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

Chou-Long Huang1, Chih-Jen Cheng2

  • 1Department of Internal Medicine, Division of Nephrology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-8856, USA. Chou-Long.Huang@UTSouthwestern.edu.

Pflugers Archiv : European Journal of Physiology
|April 24, 2015
PubMed

Insights

With-no-lysine [K] (WNK) kinases WNK1 and WNK4 stimulate sodium-chloride cotransporter (NCC) activity. This review supports a model where WNKs regulate NCC, potentially via chloride sensing, contributing to hypertension in PHA2.

Area of Science:

  • Molecular biology
  • Physiology
  • Nephrology

Background:

  • Mammalian with-no-lysine [K] (WNK) kinases (WNK1-4) are serine-threonine kinases.
  • Mutations in WNK1 and WNK4 cause pseudohypoaldosteronism type II (PHA2), leading to hypertension and hyperkalemia.
  • Increased renal sodium-chloride cotransporter (NCC) activity contributes to PHA2 pathogenesis.

Purpose of the Study:

  • To review the current literature on the regulation of NCC by WNK1 and WNK4.
  • To present a model where WNK1 and WNK4 stimulate NCC activity.
  • To explore the role of intracellular chloride sensing in WNK kinase function.

Main Methods:

  • Literature review of existing studies on WNK kinases and NCC regulation.
  • Analysis of data supporting a model of WNK-NCC interaction.
  • Discussion of emerging concepts, including chloride sensing by WNK kinases.

Main Results:

  • Evidence suggests WNK1 and WNK4 collaboratively stimulate NCC.
  • The precise regulatory mechanism remains under investigation, but effects are likely additive.
  • WNK kinases may act as intracellular chloride sensors, linking chloride levels to NCC activity.

Conclusions:

  • WNK1 and WNK4 play a significant role in stimulating NCC.
  • Intracellular chloride concentration may mediate WNK kinase regulation of NCC.
  • Further research, including in vivo studies, is needed to elucidate these mechanisms.
Keywords:
Cullin3Kelch-likeNCCNKCC2WNK1WNK4

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