Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl cotransporter, increases Na excretion and lowers blood pressure

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 o...

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Bibliographic Details
Published in:Human molecular genetics 2009-10, Vol.18 (20), p.3978-3986
Main Authors: Ohta, Akihito, Rai, Tatemitsu, Yui, Naofumi, Chiga, Motoko, Yang, Sung-Sen, Lin, Shih-Hua, Sohara, Eisei, Sasaki, Sei, Uchida, Shinichi
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Biological and medical sciences
Biological Transport
Blood Pressure
Disease Models, Animal
Female
Fundamental and applied biological sciences. Psychology
Gene Silencing
Genetics of eukaryotes. Biological and molecular evolution
Male
Mice
Mice, Inbred C57BL
Molecular and cellular biology
Molecular Sequence Data
Phosphorylation
Potassium - metabolism
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Pseudohypoaldosteronism - genetics
Pseudohypoaldosteronism - metabolism
Pseudohypoaldosteronism - physiopathology
Receptors, Drug - genetics
Receptors, Drug - metabolism
Sodium - metabolism
Solute Carrier Family 12, Member 3
Symporters - genetics
Symporters - metabolism
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Summary: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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddp344