Human Molecular Genetics Advance Access originally published online on July 24, 2009
Human Molecular Genetics 2009 18(20):3978-3986; doi:10.1093/hmg/ddp344
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl cotransporter, increases Na excretion and lowers blood pressure
1 Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan and 2 Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Taipei, Taiwan
* To whom correspondence should be addressed at: Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan. Tel: +81 358035214; Fax: +81 358035215; Email: suchida.kid{at}tmd.ac.jp
Received June 15, 2009; Revised July 13, 2009; Accepted July 22, 2009
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.