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Kidney Week

Abstract: SA-PO1040

KS-WNK1: An Aldosterone-Induced Inhibitor of ENaC?

Session Information

  • Na+, K+, Cl-
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Fluid, Electrolytes, and Acid-Base

  • 703 Na+, K+, Cl- Basic

Authors

  • Chavez-Canales, Maria, INSERM, Paris, France
  • Wu, Peng, New York Medical College, Valhalla, New York, United States
  • Sheng, Shaohu, INSERM, Paris, France
  • Chen, Jingxin, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Serbin, Bettina, INSERM, Paris, France
  • Radionov, Nikita, INSERM, Paris, France
  • Soukaseum, Christelle, INSERM, Paris, France
  • Wang, WenHui, New York Medical College, Valhalla, New York, United States
  • Kleyman, Thomas R., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Hadchouel, Juliette, INSERM, Paris, France
Background

Mutations in the gene encoding the serine threonine kinase WNK1 [With No lysine (K)] result in an increased expression of the catalytic isoform, thus causing Familial Hyperkalemic Hypertension, a rare form of human hypertension. Another isoform, KS-WNK1, is also produced from the WNK1 gene. Devoid of kinase activity, it is expressed specifically in the distal nephron. In vitro data suggest that KS-WNK1 inhibits the activity of other WNK kinases. We previously showed that the inactivation of KS-WNK1 in mice leads to an increased expression of the Na-Cl cotransporter NCC, which could result from an increased activity of WNK1 and/or WNK4. However, aldosterone secretion is decreased in KS-WNK1-/- mice while renin is not, suggesting that potassium balance is impaired, which could also explain the increased NCC expression.

Methods

KS-WNK1 is expressed in the distal convoluted tubule but also in the connecting tubule (CNT) and cortical collecting duct (CCD). In order to characterize its role in potassium balance independently from the DCT, we generated a mouse model of KS-WNK1 inactivation specifically in the CNT-CCD (WNK1AQP2/AQP2 mice).

Results

As in KS-WNK1-/- mice, the secretion of aldosterone, but not renin, is decreased in WNK1AQP2/AQP2 mice. An increase in aldosterone, by chronic infusion or potassium load, as well as a sodium load provoke a significant decrease in plasma potassium in WNK1AQP2/AQP2 mice, suggesting that the activity of the Na channel ENaC is increased. Using patch-clamp on isolated tubules, we confirmed that ENaC activity is increased in the CNT of WNK1AQP2/AQP2 mice. Accordingly, overexpression of KS-WNK1 in Xenopus laevis oocytes decreases the activity of the sodium channel.

Conclusion

Taken together, these data suggest that KS-WNK1 is an inhibitor of ENaC in a Nedd4-2 independent manner. Since the expression of KS-WNK1 is induced by aldosterone infusion or potassium load, KS-WNK1 could therefore be an aldosterone-induced inhibitor of ENaC.

Funding

  • NIDDK Support