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A unifying mechanism for WNK kinase regulation of sodium-chloride cotransporter

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Abstract

Mammalian with-no-lysine [K] (WNK) kinases are a family of four serine-threonine protein kinases, WNK1-4. Mutations of WNK1 and WNK4 in humans cause pseudohypoaldosteronism type II (PHA2), an autosomal-dominant disease characterized by hypertension and hyperkalemia. Increased Na+ reabsorption through Na+–Cl− cotransporter (NCC) in the distal convoluted tubule plays an important role in the pathogenesis of hypertension in patients with PHA2. However, how WNK1 and WNK4 regulate NCC and how mutations of WNKs cause activation of NCC have been controversial. Here, we review current state of literature supporting a compelling model that WNK1 and WNK4 both contribute to stimulation of NCC. The precise combined effects of WNK1 and WNK4 on NCC remain unclear but likely are positive rather than antagonistic. The recent discovery that WNK kinases may function as an intracellular chloride sensor adds a new dimension to the physiological role of WNK kinases. Intracellular chloride-dependent regulation of WNK’s may underlie the mechanism of regulation of NCC by extracellular K+. Definite answer yet will require future investigation by tubular perfusion in mice with altered WNK kinase expression.

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Acknowledgments

Work in authors’ lab is supported by grants from the National Institutes of Health of USA (DK59530 to CLH) and from National Science Council of Taiwan (MOST 103-2628-B-016-001-MY3 to CJC).

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  1. Department of Internal Medicine, Division of Nephrology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-8856, USA

    Chou-Long Huang

  2. Department of Medicine, Division of Nephrology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

    Chih-Jen Cheng

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Correspondence to Chou-Long Huang.

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Huang, CL., Cheng, CJ. A unifying mechanism for WNK kinase regulation of sodium-chloride cotransporter. Pflugers Arch - Eur J Physiol 467, 2235–2241 (2015). https://doi.org/10.1007/s00424-015-1708-2

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