Deletion of Kir5.1 abolishes the effect of high Na+ intake on Kir4.1 and Na+-Cl- cotransporter.

High sodium (HS) intake inhibited epithelial Na+ channel (ENaC) in the aldosterone-sensitive distal nephron and Na+ -Cl- cotransporter (NCC) by suppressing basolateral Kir4.1/Kir5.1 in the distal convoluted tubule (DCT), thereby increasing renal Na+ excretion but not affecting Na+ excretion. The aim of the present study was to explore whether deletion of Kir5.1 compromises the inhibitory effect of HS on NCC expression/activity and renal Na+ excretion. Patch-clamp experiments demonstrated that HS failed to inhibit DCT basolateral Na+ channels and did not depolarize Na+ current reversal potential of the DCT in Kir5.1 knockout (KO) mice. Moreover, deletion of Kir5.1 not only increased the expression of Kir4.1, phospho-NCC, and total NCC but also abolished the inhibitory effect of HS on the expression of Kir4.1, phospho-NCC, and total NCC and thiazide-induced natriuresis. Also, low sodium-induced stimulation of NCC expression/activity and basolateral Na+ channels in the DCT were absent in Kir5.1 KO mice. Deletion of Kir5.1 decreased ENaC currents in the late DCT, and HS further inhibited ENaC activity in Kir5.1 KO mice. Finally, measurement of the basal renal Na+ excretion rate with the modified renal clearance method demonstrated that longterm HS inhibited the renal Na+ excretion rate and steadily increased plasma Na+ levels in Kir5.1 KO mice but not in wild-type mice. We conclude that Kir5.1 plays an important role in mediating the effect of HS intake on basolateral Na+ channels in the DCT and NCC activity/expression. Kir5.1 is involved in maintaining renal ability of Na+ excretion during HS intake. [ABSTRACT FROM AUTHOR]