Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl cotransporter, increases Na excretion and lowers blood pressure.
We recently generated Wnk4(D561A/+) 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.
Ohta
Akihito
A
Department of Nephrology, Tokyo Medical and Dental University, Japan.
Rai
Tatemitsu
T
Yui
Naofumi
N
Chiga
Motoko
M
Yang
Sung-Sen
SS
Lin
Shih-Hua
SH
Sohara
Eisei
E
Sasaki
Sei
S
Uchida
Shinichi
S
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D001794:Blood Pressure; D004195:Disease Models, Animal; D005260:Female; D020868:Gene Silencing; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011188:Potassium / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011546:Pseudohypoaldosteronism / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000235:genetics / Q000378:metabolism*
D011955:Receptors, Drug; C578875:Slc12a3 protein, mouse; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D012964:Sodium; C499024:Prkwnk4 protein, mouse; C486407:Stk39 protein, mouse; D017346:Protein Serine-Threonine Kinases; D011188:Potassium