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1 Division of Nephrology and Hypertension, Department of Medicine and the Heart Research Center, Oregon Health & Science University, Portland, OR, USA
2 Division of Nephrology and Hypertension, Department of Medicine and the Heart Research Center, Oregon Health & Science University, Portland, OR, USA; Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR, USA; Portland VA Medical Center, Portland, OR, USA
* To whom correspondence should be addressed. E-mail: ellisond{at}ohsu.edu.
With-no-lysine kinase-1 (WNK1) gene mutations cause familial hyperkalemic hypertension (FHHt), a Mendelian disorder of excessive renal sodium and potassium retention. Through its catalytic activity, full-length kinase-sufficient WNK1 (L-WNK1) suppresses its paralog, WNK4, thereby upregulating thiazide-sensitive 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.
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