WNK kinases regulate thiazide-sensitive Na-Cl cotransport

Chao-Ling Yang, Jordan Angell, Rose Mitchell, David Ellison

Research output: Contribution to journalArticle

360 Citations (Scopus)

Abstract

Pseudohypoaldosteronism type II (PHAII) is an autosomal dominant disorder of hyperkalemia and hypertension. Mutations in two members of the WNK kinase family, WNK1 and WNK4, cause the disease. WNK1 mutations are believed to increase WNK1 expression; the effect of WNK4 mutations remains unknown. The clinical phenotype of PHAII is opposite to Gitelman syndrome, a disease caused by dysfunction of the thiazide-sensitive Na-Cl cotransporter. We tested the hypothesis that WNK kinases regulate the mammalian thiazide-sensitive Na-Cl cotransporter (NCC). Mouse WNK4 was cloned and expressed in Xenopus oocytes with or without NCC. Coexpression with WNK4 suppressed NCC activity by more than 85%. This effect did not result from defects in NCC synthesis or processing, but was associated with an 85% reduction in NCC abundance at the plasma membrane. Unlike WNK4, WNK1 did not affect NCC activity directly. WNK1, however, completely prevented WNK4 inhibition of NCC. Some WNK4 mutations that cause PHAII retained NCC-inhibiting activity, but the Q562E WNK4 demonstrated diminished activity, suggesting that some PHAII mutations lead to loss of NCC inhibition. Gain-of-function WNK1 mutations would be expected to inhibit WNK4 activity, thereby activating NCC, contributing to the PHAII phenotype. Together, these results identify WNK kinases as a previously unrecognized sodium regulatory pathway of the distal nephron. This pathway likely contributes to normal and pathological blood pressure homeostasis.

Original languageEnglish (US)
Pages (from-to)1039-1045
Number of pages7
JournalJournal of Clinical Investigation
Volume111
Issue number7
DOIs
StatePublished - Apr 2003

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Member 3 Solute Carrier Family 12
Thiazides
Pseudohypoaldosteronism
Phosphotransferases
Mutation
Gitelman Syndrome
Phenotype
Hyperkalemia
Nephrons
Xenopus
Oocytes
Homeostasis
Sodium
Cell Membrane

ASJC Scopus subject areas

  • Medicine(all)

Cite this

WNK kinases regulate thiazide-sensitive Na-Cl cotransport. / Yang, Chao-Ling; Angell, Jordan; Mitchell, Rose; Ellison, David.

In: Journal of Clinical Investigation, Vol. 111, No. 7, 04.2003, p. 1039-1045.

Research output: Contribution to journalArticle

Yang, Chao-Ling ; Angell, Jordan ; Mitchell, Rose ; Ellison, David. / WNK kinases regulate thiazide-sensitive Na-Cl cotransport. In: Journal of Clinical Investigation. 2003 ; Vol. 111, No. 7. pp. 1039-1045.
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