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Am J Physiol Renal Physiol 290: F619-F624, 2006. First published October 4, 2005; doi:10.1152/ajprenal.00280.2005
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Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoform

Arohan R. Subramanya,1,2 Chao-Ling Yang,1,2 Xiaoman Zhu,1,2 and David H. Ellison1,2,3,4

1Division of Nephrology and Hypertension, Department of Medicine, 2Heart Research Center, and 3Department of Physiology and Pharmacology, Oregon Health and Science University, and 4Portland Veterans Affairs Medical Center, Portland, Oregon

Submitted 8 July 2005 ; accepted in final form 23 September 2005

ABSTRACT

With-no-lysine kinase-1 (WNK1) gene mutations cause familial hyperkalemic hypertension (FHHt), a Mendelian disorder of excessive renal Na+ and K+ retention. Through its catalytic activity, full-length kinase-sufficient WNK1 (L-WNK1) suppresses its paralog, WNK4, thereby upregulating thiazide-sensitive Na-Cl cotransporter (NCC) activity. The predominant renal WNK1 isoform, KS-WNK1, expressed exclusively and at high levels in distal nephron, is a shorter kinase-defective product; the function of KS-WNK1 must therefore be kinase independent. Here, we report a novel role for KS-WNK1 as a dominant-negative regulator of L-WNK1. Na+ transport studies in Xenopus laevis oocytes demonstrate that KS-WNK1 downregulates NCC activity indirectly, by inhibiting L-WNK1. KS-WNK1 also associates with L-WNK1 in protein complexes in oocytes and attenuates L-WNK1 kinase activity in vitro. These observations suggest that KS-WNK1 plays an essential role in the renal molecular switch regulating Na+ and K+ balance; they provide insight into the kidney-specific phenotype of FHHt.

distal nephron; thiazide-sensitive sodium-chloride cotransporter; with-no-lysine kinases; aldosterone


Address for reprint requests and other correspondence: D. H. Ellison, Div. of Nephrology and Hypertension, Oregon Health and Science Univ., PP262, 3314 SW US Veterans Hospital Rd., Portland, OR 97239 (e-mail: ellisond{at}ohsu.edu)




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