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XB-ART-1287
Am J Physiol Renal Physiol 2006 Mar 01;2903:F619-24. doi: 10.1152/ajprenal.00280.2005.
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Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoform.

Subramanya AR , Yang CL , Zhu X , Ellison DH .


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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.

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Species referenced: Xenopus laevis
Genes referenced: slc12a3 wnk1 wnk4

References :
Yu, WNK signaling in the distal tubule: an inhibitory cascade regulating salt transport. 2006, Pubmed