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

TLDR

The renin–angiotensin system regulates blood pressure and fluid balance, and Ang-(1–7) is a heptapeptide that counteracts Ang II’s effects through a distinct, as‑yet‑unidentified receptor. Deletion of the Mas receptor eliminates Ang-(1–7) binding, antidiuretic, and vasorelaxant actions, demonstrating that Mas is the functional receptor mediating Ang-(1–7)’s physiological effects.

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.