Compromised regulation of the collecting duct ENaC activity in mice lacking AT_1a receptor

ENaC-mediated sodium reabsorption in the collecting duct (CD) is a critical determinant of urinary sodium excretion. Existing evidence suggest direct stimulatory actions of Angiotensin II (Ang II) on ENaC in the CD, independently of the aldosterone-mineralocorticoid receptor (MR) signaling. Deletion of the major renal AT₁ receptor isoform, AT_1aR, decreases blood pressure and reduces ENaC abundance despite elevated aldosterone levels. The mechanism of this insufficient compensation is not known. Here, we used patch clamp electrophysiology in freshly isolated split-opened CDs to investigate how AT_1aR dysfunction compromises functional ENaC activity and its regulation by dietary salt intake. Ang II had no effect on ENaC activity in CDs from AT_1aR −/− mice suggesting no complementary contribution of AT₂ receptors. We next found that AT_1aR deficient mice had lower ENaC activity when fed with low (<0.01% Na⁺) and regular (0.32% Na⁺) but not with high (∼2% Na⁺) salt diet, when compared to the respective values obtained in Wild type (WT) animals. Inhibition of AT₁R with losartan in wild-type animals reproduces the effects of genetic ablation of AT_1aR on ENaC activity arguing against contribution of developmental factors. Interestingly, manipulation with aldosterone-MR signaling via deoxycosterone acetate (DOCA) and spironolactone had much reduced influence on ENaC activity upon AT_1aR deletion. Consistently, AT_1aR −/− mice have a markedly diminished MR abundance in cytosol. Overall, we conclude that AT_1aR deficiency elicits a complex inhibitory effect on ENaC activity by attenuating ENaC P_o and precluding adequate compensation via aldosterone cascade due to decreased MR availability.