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

Authors: Subramanya, AR  Yang, CL  Zhu, X  Ellison, DH 
Citation: Subramanya AR, etal., Am J Physiol Renal Physiol. 2006 Mar;290(3):F619-24. Epub 2005 Oct 4.
Pubmed: (View Article at PubMed) PMID:16204408
DOI: Full-text: DOI:10.1152/ajprenal.00280.2005

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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RGD Object Information
RGD ID: 11535105
Created: 2016-09-21
Species: All species
Last Modified: 2016-09-21
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.