AT2 Receptor Activation Induces Natriuresis and Lowers Blood Pressure
Rationale: Compound 21 (C-21) is a highly selective non-peptide AT2 receptor (AT2R) agonist.
Objective: To test the hypothesis that renal proximal tubule AT2Rs induce natriuresis and lower blood pressure (BP) in Sprague-Dawley rats and mice.
Methods and Results: In rats, AT2R activation with intravenous C-21 increased urinary sodium (Na+) excretion (UNaV) by 10-fold (P<0.0001); this natriuresis was abolished by direct renal interstitial (RI) infusion of specific AT2R antagonist PD-123319 (PD). C-21 increased fractional excretion of Na+ (FENa; P<0.05) and lithium (FELi; P<0.01) without altering renal hemodynamic function. AT2R activation increased renal proximal tubule cell (RPTC) apical membrane AT2R protein (P<0.001) without changing total AT2R expression and internalized/inactivated Na+- H+ exchanger-3 (NHE-3) and Na+/K+ATPase (NKA). C-21-induced natriuresis was accompanied by an increase in RI cyclic GMP (cGMP; P<0.01); C-21-induced increases in UNaV and RI cGMP were abolished by RI nitric oxide (NO) synthase inhibitor L-NAME or bradykinin (BK) B2 receptor antagonist icatibant. Renal AT2R activation with C-21 prevented Na+ retention and lowered BP in the angiotensin II (Ang II) infusion model of experimental hypertension.
Conclusions: AT2R activation initiates its translocation to the RPTC apical membrane and the internalization of NHE-3 and NKA inducing natriuresis in a BK-NO-cGMP-dependent manner. Intrarenal AT2R activation prevents Na+ retention and lowers BP in Ang II-dependent hypertension. AT2R activation holds promise as a RPT natriuretic/diuretic target for the treatment of fluid retaining states and hypertension.
- Received April 2, 2014.
- Revision received June 2, 2014.
- Accepted June 4, 2014.