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

TY - JOUR

T1 - Reducing αENaC expression in kidney connecting tubule induces pseudohypoaldosteronism type 1 symptoms during K+ loading

AU - Poulsen, Søren Brandt

AU - Praetorius, Jeppe

AU - Damkier, Helle H

AU - Miller, Lance

AU - Nelson, Raoul D

AU - Hummler, Edith

AU - Christensen, Birgitte M

N1 - Copyright © 2015, American Journal of Physiology - Renal Physiology.

PY - 2016/2/15

Y1 - 2016/2/15

N2 - 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.

AB - 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.

U2 - 10.1152/ajprenal.00258.2015

DO - 10.1152/ajprenal.00258.2015

M3 - Journal article

C2 - 26582762

SN - 1931-857X

VL - 310

SP - 300

EP - 310

JO - American Journal of Physiology: Renal Physiology

JF - American Journal of Physiology: Renal Physiology

IS - 4

ER -