Effect of heterozygous deletion of WNK1 on the WNK-OSR1/SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood vessels.

Susa, Koichiro; Kita, Satomi; Iwamoto, Takahiro; Yang, Sung-Sen; Lin, Shih-Hua; Ohta, Akihito; Sohara, Eisei; Rai, Tatemitsu; Sasaki, Sei; Alessi, Dario; Uchida, Shinichi

Background: We found that a mechanism of hypertension in pseudohypoaldosteronism type II (PHAII) caused by a WNK4 missense mutation (D561A) was activation of the WNK-OSR1/SPAK-NCC signal cascade. However, the pathogenic effect of intronic deletions in WNK1 genes also observed in PHAII patients remains unclear. To understand the pathophysiological roles of WNK1 in vivo, WNK1 mice have been analyzed, because homozygous WNK1 knockout is embryonic lethal. Although WNK1 mice have been reported to have hypotension, detailed analyses of the WNK signal cascade in the kidney and other organs of WNK1 mice have not been performed. Method: We assess the effect of heterozygous deletion of WNK1 on the WNK-OSR1/SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood vessels. Results: Contrary to the previous report, the blood pressure of WNK1 mice was not decreased, even under a low-salt diet. Under a WNK4 background, the heterozygous deletion of the WNK1 gene did not reduce the high blood pressure either. We then evaluated the phosphorylation status of OSR1, SPAK, NCC, NKCC1, and NKCC2 in the kidney, but no significant decrease in the phosphorylation was observed in WNK1 mice or WNK1WNK4 mice. In contrast, a significant decrease in NKCC1 phosphorylation in the aorta and a decreased pressure-induced myogenic response in the mesenteric arteries were observed in WNK1 mice. Conclusion: The contribution of WNK1 to total WNK kinase activity in the kidney may be small, but that WNK1 may play a substantial role in the regulation of blood pressure in the arteries.

DELETION mutation; CELLULAR signal transduction; KIDNEY diseases; KIDNEY blood-vessels; HYPERTENSION; MISSENSE mutation; PATHOLOGICAL physiology

Clinical & Experimental Nephrology, 2012, Vol 16, Issue 4, p530

1342-1751

Academic Journal

10.1007/s10157-012-0590-x