Cotransporters, WNKs and hypertension: an update

P. W. Flatman

Research output: Contribution to journalLiterature reviewpeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)186-192
Number of pages7
JournalCurrent Opinion in Nephrology and Hypertension
Issue number2
Publication statusPublished - Mar 2008

Keywords / Materials (for Non-textual outputs)

  • diuretics
  • hypertension
  • protein-serine-threonine kinases
  • sodium-chloride symporters
  • sodium-potassium-chloride symporters


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