Cotransporters, WNKs and hypertension: an update

Curr Opin Nephrol Hypertens. 2008 Mar;17(2):186-92. doi: 10.1097/MNH.0b013e3282f5244e.


Purpose of review: Studies of inherited conditions characterized by high or low blood pressure reveal the importance of a new signalling cascade, With no Lysine kinases (WNK) --> ste20/SPS1-related proline/alanine-rich kinase (SPAK)/oxidative stress-responsive kinase-1 (OSR1) --> Cation-Chloride Cotransporters (CCC), in regulating blood pressure and in the pathogenesis of essential hypertension. This review explores how these molecules interact to co-ordinate sodium homeostasis and how errors in these interactions may result in hypertension.

Recent findings: Studies using transgenic animals and gene knockins have clarified the role of mutant WNK4 in hypertension, by revealing its main action to be increasing the expression and activity of sodium-chloride cotransporter (NCC) in the kidney. Functional studies show how phosphorylation of WNK1 regulates both its activity and ability to interact with SPAK/OSR1, and clearly place it upstream of SPAK/OSR1 in the cascade. The structural basis for the interactions between SPAK/OSR1 and targets has been identified.

Summary: WNKs, activated by upstream kinases or autophosphorylation, bind and phosphorylate SPAK/OSR1, which in turn phosphorylate and activate NCCs and Na-K-Cl cotransporters (NKCCs). This increases sodium retention in the kidney (NKCC2, NCC) and vascular resistance (NKCC1), but decreases renin release (NKCC1). Hypertension-associated mutant WNKs increase surface expression and activation of renal tubular NKCC2 and NCC. Whether this adequately explains the hypertension awaits studies of these mutants in other tissues.

Publication types

  • Review

MeSH terms

  • Alternative Splicing
  • Animals
  • Bartter Syndrome / metabolism
  • Bartter Syndrome / physiopathology
  • Blood Pressure*
  • Gitelman Syndrome / metabolism
  • Gitelman Syndrome / physiopathology
  • Humans
  • Hypertension / enzymology
  • Hypertension / metabolism*
  • Hypertension / physiopathology
  • Mice
  • Mice, Transgenic
  • Minor Histocompatibility Antigens
  • Models, Animal
  • Oocytes / metabolism
  • Protein Isoforms / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction*
  • Sodium-Potassium-Chloride Symporters / metabolism
  • Solute Carrier Family 12, Member 1
  • Solute Carrier Family 12, Member 2
  • Symporters / genetics
  • Symporters / metabolism*
  • WNK Lysine-Deficient Protein Kinase 1
  • Xenopus


  • Minor Histocompatibility Antigens
  • Protein Isoforms
  • SLC12A1 protein, human
  • SLC12A2 protein, human
  • Slc12a1 protein, mouse
  • Slc12a2 protein, mouse
  • Sodium-Potassium-Chloride Symporters
  • Solute Carrier Family 12, Member 1
  • Solute Carrier Family 12, Member 2
  • Symporters
  • Prkwnk4 protein, mouse
  • Protein Serine-Threonine Kinases
  • WNK Lysine-Deficient Protein Kinase 1
  • Wnk1 protein, mouse