Published Online
on August 23, 2004

A more recent version of this article appeared on October 1, 2004

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Submitted on December 4, 2003
Revised on January 3, 2004

Nonpeptide AVE 0991 Is an Angiotensin-(1-7) Receptor Mas Agonist in the Mouse Kidney

Sérgio Veloso Brant Pinheiro; Ana Cristina Simões e Silva; Walkyria Oliveira Sampaio; Renata Dutra de Paula; Elizabeth Pereira Mendes; Elizabete Dias Bontempo; João Bosco Pesquero; Thomas Walther; Natalia Alenina; Michael Bader; Markus Bleich; and Robson Augusto Souza Santos^*

From the Departamento de Fisiologia e Biofísica (S.V.B.P., W.O.S., R.D.D., E.P.M., E.D.B., R.A.S.S.), Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Brazil; Departamento de Pediatria (A.C.S.), Faculdade de Medicina, Universidade Federal de Minas Gerais, Brazil; Departamento de Biofísica da Universidade Federal de São Paulo, Brazil (J.B.P.); Department of Pharmacology (T.W.), Erasmus Medical Center, Rotterdam, Netherlands; Max-Delbrück Center for Molecular Medicine (N.A., M. Bader), Berlin, Germany; and Physiologisches Institut (M. Bleich), Christan-Albrechts-University of Kiel, Germany.

^* To whom correspondence should be addressed. E-mail: marrob{at}dedalus.lcc.ufmg.br.

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=4.75x10^-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.

Key words: receptors, angiotensin • angiotensin • angiotensin II

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