Angiotensin-(1-7) and Its Effects in the Kidney

Abstract

Angiotensin-(1-7) (Ang-[1-7]) is a heptapeptide member of the renin-angiotensin system (RAS), and acts as a vasodilator and antagonist of angiotensin II (Ang II) in the vasculature. The role of Ang-(1-7) in regulating kidney function is not well understood. Within the kidneys, Ang-(1-7) is generated by angiotensin-converting enzyme 2 (ACE2)–mediated degradation of Ang II, sequential cleavage of the precursor angiotensin I (Ang I) by ACE2 and ACE, or the actions of brush-border membrane peptidases on Ang I. Ang-(1-7) mediates its effects via binding to kidney Mas receptors, although some actions may occur via Ang II AT1 or AT2 receptors. In vitro studies suggest that Ang-(1-7) is an intrarenal vasodilator. Ang-(1-7) has been reported to induce either natriuresis/diuresis or sodium and water retention, via modulation of sodium transporters in the proximal tubule and loop of Henle, and collecting duct water transport. In the proximal tubule, Ang-(1-7) antagonizes growth-promoting signaling pathways via activation of a protein tyrosine phosphatase, whereas in mesangial cells, Ang-(1-7) stimulates cell growth via activation of mitogen-activated protein kinases. The phenotype of the Mas gene knockout mouse suggests that Ang-(1-7)–signaling events exert cardiovascular protection by regulating blood pressure, and by limiting production of reactive oxygen species and extracellular matrix proteins. Ang-(1-7) also protects against renal injury in the renal wrap hypertension model, independent of effects on blood pressure. In diabetic nephropathy, however, the role of Ang-(1-7) on disease progression remains unclear. In summary, Ang-(1-7) and its receptor Mas have emerged as important components of the intrarenal RAS. The signaling and downstream effects of Ang-(1-7) in the kidney are complex and appear to be cell specific. The body of evidence suggests that Ang-(1-7) is protective against endothelial dysfunction or Ang II–stimulated proximal tubular injury, although the overall effects on glomerular function require further study.