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Nonpeptide AVE 0991 is an angiotensin-(1-7) receptor Mas agonist in the mouse kidney

Item Type:Article
Title:Nonpeptide AVE 0991 is an angiotensin-(1-7) receptor Mas agonist in the mouse kidney
Creators Name:Pinheiro, S.V.B. and Simoes e Silva, A.C. and Sampaio, W.O. and de Paula, R.D. and Mendes, E.P. and Bontempo, E.D. and Pesquero, J.B. and Walther, T. and Alenina, N. and Bader, M. and Bleich, M. and Santos, R.A.S.
Abstract:It has been described recently that the nonpeptide AVE 0991 (AVE) mimics the effects of angiotensin-(1-7) [Ang-(1-7)] in bovine endothelial cells. In this study, we tested the possibility that AVE is an agonist of the Ang-(1-7) receptor Mas, in vitro and in vivo. In water-loaded C57BL/6 mice, AVE (0.58 nmol/g body weight) produced a significant reduction in urinary volume (0.06±0.03 mL/60 min [n=9] versus 0.27±0.05 [n=9]; P<0.01), associated with an increase in urinary osmolality. The Ang-(1-7) antagonist A-779 completely blocked the antidiuretic effect of AVE. As observed previously for Ang-(1-7), the antidiuretic effect of AVE after water load was blunted in Mas-knockout mice (0.37±0.10 mL/60 min [n=9] versus 0.27±0.03 mL/60 min [n=11] AVE-treated mice). In vitro receptor autoradiography in C57BL/6 mice showed that the specific binding of 125I-Ang-(1-7) to mouse kidney slices was displaced by AVE, whereas no effects were observed in the binding of 125I-angiotensin II or 125I-angiotensin IV. Furthermore, AVE displaced the binding of 125I-Ang-(1-7) in Mas-transfected monkey kidney cells (COS) cells (IC50=4. 75×10-8 mol/L) and of rhodamine-Ang-(1-7) in Mas-transfected Chinese hamster ovary (CHO) cells. It also produced NO release in Mas-transfected CHO cells blocked by A-779 but not by angiotensin II type-1 (AT1) and AT2 antagonists. Contrasting with these data, the antidiuretic effect of AVE was totally blocked by AT2 antagonists and partially blocked (≈60%) by AT1 antagonists. The binding data, the results obtained in Mas-knockout mice and in Mas-transfected cells, show that AVE is a Mas receptor agonist. Our data also suggest the involvement of AT2/AT1-related mechanisms, including functional antagonism, oligomerization or cross-talk, in the renal responses to AVE.
Keywords:Angiotensin, Angiotensin II, Angiotensin Receptors, Animals, Mice
Publisher:American Heart Association (U.S.A.)
Page Range:490-496
Date:1 October 2004
Official Publication:https://doi.org/10.1161/01.HYP.0000141438.64887.42
PubMed:View item in PubMed

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