Compound 21 (C-21) is a highly selective nonpeptide AT2 receptor (AT2R) agonist.Objective:
To test the hypothesis that renal proximal tubule AT2Rs induce natriuresis and lower blood pressure in Sprague-Dawley rats and mice.Methods and Results:
In rats, AT2R activation with intravenous C-21 increased urinary sodium excretion by 10-fold (P<0.0001); this natriuresis was abolished by direct renal interstitial infusion of specific AT2R antagonist PD-123319. C-21 increased fractional excretion of Na+ (P<0.05) and lithium (P<0.01) without altering renal hemodynamic function. AT2R activation increased renal proximal tubule cell apical membrane AT2R protein (P<0.001) without changing total AT2R expression and internalized/inactivated Na+-H+ exchanger-3 and Na+/K+ATPase. C-21–induced natriuresis was accompanied by an increase in renal interstitial cGMP (P<0.01); C-21–induced increases in urinary sodium excretion and renal interstitial cGMP were abolished by renal interstitial nitric oxide synthase inhibitor L-N6-nitroarginine methyl ester or bradykinin B2 receptor antagonist icatibant. Renal AT2R activation with C-21 prevented Na+ retention and lowered blood pressure in the angiotensin II infusion model of experimental hypertension.Conclusions:
AT2R activation initiates its translocation to the renal proximal tubule cell apical membrane and the internalization of Na+-H+ exchanger-3 and Na+/K+ATPase, inducing natriuresis in a bradykinin-nitric oxide-cGMP–dependent manner. Intrarenal AT2R activation prevents Na+ retention and lowers blood pressure in angiotensin II–dependent hypertension. AT2R activation holds promise as a renal proximal tubule natriuretic/diuretic target for the treatment of fluid-retaining states and hypertension.