Journal article
Differential roles of WNK4 in regulation of NCC in vivo
American journal of physiology. Renal physiology, Vol.314(5), pp.F999-F1007
05/01/2018
DOI: 10.1152/ajprenal.00177.2017
PMCID: PMC6031911
PMID: 29384416
Abstract
The Na+-Cl− cotransporter (NCC) in distal convoluted tubule (DCT) plays important roles in renal NaCl reabsorption. The current hypothesis for the mechanism of regulation of NCC focuses on WNK4 and intracellular Cl− concentration ([Cl−]i). WNK kinases bind Cl−, and Cl− binding decreases the catalytic activity. It is believed that hypokalemia under low K+ intake decreases [Cl−]i to activate WNK4, which thereby phosphorylates and stimulates NCC through activation of SPAK. However, increased NCC activity and apical NaCl entry would mitigate the fall in [Cl−]i. Whether [Cl−]i in DCT under low-K+ diet is sufficiently low to activate WNK4 is unknown. Furthermore, increased luminal NaCl delivery also stimulates NCC and causes upregulation of the transporter. Unlike low K+ intake, increased luminal NaCl delivery would tend to increase [Cl−]i. Thus we investigated the role of WNK4 and [Cl−]i in regulating NCC. We generated Wnk4-knockout mice and examined regulation of NCC by low K+ intake and by increased luminal NaCl delivery in knockout (KO) and wild-type mice. Wnk4-KO mice have marked reduction in the abundance, phosphorylation, and functional activity of NCC vs. wild type. Low K+ intake increases NCC phosphorylation and functional activity in wild-type mice, but not in Wnk4-KO mice. Increased luminal NaCl delivery similarly upregulates NCC, which, contrary to low K+ intake, is not abolished in Wnk4-KO mice. The results reveal that modulation of WNK4 activity by [Cl−]i is not the sole mechanism for regulating NCC. Increased luminal NaCl delivery upregulates NCC via yet unknown mechanism(s) that may override inhibition of WNK4 by high [Cl−]i.
Details
- Title: Subtitle
- Differential roles of WNK4 in regulation of NCC in vivo
- Creators
- Yih-Sheng Yang - Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center , Dallas, TexasJian Xie - Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center , Dallas, TexasSung-Sen Yang - Graduate Institute of Biomedical Sciences, Academia Sinica, Taipei , TaiwanShih-Hua Lin - Division of Nephrology, Department of Medicine, Tri-Service General Hospital, and Graduate Institute of Medical Sciences, National Defense Medical Center , Taipei , TaiwanChou-Long Huang - Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center , Dallas, Texas
- Resource Type
- Journal article
- Publication Details
- American journal of physiology. Renal physiology, Vol.314(5), pp.F999-F1007
- DOI
- 10.1152/ajprenal.00177.2017
- PMID
- 29384416
- PMCID
- PMC6031911
- ISSN
- 0363-6127
- eISSN
- 1522-1466
- Grant note
- R01 DK111542 / NIDDK NIH HHS
- Language
- English
- Date published
- 05/01/2018
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984094537302771
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