Cotransporters, WNKs and hypertension: an update.

Abstract

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.

• Authors: Peter W Flatman
• Journal: Current opinion in nephrology and hypertension (Curr Opin Nephrol Hypertens) Vol. 17 Issue 2 Pg. 186-92 (Mar 2008) ISSN: 1062-4821 [Print] England
• PMID: 18277153 (Publication Type: Journal Article, Review)

Chemical References

• 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

Topics

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