The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex.

Abstract	The pathogenesis of essential hypertension remains unknown, but thiazide diuretics are frequently recommended as first-line treatment. Recently, familial hyperkalemic hypertension (FHHt) was shown to result from activation of the thiazide-sensitive Na-Cl cotransporter (NCC) by mutations in WNK4, although the mechanism for this effect remains unknown. WNK kinases are unique members of the human kinome, intimately involved in maintaining electrolyte balance across cell membranes and epithelia. Previous work showed that WNK1, WNK4, and a kidney-specific isoform of WNK1 interact to regulate NCC activity, suggesting that WNK kinases form a signaling complex. Here, we report that WNK3, another member of the WNK kinase family expressed by distal tubule cells, interacts with WNK4 and WNK1 to regulate NCC in both human kidney cells and Xenopus oocytes, further supporting the WNK signaling complex hypothesis. We demonstrate that physiological regulation of NCC in oocytes results from antagonism between WNK3 and WNK4 and that FHHt-causing WNK4 mutations exert a dominant-negative effect on wild-type (WT) WNK4 to mimic a state of WNK3 excess. The results provide a mechanistic explanation for the divergent effects of WT and FHHt-mutant WNK4 on NCC activity, and for the dominant nature of FHHt in humans and genetically modified mice.
Authors	Chao-Ling Yang, Xiaoman Zhu, David H Ellison
Journal	The Journal of clinical investigation (J Clin Invest) Vol. 117 Issue 11 Pg. 3403-11 (Nov 2007) ISSN: 0021-9738 [Print] United States
PMID	17975670 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	Claudins Intracellular Signaling Peptides and Proteins Membrane Proteins Minor Histocompatibility Antigens Receptors, Drug Recombinant Fusion Proteins Sodium Chloride Symporters Thiazides Xenopus Proteins claudin protein, Xenopus thiazide receptor Protein Serine-Threonine Kinases WNK Lysine-Deficient Protein Kinase 1 WNK1 protein, human WNK3 protein, human WNK4 protein, human
Topics	Amino Acid Sequence Animals Cell Line Claudins Humans Intracellular Signaling Peptides and Proteins Kidney (enzymology) Membrane Proteins (genetics, metabolism) Mice Minor Histocompatibility Antigens Molecular Sequence Data Oocytes (physiology) Phosphorylation Protein Serine-Threonine Kinases (genetics, metabolism) Rats Receptors, Drug (genetics, metabolism) Recombinant Fusion Proteins (genetics, metabolism) Sequence Alignment Signal Transduction (physiology) Sodium Chloride Symporters (genetics, metabolism) Thiazides (metabolism) WNK Lysine-Deficient Protein Kinase 1 Xenopus Proteins (genetics, metabolism) Xenopus laevis

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