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WNK1 activates SGK1 to regulate the epithelial sodium channel.

WNK (with no lysine [K]) kinases are serine-threonine protein kinases with an atypical placement of the catalytic lysine. Intronic deletions increase the expression of WNK1 in humans and cause pseudohypoaldosteronism type II, a form of hypertension. WNKs have been linked to ion carriers, but the underlying regulatory mechanisms are unknown. Here, we report a mechanism for the control of ion permeability by WNK1. We show that WNK1 activates the serum- and glucocorticoid-inducible protein kinase SGK1, leading to activation of the epithelial sodium channel. Increased channel activity induced by WNK1 depends on SGK1 and the E3 ubiquitin ligase Nedd4-2. This finding provides compelling evidence that this molecular mechanism contributes to the pathogenesis of hypertension in pseudohypoaldosteronism type II caused by WNK1 and, possibly, in other forms of hypertension.

Pubmed ID: 16006511


  • Xu BE
  • Stippec S
  • Chu PY
  • Lazrak A
  • Li XJ
  • Lee BH
  • English JM
  • Ortega B
  • Huang CL
  • Cobb MH


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

July 19, 2005

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK54368
  • Agency: NIDDK NIH HHS, Id: DK59530
  • Agency: NIGMS NIH HHS, Id: GM53032

Mesh Terms

  • Animals
  • CHO Cells
  • Cells, Cultured
  • Cricetinae
  • Cricetulus
  • Endosomal Sorting Complexes Required for Transport
  • Enzyme Activation
  • Epithelial Sodium Channels
  • Humans
  • Immediate-Early Proteins
  • Immunoblotting
  • Immunoprecipitation
  • Intracellular Signaling Peptides and Proteins
  • Patch-Clamp Techniques
  • Protein-Serine-Threonine Kinases
  • Pseudohypoaldosteronism
  • Sodium Channels
  • Two-Hybrid System Techniques
  • Ubiquitin-Protein Ligases