Molecular pathogenesis of pseudohypoaldosteronism type II: generation and analysis of a Wnk4(D561A/+) knockin mouse model

Cell Metab. 2007 May;5(5):331-44. doi: 10.1016/j.cmet.2007.03.009.


WNK1 and WNK4 mutations have been reported to cause pseudohypoaldosteronism type II (PHAII), an autosomal-dominant disorder characterized by hyperkalemia and hypertension. To elucidate the molecular pathophysiology of PHAII, we generated Wnk4(D561A/+) knockin mice presenting the phenotypes of PHAII. The knockin mice showed increased apical expression of phosphorylated Na-Cl cotransporter (NCC) in the distal convoluted tubules. Increased phosphorylation of the kinases OSR1 and SPAK was also observed in the knockin mice. Apical localization of the ROMK potassium channel and transepithelial Cl(-) permeability in the cortical collecting ducts were not affected in the knockin mice, whereas activity of epithelial Na(+) channels (ENaC) was increased. This increase, however, was not evident after hydrochlorothiazide treatment, suggesting that the regulation of ENaC was not a genetic but a secondary effect. Thus, the pathogenesis of PHAII caused by a missense mutation of WNK4 was identified to be increased function of NCC through activation of the OSR1/SPAK-NCC phosphorylation cascade.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Chemical Analysis
  • Blood Pressure
  • Disease Models, Animal*
  • Epithelial Sodium Channels / metabolism
  • Genetic Vectors / genetics
  • Kidney Tubules, Distal / metabolism
  • Mice
  • Microscopy, Fluorescence
  • Mutation, Missense / genetics
  • Phosphorylation
  • Potassium Channels, Inwardly Rectifying / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Pseudohypoaldosteronism / physiopathology*
  • Sodium Chloride Symporters / metabolism
  • Urine / chemistry


  • Epithelial Sodium Channels
  • Kcnj1 protein, mouse
  • Potassium Channels, Inwardly Rectifying
  • Sodium Chloride Symporters
  • Prkwnk4 protein, mouse
  • Stk39 protein, mouse
  • OXSR1 protein, mouse
  • Protein Serine-Threonine Kinases