Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoform

Am J Physiol Renal Physiol. 2006 Mar;290(3):F619-24. doi: 10.1152/ajprenal.00280.2005. Epub 2005 Oct 4.

Abstract

With-no-lysine kinase-1 (WNK1) gene mutations cause familial hyperkalemic hypertension (FHHt), a Mendelian disorder of excessive renal Na+ and K+ retention. Through its catalytic activity, full-length kinase-sufficient WNK1 (L-WNK1) suppresses its paralog, WNK4, thereby upregulating thiazide-sensitive Na-Cl cotransporter (NCC) activity. The predominant renal WNK1 isoform, KS-WNK1, expressed exclusively and at high levels in distal nephron, is a shorter kinase-defective product; the function of KS-WNK1 must therefore be kinase independent. Here, we report a novel role for KS-WNK1 as a dominant-negative regulator of L-WNK1. Na+ transport studies in Xenopus laevis oocytes demonstrate that KS-WNK1 downregulates NCC activity indirectly, by inhibiting L-WNK1. KS-WNK1 also associates with L-WNK1 in protein complexes in oocytes and attenuates L-WNK1 kinase activity in vitro. These observations suggest that KS-WNK1 plays an essential role in the renal molecular switch regulating Na+ and K+ balance; they provide insight into the kidney-specific phenotype of FHHt.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Biological Transport
  • Conserved Sequence
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes / deficiency
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Mice
  • Minor Histocompatibility Antigens
  • Molecular Sequence Data
  • Oocytes / physiology
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Sodium / metabolism
  • WNK Lysine-Deficient Protein Kinase 1
  • Xenopus laevis

Substances

  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes
  • Minor Histocompatibility Antigens
  • Sodium
  • Protein-Serine-Threonine Kinases
  • WNK Lysine-Deficient Protein Kinase 1
  • WNK1 protein, human
  • Wnk1 protein, mouse
  • Wnk1 protein, rat