Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl cotransporter, increases Na excretion and lowers blood pressure

Hum Mol Genet. 2009 Oct 15;18(20):3978-86. doi: 10.1093/hmg/ddp344. Epub 2009 Jul 24.


We recently generated Wnk4(D561A/+) knockin mice and found that a major pathogenesis of pseudohypoaldosteronism type II was the activation of the OSR1/SPAK kinase-NaCl cotransporter (NCC) phosphorylation cascade by the mutant WNK4. However, the physiological roles of wild-type WNK4 on the regulation of Na excretion and blood pressure, and whether wild-type WNK4 functions positively or negatively in this cascade, remained to be determined. In the present study, we generated WNK4 hypomorphic mice by deleting exon 7 of the Wnk4 gene. These mice did not show hypokalemia and metabolic alkalosis, but they did exhibit low blood pressure and increased Na and K excretion under low-salt diet. Phosphorylation of OSR1/SPAK and NCC was significantly reduced in the mutant mice as compared with their wild-type littermates. Protein levels of ROMK and Maxi K were not changed, but epithelial Na channel appeared to be activated as a compensatory mechanism for the reduced NCC function. Thus, wild-type WNK4 is a positive regulator for the WNK-OSR1/SPAK-NCC cascade, and WNK4 is a potential target of anti-hypertensive drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Biological Transport
  • Blood Pressure*
  • Disease Models, Animal
  • Female
  • Gene Silencing*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Phosphorylation
  • Potassium / metabolism
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Pseudohypoaldosteronism / genetics
  • Pseudohypoaldosteronism / metabolism*
  • Pseudohypoaldosteronism / physiopathology
  • Receptors, Drug / genetics
  • Receptors, Drug / metabolism*
  • Sodium / metabolism*
  • Solute Carrier Family 12, Member 3
  • Symporters / genetics
  • Symporters / metabolism*


  • Receptors, Drug
  • Slc12a3 protein, mouse
  • Solute Carrier Family 12, Member 3
  • Symporters
  • Sodium
  • Prkwnk4 protein, mouse
  • Stk39 protein, mouse
  • Protein Serine-Threonine Kinases
  • Potassium