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Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoform

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

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