title: Molecular pathogenesis of pseudohypoaldosteronism type II: generation and analysis of a Wnk4(D561A/+) knockin mouse model.
abstract: WNK1 and WNK4 mutations have been reported to cause pseudohypoaldosteronism type II (PHAII), an autosomal-dominant disorder characterized by hyperkalemia and hypertension. To elucidate the molecular pathophysiology of PHAII, we generated Wnk4(D561A/+) knockin mice presenting the phenotypes of PHAII. The knockin mice showed increased apical expression of phosphorylated Na-Cl cotransporter (NCC) in the distal convoluted tubules. Increased phosphorylation of the kinases OSR1 and SPAK was also observed in the knockin mice. Apical localization of the ROMK potassium channel and transepithelial Cl(-) permeability in the cortical collecting ducts were not affected in the knockin mice, whereas activity of epithelial Na(+) channels (ENaC) was increased. This increase, however, was not evident after hydrochlorothiazide treatment, suggesting that the regulation of ENaC was not a genetic but a secondary effect. Thus, the pathogenesis of PHAII caused by a missense mutation of WNK4 was identified to be increased function of NCC through activation of the OSR1/SPAK-NCC phosphorylation cascade.
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan.
authors.forename: Sung-Sen
authors.initials: SS
authors.lastname: Yang
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Morimoto
authors.forename: Tatemitsu
authors.initials: T
authors.lastname: Rai
authors.forename: Motoko
authors.initials: M
authors.lastname: Chiga
authors.forename: Eisei
authors.initials: E
authors.lastname: Sohara
authors.forename: Mayuko
authors.initials: M
authors.lastname: Ohno
authors.forename: Keiko
authors.initials: K
authors.lastname: Uchida
authors.forename: Shih-Hua
authors.initials: SH
authors.lastname: Lin
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Moriguchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shibuya
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kondo
authors.forename: Sei
authors.initials: S
authors.lastname: Sasaki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchida
mesh_terms: D000818:Animals; D001774:Blood Chemical Analysis; D001794:Blood Pressure; D004195:Disease Models, Animal; D053503:Epithelial Sodium Channels / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics; D007686:Kidney Tubules, Distal / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D020125:Mutation, Missense / Q000235:genetics; D010766:Phosphorylation; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011546:Pseudohypoaldosteronism / Q000503:physiopathology*; D049992:Sodium Chloride Symporters / Q000378:metabolism; D014556:Urine / Q000737:chemistry
chemical_list: D053503:Epithelial Sodium Channels; C510693:Kcnj1 protein, mouse; D024661:Potassium Channels, Inwardly Rectifying; D049992:Sodium Chloride Symporters; C499024:Prkwnk4 protein, mouse; C486407:Stk39 protein, mouse; C534421:OXSR1 protein, mouse; D017346:Protein Serine-Threonine Kinases