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

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 I-125-Ang-(1-7) to mouse kidney slices was displaced by AVE, whereas no effects were observed in the binding of I-125-angiotensin II or I-125-angiotensin IV. Furthermore, AVE displaced the binding of I-125-Ang-(1-7) in Mas-transfected monkey kidney cells (COS) cells (IC50 = 4.75 x 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 (approximate to 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 AT(2)/AT(1)-related mechanisms, including functional antagonism, oligomerization or cross-talk, in the renal responses to AVE.Univ Fed Minas Gerais, Inst Biol Sci, Dept Physiol & Biophys, BR-31270901 Belo Horizonte, MG, BrazilUniv Fed Minas Gerais, Fac Med, Dept Pediat, Belo Horizonte, MG, BrazilUniversidade Federal de São Paulo, Dept Biofis, São Paulo, BrazilErasmus MC, Dept Pharmacol, Rotterdam, NetherlandsMax Delbruck Ctr Mol Med, Berlin, GermanyUniv Kiel, Inst Physiol, D-2300 Kiel, GermanyUniversidade Federal de São Paulo, Dept Biofis, São Paulo, BrazilWeb of Scienc