of a role for protein kinase C (PKC). However, the inhibition of contraction-induced growth was due in part to a reduction in the rate of contraction. It was concluded that: significant differences existed in the time course of growth stimulation and RNA accumulation, depending on the stimulus; and growth inhibition by staurosporine is suggestive of an important role of PKC in hypertrophic growth induced by these stimuli.

  7. CYP4A2-Induced Hypertension is 20-HETE and Angiotensin II-Dependent

    PubMed Central

    Sodhi, Komal; Wu, Cheng-Chia; Cheng, Jennifer; Gotlinger, Katherine; Inoue, Kazuyoshi; Goli, Mohan; Falck, John R.; Abraham, Nader G.; Schwartzman, Michal L.

    2010-01-01

    We have previously shown that increased vascular endothelial expression of CYP4A2 leads to 20-HETE-dependent hypertension. The renin-angiotensin system (RAS) is a key regulator of blood pressure. In this study, we examined possible interactions between 20-HETE and RAS. In normotensive (110±3 mmHg) Sprague Dawley rats transduced with a lentivirus expressing the CYP4A2 cDNA under the control of an endothelial-specific promoter (VECAD-4A2), systolic blood pressure increased rapidly, reaching 139±1, 145±3 and 150±2 mmHg at 3, 5 and 10 days after transduction; blood pressure remained elevated, thereafter, with maximum levels of 163±3 mmHg. Treatment with lisinopril, losartan or the 20-HETE antagonist 20-hydroxyeicosa-6(Z), 15(Z)-dienoic acid (20-HEDE) decreased blood pressure to control values, but blood pressure returned to its high levels after cessation of treatment. Endothelial-specific overexpression of CYP4A2 resulted in increased expression of vascular angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) and increased levels of plasma and tissue Angiotensin II; all were attenuated by treatment with HET0016, an inhibitor of 20-HETE synthesis, or with 20-HEDE. In cultured endothelial cells, 20-HETE specifically and potently induced ACE expression without altering the expression of ACE2, angiotensinogen or angiotensin II receptors. This is the first study to demonstrate that 20-HETE, a key constrictor eicosanoid in the microcirculation, induces ACE and AT1R expression and increases Angiotensin II levels, suggesting that the mechanisms by which 20-HETE promotes hypertension include activation of RAS that is likely initiated at the level of ACE induction. PMID:20837888

  8. 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

  9. ACE2 Decreases Formation and Severity of Angiotensin II-induced Abdominal Aortic Aneurysms

    PubMed Central

    Thatcher, Sean E.; Zhang, Xuan; Howatt, Deborah A.; Yiannikouris, Frederique; Gurley, Susan B.; Ennis, Terri; Curci, John A.; Daugherty, Alan; Cassis, Lisa A.

    2014-01-01

    Objective Angiotensin converting enzyme 2 (ACE2) cleaves angiotensin II (AngII) to form angiotensin-(1-7) (Ang-(1-7)), which generally opposes effects of AngII. AngII infusion into hypercholesterolemic male mice induces formation of abdominal aortic aneurysms (AAAs). This study tests the hypothesis that deficiency of ACE2 promotes AngII-induced AAAs, while ACE2 activation suppresses aneurysm formation. Approach and Results ACE2 protein was detectable by immunostaining in mice and human AAAs. Whole body deficiency of ACE2 significantly increased aortic lumen diameters and external diameters of suprarenal aortas from AngII-infused mice. Conversely, ACE2 deficiency in bone marrow-derived cells had no effect on AngII-induced AAAs. In contrast to AngII-induced AAAs, ACE2 deficiency had no significant effect on external aortic diameters of elastase-induced AAAs. Since ACE2 deficiency promoted AAA formation in AngII-infused mice, we determined if ACE2 activation suppressed AAAs. ACE2 activation by administration of diminazine aceturate (DIZE, 30 mg/kg/day) to Ldlr−/− mice increased kidney ACE2 mRNA abundance and activity and elevated plasma Ang-(1-7) concentrations. Unexpectedly, administration of DIZE significantly reduced total sera cholesterol and VLDL-cholesterol concentrations. Notably, DIZE significantly decreased aortic lumen diameters and aortic external diameters of AngII-infused mice resulting in a marked reduction in AAA incidence (from 73 to 29%). None of these effects of DIZE were observed in the Ace2−/y mice. Conclusions These results demonstrate that ACE2 exerts a modulatory role in AngII-induced AAA formation, and that therapeutic stimulation of ACE2 could be a benefit to reduce AAA expansion and rupture in patients with an activated renin-angiotensin system. PMID:25301841

  10. Angiotensin II AT2 receptors regulate NGF-mediated neurite outgrowth via the NO-cGMP pathway.

    PubMed

    Hashikawa-Hobara, Narumi; Hashikawa, Naoya

    2016-09-16

    We investigated whether Angiotensin II type 2 (AT2) receptor activation was involved in NGF-induced nerve regeneration. NGF-mediated neurite outgrowth in cultured dorsal root ganglia (DRG) cells was significantly inhibited by AT2 receptor antagonist (PD123,319) treatment. AT2 receptor knockdown also inhibited NGF-mediated neurite outgrowth. To determine the mechanisms, we analyzed the NO-cGMP pathway. The cGMP analog increased NGF-mediated nerve elongation, which inhibited by PD123,319. Furthermore, soluble guanylate cyclase expression was significantly less in NGF and PD123,319 treatment DRG than in NGF treatment alone. These results suggest that NGF-mediated neurite outgrowth is suppressed by AT2 receptor signaling via the NO-cGMP-PKG pathway. PMID:27524238