Clinical and Experimental Nephrology

, Volume 16, Issue 4, pp 530–538

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

  • Koichiro Susa
  • Satomi Kita
  • Takahiro Iwamoto
  • Sung-Sen Yang
  • Shih-Hua Lin
  • Akihito Ohta
  • Eisei Sohara
  • Tatemitsu Rai
  • Sei Sasaki
  • Dario R. Alessi
  • Shinichi Uchida
Original Article

DOI: 10.1007/s10157-012-0590-x

Cite this article as:
Susa, K., Kita, S., Iwamoto, T. et al. Clin Exp Nephrol (2012) 16: 530. doi:10.1007/s10157-012-0590-x

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.

Keywords

WNK kinase Blood pressure Na–K–2Cl cotransporter Vascular smooth muscle cell Myogenic tone 

Copyright information

© Japanese Society of Nephrology 2012

Authors and Affiliations

  • Koichiro Susa
    • 1
  • Satomi Kita
    • 2
  • Takahiro Iwamoto
    • 2
  • Sung-Sen Yang
    • 3
  • Shih-Hua Lin
    • 3
  • Akihito Ohta
    • 1
    • 4
  • Eisei Sohara
    • 1
  • Tatemitsu Rai
    • 1
  • Sei Sasaki
    • 1
  • Dario R. Alessi
    • 4
  • Shinichi Uchida
    • 1
  1. 1.Department of Nephrology, Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
  2. 2.Department of Pharmacology, School of MedicineFukuoka UniversityFukuokaJapan
  3. 3.Division of Nephrology, Department of MedicineTri-Service General HospitalTaipeiTaiwan
  4. 4.MRC Protein Phosphorylation Unit, MSI/WTB ComplexUniversity of DundeeDundeeUK

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