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- Title
Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl cotransporter, increases Na excretion and lowers blood pressure.
- Authors
Ohta, Akihito; Rai, Tatemitsu; Yui, Naofumi; Chiga, Motoko; Yang, Sung-Sen; Lin, Shih-Hua; Sohara, Eisei; Sasaki, Sei; Uchida, Shinichi
- Abstract
We recently generated Wnk4D561A/+ knockin mice and found that a major pathogenesis of pseudohypoaldosteronism type II was the activation of the OSR1/SPAK kinase-NaCl cotransporter (NCC) phosphorylation cascade by the mutant WNK4. However, the physiological roles of wild-type WNK4 on the regulation of Na excretion and blood pressure, and whether wild-type WNK4 functions positively or negatively in this cascade, remained to be determined. In the present study, we generated WNK4 hypomorphic mice by deleting exon 7 of the Wnk4 gene. These mice did not show hypokalemia and metabolic alkalosis, but they did exhibit low blood pressure and increased Na and K excretion under low-salt diet. Phosphorylation of OSR1/SPAK and NCC was significantly reduced in the mutant mice as compared with their wild-type littermates. Protein levels of ROMK and Maxi K were not changed, but epithelial Na channel appeared to be activated as a compensatory mechanism for the reduced NCC function. Thus, wild-type WNK4 is a positive regulator for the WNK-OSR1/SPAK-NCC cascade, and WNK4 is a potential target of anti-hypertensive drugs.
- Publication
Human Molecular Genetics, 2009, Vol 18, Issue 20, p3978
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddp344