Nature Genetics
- 38, 1124 - 1132 (2006)
Published online: 10 September 2006; | doi:10.1038/ng1877
Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubuleMaria D Lalioti1, 6, Junhui Zhang2, Heather M Volkman1, Kristopher T Kahle1, Kristin E Hoffmann1, Hakan R Toka1, 6, Carol Nelson-Williams1, David H Ellison3, Richard Flavell4, Carmen J Booth5, Yin Lu1, David S Geller2 & Richard P Lifton1, 21
Department of Genetics, Howard Hughes Medical, Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA. 2
Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA. 3
Division of Nephrology & Hypertension, Oregon Health & Sciences University, Portland, Oregon 97239, USA. 4
Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA. 5
Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA. 6
Present addresses: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA (M.D.L.) and Department of Medicine, University of Massachusetts, Worcester, Massachusetts 01605, USA (H.R.T.).
Correspondence should be addressed to Richard P Lifton richard.lifton@yale.edu The mechanisms that govern homeostasis of complex systems have been elusive but can be illuminated by mutations that disrupt system behavior. Mutations in the gene encoding the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and hyperkalemia. We show that physiology in mice transgenic for genomic segments harboring wild-type (TgWnk4WT) or PHAII mutant (TgWnk4PHAII) Wnk4 is changed in opposite directions: TgWnk4PHAII mice have higher blood pressure, hyperkalemia, hypercalciuria and marked hyperplasia of the distal convoluted tubule (DCT), whereas the opposite is true in TgWnk4WT mice. Genetic deficiency for the Na-Cl cotransporter of the DCT (NCC) reverses phenotypes seen in TgWnk4PHAII mice, demonstrating that the effects of the PHAII mutation are due to altered NCC activity. These findings establish that Wnk4 is a molecular switch that regulates the balance between NaCl reabsorption and K+ secretion by altering the mass and function of the DCT through its effect on NCC.
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