Pathophysiological roles of WNK kinases in the kidney

Since the discovery of mutations in the WNK1 and WNK4 genes in pseudohypoaldosteronism type II (PHAII), the pathophysiological role of WNK kinases in hypertension and renal ion transport has been a hot topic for investigation. Analyses from a mouse model carrying the same mutation as seen in PHAII p...

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Bibliographic Details
Published in:Pflügers Archiv 2010-09, Vol.460 (4), p.695-702
Main Author: Uchida, Shinichi
Format: Article
Language:English
Subjects:
Animals
Biomedical and Life Sciences
Biomedicine
Cell Biology
Human Physiology
Humans
Hypertension - physiopathology
Invited Review
Kidney - enzymology
Kidney - physiopathology
Mice
Molecular Medicine
Neurosciences
Protein-Serine-Threonine Kinases - physiology
Rats
Receptors
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Summary:Since the discovery of mutations in the WNK1 and WNK4 genes in pseudohypoaldosteronism type II (PHAII), the pathophysiological role of WNK kinases in hypertension and renal ion transport has been a hot topic for investigation. Analyses from a mouse model carrying the same mutation as seen in PHAII patients, reveal a new signal cascade in the kidney that regulates NaCl and K balance in the body. WNK kinases phosphorylate and activate oxidative stress responsive kinase 1 (OSR1) and STE20-like proline and alanine-rich kinase (SPAK), and OSR1 and SPAK phosphorylate and activate the thiazide-sensitive Na-Cl cotransporter (NCC). Furthermore, this cascade is regulated by aldosterone, indicating that WNK-OSR1/SPAK-NCC cooperates with this system including the epithelial Na channel (ENaC) to conserve NaCl. With regard to K excretion, however, both systems work in opposite directions whereby PHAII and Liddle syndrome show hyperkalemia and hypokalemia, respectively. Thus, the identification of such aldosterone effecters other than ENaC, will reveal a novel regulatory mechanism of K excretion in the distal nephron, and also provides basic evidence for the therapeutic use of thiazide in various clinical situations.
ISSN:0031-6768
1432-2013
DOI:10.1007/s00424-010-0848-7