Loss of Wnk3 is Compensated for by ks‐Wnk1 in the Kidney of the Mouse

Abstract

Wnk3 kinase is expressed throughout the nephron and acts as a positive regulator of NKCC2 and NCC in vitro. Here we addressed the in vivo relevance of Wnk3 by the use of Wnk3‐deficient mice. Wnk3−/− mice were viable and showed no gross abnormalities. Net tubular function was similar in WT and Wnk3−/− mice as assessed by determination of 24‐hr urine output (1.7±.2 in WT and 1.6±.2 mL in Wnk3−/−, p=.52) and ambient urine osmolarity (1680±170 vs. 1780±170 mosmol/kg; p=.11, n=10). Water restriction (48 hrs) increased urine osmolarity to 3440±220 and 3200±180 mosmol/kg in WT and Wnk3−/−, respectively (n=10, p=.41). During a salt‐restricted diet (7d, 0.02% NaCl) urine osmolarity tended to decrease in WT (1584±200 mosmol/kg; p=.34 vs. standard diet) whereas it was reduced significantly in Wnk3−/− mice (1183±130 mosmol/kg; p=.025 vs. standard diet). Glomerular filtration rate (343±22 vs. 315±13 mL/min), renal blood flow (1.35±.1 vs. 1.42±.04 mL), and plasma renin concentration (160±38 vs. 135±19 ng AngI/mL/hr) were similar in WT and Wnk3−/− (p>.05). The abundance of the kidney‐specific Wnk1 isoform (ks‐Wnk1) was markedly enhanced in Wnk3−/− compared to WT mice, whereas expression of full‐length Wnk1 and Wnk4 was unchanged. In summary, the function of Wnk3 can largely be compensated for by other kinases, most likely by ks‐Wnk1, and this may cause compensatory activation of downstream targets like eNaC.