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

J Clin Invest. 2007 Nov;117(11):3403-11. doi: 10.1172/JCI32033.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Claudins
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Kidney / enzymology*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Minor Histocompatibility Antigens
  • Molecular Sequence Data
  • Oocytes / physiology
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Receptors, Drug / genetics
  • Receptors, Drug / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sequence Alignment
  • Signal Transduction / physiology
  • Sodium Chloride Symporters / genetics
  • Sodium Chloride Symporters / metabolism*
  • Thiazides / metabolism*
  • WNK Lysine-Deficient Protein Kinase 1
  • Xenopus Proteins / genetics
  • Xenopus Proteins / metabolism
  • Xenopus laevis


  • 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