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. 2003 Jul 8;100(14):8258-63.
doi: 10.1073/pnas.1432869100. Epub 2003 Jun 26.

Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas

Robson A S Santos  1 , Ana C Simoes e Silva, Christine Maric, Denise M R Silva, Raquel Pillar Machado, Insa de Buhr, Silvia Heringer-Walther, Sergio Veloso B Pinheiro, Myriam Teresa Lopes, Michael Bader, Elizabeth P Mendes, Virgina Soares Lemos, Maria Jose Campagnole-Santos, Heinz-Peter Schultheiss, Robert Speth, Thomas Walther
Affiliations

Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas

Robson A S Santos et al. Proc Natl Acad Sci U S A. .

Abstract

The renin-angiotensin system plays a critical role in blood pressure control and body fluid and electrolyte homeostasis. Besides angiotensin (Ang) II, other Ang peptides, such as Ang III [Ang-(2-8)], Ang IV [Ang-(3-8)], and Ang-(1-7) may also have important biological activities. Ang-(1-7) has become an angiotensin of interest in the past few years, because its cardiovascular and baroreflex actions counteract those of Ang II. Unique angiotensin-binding sites specific for this heptapeptide and studies with a selective Ang-(1-7) antagonist indicated the existence of a distinct Ang-(1-7) receptor. We demonstrate that genetic deletion of the G protein-coupled receptor encoded by the Mas protooncogene abolishes the binding of Ang-(1-7) to mouse kidneys. Accordingly, Mas-deficient mice completely lack the antidiuretic action of Ang-(1-7) after an acute water load. Ang-(1-7) binds to Mas-transfected cells and elicits arachidonic acid release. Furthermore, Mas-deficient aortas lose their Ang-(1-7)-induced relaxation response. Collectively, these findings identify Mas as a functional receptor for Ang-(1-7) and provide a clear molecular basis for the physiological actions of this biologically active peptide.

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Figures

Fig. 1.
Fig. 1.
Angiotensin receptor binding in WT and Mas knockout (KO) mouse kidneys. (A) Nonspecific, total AT1, and total AT2 binding of 125I-[Sar-1, Ile-8]Ang II binding in WT (Upper) and Mas-knockout (Lower) kidneys. (B) Nonspecific and total 125I-Ang (1–7) binding in WT (Upper) and Mas-knockout (Lower) kidneys. (C) Specific binding of 125I-[Sar-1, Ile-8] Ang II to AT1 (AT1 R) and AT2 (AT2 R) receptors in WT (+/+) and Mas-deficient (-/-) kidneys (Left) and specific binding of 125I-Ang (1–7) binding to WT (+/+) and Mas-knockout (-/-) kidneys (Right). Bars represent mean of six kidneys ± SEM. (D) Representative autoradiographic localizations of 125I-angiotensin IV binding in WT and Mas knockout mouse kidneys. Color bars (Right)reflect pseudocolor imaging of different levels of exposure of the autoradiogram converted to units of fmol/g as described in Materials and Methods. (Bar = 2 mm.)
Fig. 2.
Fig. 2.
(A) Saturation isotherm and scatchard plot (Inset) of specific 125I-Ang-(1–7) binding to Mas-transfected COS cells. Cells were incubated with increasing concentrations of 125I-Ang-(1–7). No specific binding was determined in the presence of 1 μmol/liter Ang-(1–7). These data are represented as mean ± SEM of three different experiments. In the conditions used, the nonspecific binding averaged 40–60% of the total binding. (B) Competition for 125I-Ang-(1–7) binding to Mas-transfected CHO cells by Ang-(1–7) and receptor antagonists. Competition curves were generated by adding increasing concentrations of CV-9174, PD 123319, A-779, and Ang-(1–7) to the incubation buffer containing 0.4 nmol/liter of 125I-Ang-(1–7). Data are presented as mean ± SEM of three to six independent experiments.
Fig. 3.
Fig. 3.
Effect of the Ang-(1–7) antagonist A-779 on the Ang-(1–7)-induced [3H]AA release from Mas-transfected CHO cells. Data are presented as mean ± SEM of three to six independent experiments performed in triplicate. **, P < 0.01 compared with untreated Mas-transfected CHO, ANOVA followed by Newman–Keuls test; #, P < 0.05 compared with Ang-(1–7) 10-8 M, nonpaired t test.
Fig. 4.
Fig. 4.
Effect of the Ang-(1–7) antagonist A-779, irbesartan (AT1 receptor antagonist) or PD123319 (AT2 receptor antagonist) on Ang-(1–7)-induced [3H]AA release from Mas-transfected COS cells. Data are presented as mean ± SEM of three to six independent experiments performed in triplicate.
Fig. 5.
Fig. 5.
Antidiuretic effect of Ang-(1–7) and AVP in water-loaded mice. Male control (n = 25) and Mas-deficient (n = 24) mice (25–35 g) were used. (A) Effect of Ang-(1–7) on water diuresis. (B) Effect of Ang-(1–7) on urine osmolality. (C) Effect of AVP on water diuresis (the same experimental protocol was used). Data are presented as mean ± SEM. *, P < 0.05 compared with the vehicle-treated mice (ANOVA followed by Newman–Keuls test).
Fig. 6.
Fig. 6.
Vasodilator effect of Ang-(1–7) in endothelium-containing aortic rings from WT (control) and Mas-knockout mice (knockout). (A) Tracing illustrating the effect of Ang-(1–7) on preconstricted aorta rings. Vessels were preconstricted by incubation with 0.3 mM phenylephrine. Numbers below the arrows indicate log of the peptide concentration (0.0001–0.3 μM). The arrows without numbers indicate concentrations 3-fold higher than the previous addition. (B) Diagram summarizing the vasodilator effect of Ang-(1–7) in the aortic rings of both animal models. Each point represents mean ± SEM generated from five separated experiments. P < 0.001 (two-way ANOVA).
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