Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC

American Journal of Physiology. Renal Physiology
Eduardo R ArgaizGerardo Gamba

Abstract

Familial hyperkalemic hypertension (FHHt) can be mainly attributed to increased activity of the renal Na+:Cl- cotransporter (NCC), which is caused by altered expression and regulation of the with-no-lysine (K) 1 (WNK1) or WNK4 kinases. The WNK1 gene gives rise to a kidney-specific isoform that lacks the kinase domain (KS-WNK1), the expression of which occurs primarily in the distal convoluted tubule. The role played by KS-WNK1 in the modulation of the WNK/STE20-proline-alanine rich kinase (SPAK)/NCC pathway remains elusive. In the present study, we assessed the effect of human KS-WNK1 on NCC activity and on the WNK4-SPAK pathway. Microinjection of oocytes with human KS-WNK1 cRNA induces remarkable activation and phosphorylation of SPAK and NCC. The effect of KS-WNK1 was abrogated by eliminating a WNK-WNK-interacting domain and by a specific WNK inhibitor, WNK463, indicating that the activation of SPAK/NCC by KS-WNK1 is due to interaction with another WNK kinase. Under control conditions in oocytes, the activating serine 335 of the WNK4 T loop is not phosphorylated. In contrast, this serine becomes phosphorylated when the intracellular chloride concentration ([Cl-]i) is reduced or when KS-WNK1 is coexpressed with WNK4. KS-WNK1-m...Continue Reading

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Citations

Jun 21, 2018·The Journal of Biological Chemistry·Adrián Rafael Murillo-de-OzoresMaria Castañeda-Bueno
Aug 9, 2018·American Journal of Physiology. Renal Physiology·Mauricio Ostrosky-FridGerardo Gamba
Dec 6, 2018·American Journal of Physiology. Renal Physiology·Anita T Layton
Oct 15, 2019·American Journal of Physiology. Renal Physiology·Alissa A FrameRichard D Wainford
Apr 15, 2020·Hypertension Research : Official Journal of the Japanese Society of Hypertension·Taisuke FurushoEisei Sohara
Jun 25, 2020·American Journal of Physiology. Cell Physiology·Diana Pacheco-AlvarezGerardo Gamba
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Jan 5, 2021·Current Opinion in Nephrology and Hypertension·Jen-Chi ChenChih-Jen Cheng
Aug 14, 2020·The Journal of Clinical Investigation·Hélène Louis-Dit-PicardXavier Jeunemaitre
Mar 9, 2021·American Journal of Physiology. Renal Physiology·Mauricio Ostrosky-FridGerardo Gamba
Jan 26, 2021·American Journal of Physiology. Renal Physiology·Adrián Rafael Murillo-de-OzoresMaría Castañeda-Bueno
Jun 8, 2021·Acta Pharmaceutica Sinica. B·Nur Farah Meor AzlanJinwei Zhang

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Methods Mentioned

BETA
ubiquitination
Immunoprecipitation
coimmunoprecipitation

Software Mentioned

GraphPad
ImageStudioLite
GraphPad Prism

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