Compromised Salt Dependence of ENaC Activity Upon Deletion of AT1 Receptors

Abstract

ENaC-mediated sodium reabsorption in the collecting duct (CD) is an essential determinant of blood pressure in humans. Cumulative evidence suggests direct action of Angiotensin II (Ang II) on ENaC activity in the CD, independently of the classical aldosterone signaling. The significance of regulation by Ang II becomes particularly important during Ang II dependent hypertension, when overactive ENaC is poorly regulated via aldosterone – mineralocorticoid receptor (MR) axis. Stimulatory Ang II actions on ENaC are mediated by AT1 receptors (AT1R). AT1R knockouts have decreased blood pressure despite elevated aldosterone levels. This indicates that aldosterone-MR cascade alone cannot provide sufficient input to adequately regulate ENaC-dependent sodium re-uptake. Using freshly isolated split-opened CDs we found that genetic deletion of AT1R markedly diminishes ENaC activity on low and regular sodium intake, significantly blunting salt-dependent regulation of ENaC. The observed decrease of ENaC activity was mainly attributed to a reduced channel open probability (Po). Pharmacological inhibition of AT1R with losartan in wild-type animals reproduces the effect of genetic ablation of AT1R on ENaC activity. Interestingly, saturation of aldosterone signaling with DOCA has minimal stimulatory effect on ENaC upon AT1R deletion, which can be explained by a markedly diminished MR abundance in the CD cells of the knockouts. Overall, genetic ablation of AR1R elicits a complex inhibitory effect on ENaC activity, directly attenuating ENaC Po and precluding adequate compensation by aldosterone cascade due to decreased MR expression.