Revisiting the NaCl cotransporter regulation by with-no-lysine kinases

Am J Physiol Cell Physiol. 2015 May 15;308(10):C779-91. doi: 10.1152/ajpcell.00065.2015. Epub 2015 Mar 18.


The renal thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC) is the salt transporter in the distal convoluted tubule. Its activity is fundamental for defining blood pressure levels. Decreased NCC activity is associated with salt-remediable arterial hypotension with hypokalemia (Gitelman disease), while increased activity results in salt-sensitive arterial hypertension with hyperkalemia (pseudohypoaldosteronism type II; PHAII). The discovery of four different genes causing PHAII revealed a complex multiprotein system that regulates the activity of NCC. Two genes encode for with-no-lysine (K) kinases WNK1 and WNK4, while two encode for kelch-like 3 (KLHL3) and cullin 3 (CUL3) proteins that form a RING type E3 ubiquitin ligase complex. Extensive research has shown that WNK1 and WNK4 are the targets for the KLHL3-CUL3 complex and that WNKs modulate the activity of NCC by means of intermediary Ste20-type kinases known as SPAK or OSR1. The understanding of the effect of WNKs on NCC is a complex issue, but recent evidence discussed in this review suggests that we could be reaching the end of the dark ages regarding this matter.

Keywords: WNK4; distal tubule; diuretics; hypertension; ion transport.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Kidney / metabolism
  • Lysine / metabolism
  • Protein-Serine-Threonine Kinases / metabolism*
  • Sodium-Potassium-Chloride Symporters / metabolism*
  • Ubiquitin-Protein Ligases / metabolism


  • Intracellular Signaling Peptides and Proteins
  • Sodium-Potassium-Chloride Symporters
  • Ubiquitin-Protein Ligases
  • Protein-Serine-Threonine Kinases
  • Lysine