WNK4 is required for the Angiotensin II activation of NCC in vivo

Abstract

In Xenopus laevis oocytes and mpkDCT cells, WNK4 is required for modulation of NCC activity by angiotensin II (AngII). Additionally, in rats AngII promotes NCC phosphorylation independently of aldosterone. To define the requirement of WNK4 in AngII regulation of NCC in vivo, we used a complete WNK4‐knockout (WNK4−/−) mouse strain generated by targeted disruption in Pfizer Inc. Control littermates and WNK4−/− mice of 14 weeks were studied. WNK4 mRNA and protein expression were absent in WNK4−/− mice, which exhibited a mild Gitelman's like syndrome, with normal blood pressure, together with increased plasma renin activity, and reduction of NCC expression and phosphorylation at T‐58. Immunohistochemistry revealed normal morphology of distal convoluted tubule. Low salt diet or AngII infusion for four days induced SPAK and NCC phosphorylation at S‐383 and T‐58, respectively, in control littermates, but not in WNK4−/−. Low K+ diet aggravated hypokalemia, but induced SPAK phosphorylation in WNK4−/− mice. Thus, absence of WNK4 in vivo precludes the NCC and SPAK phosphorylation promoted by low salt diet or AngII infusion, but not by hypokalemia, suggesting that AngII action on NCC occurs by signaling through a WNK4‐SPAK dependent mechanism.