Reducing αENaC expression in the kidney connecting tubule induces pseudohypoaldosteronism type 1 symptoms during K+ loading

Abstract

Genetic inactivation of the epithelial Na+ channel α-subunit (αENaC) in the renal collecting duct (CD) does not interfere with Na+ and K+ homeostasis in mice. However, inactivation in the CD and a part of the connecting tubule (CNT) induces autosomal recessive pseudohypoaldosteronism type 1 (PHA-1) symptoms in subjects already on a standard diet. In the present study, we further examined the importance of αENaC in the CNT. Knockout mice with αENaC deleted primarily in a part of the CNT (CNT-KO) were generated using Scnn1alox/lox mice and Atp6v1b1::Cremice. With a standard diet, plasma Na+ concentration ([Na+]) and [K+], and urine Na+ and K+ output were unaffected. Seven days of Na+ restriction (0.01% Na+) led to a higher urine Na+ output only on days 3–5, and after 7 days plasma [Na+] and [K+] were unaffected. In contrast, the CNT-KO mice were highly susceptible to a 2-day 5% K+ diet and showed lower food intake and relative body weight, lower plasma [Na+], higher fractional excretion (FE) of Na+, higher plasma [K+], and lower FE of K+. The higher FE of Na+ coincided with lower abundance and phosphorylation of the Na+-Cl− cotransporter. In conclusion, reducing ENaC expression in the CNT induces clear PHA-1 symptoms during high dietary K+ loading.