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

Arohan R. Subramanya, Chao-Ling Yang, Xiaoman Zhu, David Ellison

Research output: Contribution to journalArticle

87 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume290
Issue number3
DOIs
StatePublished - Mar 2006

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Lysine
Protein Isoforms
Phosphotransferases
Kidney
Oocytes
Member 3 Solute Carrier Family 12
Hypertension
Nephrons
Xenopus laevis
Down-Regulation

Keywords

  • Aldosterone
  • Distal nephron
  • Thiazide-sensitive sodium-chloride cotransporter
  • With-no-lysine kinases

ASJC Scopus subject areas

  • Physiology

Cite this

Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoform. / Subramanya, Arohan R.; Yang, Chao-Ling; Zhu, Xiaoman; Ellison, David.

In: American Journal of Physiology - Renal Physiology, Vol. 290, No. 3, 03.2006.

Research output: Contribution to journalArticle

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