Angiotensin II AT2receptors inhibit proximal tubular Na+-K+-ATPase activity via a NO/cGMP-dependent pathway

Abstract

Angiotensin II AT₂receptors act as a functional antagonist for the AT₁receptors in various tissues. We previously reported that activation of the renal AT₂receptors promotes natriuresis and diuresis; however, the mechanism is not known. The present study was designed to investigate whether activation of AT₂receptors affects the activity of Na⁺-K⁺-ATPase (NKA), an active tubular sodium transporter, in the proximal tubules isolated from Sprague-Dawley rats. The AT₂receptor agonist CGP-42112 (10⁻¹⁰-10⁻⁷M) produced a dose-dependent inhibition of NKA activity (9–38%); the inhibition was attenuated by the presence of the AT₂receptor antagonist PD-123319 (1 μM), suggesting the involvement of the AT₂receptors. The AT₁receptor antagonist losartan (1 μM) did not affect the CGP-42112 (100 nM)-induced inhibition of NKA activity. The presence of guanylyl cyclase inhibitor ODQ (10 μM) and the nitric oxide (NO) synthase inhibitor N^ω-nitro-l-arginine methyl ester (l-NAME; 100 μM) abolished the CGP-42112 (100 nM)-induced NKA inhibition. ANG II (100 nM), in the presence of losartan, significantly inhibited NKA activity; the inhibition was attenuated by PD-123319. CGP-42112 also, in a dose-dependent manner, stimulated NO production (∼0–230%) and cGMP accumulation (∼25–100%). The CGP-42112 (100 nM)-induced NO and cGMP increases were abolished by the AT₂receptor antagonist PD-123319, ODQ, and l-NAME. The data suggest that the activation of the AT₂receptor via stimulation of the NO/cGMP pathway causes inhibition of NKA activity in the proximal tubules. This phenomenon provides a plausible mechanism responsible for the AT₂receptor-mediated natriuresis-diuresis in rodents.