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(D561A/+) 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 WNK1(+/-)WNK4(D561A/+) 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.
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(D561A/+) 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 WNK1(+/-)WNK4(D561A/+) 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.
Authors: Brian P Zambrowicz; Alejandro Abuin; Ramiro Ramirez-Solis; Lizabeth J Richter; James Piggott; Hector BeltrandelRio; Eric C Buxton; Joel Edwards; Rick A Finch; Carl J Friddle; Anupma Gupta; Gwenn Hansen; Yi Hu; Wenhu Huang; Crystal Jaing; Billie Wayne Key; Peter Kipp; Buckley Kohlhauff; Zhi-Qing Ma; Diane Markesich; Robert Payne; David G Potter; Ny Qian; Joseph Shaw; Jeff Schrick; Zheng-Zheng Shi; Mary Jean Sparks; Isaac Van Sligtenhorst; Peter Vogel; Wade Walke; Nianhua Xu; Qichao Zhu; Christophe Person; Arthur T Sands Journal: Proc Natl Acad Sci U S A Date: 2003-11-10 Impact factor: 11.205
Authors: Hashem A Dbouk; Lauren M Weil; G K Sachith Perera; Michael T Dellinger; Gray Pearson; Rolf A Brekken; Melanie H Cobb Journal: Proc Natl Acad Sci U S A Date: 2014-10-31 Impact factor: 11.205
Authors: R Curtis Morris; Olga Schmidlin; Anthony Sebastian; Masae Tanaka; Theodore W Kurtz Journal: Circulation Date: 2016-03-01 Impact factor: 29.690