120 Research Article A minor role of WNK3 in regulating phosphorylation of renal NKCC2 and NCC co-transporters in vivo Katsuyuki Oi1, Eisei Sohara1,*, Tatemitsu Rai1, Moko Misawa1, Motoko Chiga1, Dario R. Alessi2, Sei Sasaki1 and Shinichi Uchida1 1Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan 2MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK *Author for correspondence (
[email protected]) Biology Open 1, 120–127 doi: 10.1242/bio.2011048 Summary Mutations in WNK1 and WNK4 kinase genes have been knockout mice. Na+ and K+ excretion in urine in WNK3 shown to cause a human hereditary hypertensive disease, knockout mice was not affected under different salt diets. pseudohypoaldosteronism type II (PHAII). We previously Blood pressure in WNK3 knockout mice was not lower under discovered that WNK kinases phosphorylate and activate normal diet. However, lower blood pressure was observed in OSR1/SPAK kinases that regulate renal SLC12A family WNK3 knockout mice fed low-salt diet. WNK4 and WNK1 transporters such as NKCC2 and NCC, and clarified that the expression was slightly elevated in the knockout mice under constitutive activation of this cascade causes PHAII. WNK3, low-salt diet, suggesting compensation for WNK3 knockout another member of the WNK kinase family, was reported to by these WNKs. Thus, WNK3 may have some role in the be a strong activator of NCC/NKCC2 when assayed in WNK-OSR1/SPAK-NCC/NKCC2 signal cascade in the Xenopus oocytes, suggesting that WNK3 also plays a major kidney, but its contribution to total WNK kinase activity role in regulating blood pressure and sodium reabsorption in may be minimal.