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

Clinical and Experimental Nephrology Aims and scope Submit manuscript

Abstract

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 WNK4D561A/+ 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+/−WNK4D561A/+ 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.

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Acknowledgments

We thank M. Chiga and R. Inoue for help in the experiments. This study was supported in part by Grant-in-Aid for Scientific Research (A) to SU from the Japan Society for the Promotion of Science (no. 20249047), Grant-in-Aid for Scientific Research (A) to SS from the Japan Society for the Promotion of Science (no. 22249032), Grant-in-Aid for Young Scientists (B) to ES from the Ministry of Education, Culture, Sports, Science and Technology of Japan (no. 22790783), Takeda Science Foundation, Kanae Foundation for the Promotion of Medical Science, the Nakajima Foundation, and Salt Science Research Foundation (no. 1026).

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Correspondence to Shinichi Uchida.

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Susa, K., Kita, S., Iwamoto, T. et al. Effect of heterozygous deletion of WNK1 on the WNK-OSR1/SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood vessels. Clin Exp Nephrol 16, 530–538 (2012). https://doi.org/10.1007/s10157-012-0590-x

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  • DOI: https://doi.org/10.1007/s10157-012-0590-x

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