title: Pathophysiological roles of WNK kinases in the kidney.
abstract: 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.
authors.affiliation: Department of Nephrology, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan. suchida.kid@tmd.ac.jp
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchida
mesh_terms: D000818:Animals; D006801:Humans; D006973:Hypertension / Q000503:physiopathology; D007668:Kidney / Q000201:enzymology* / Q000503:physiopathology*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats
chemical_list: D017346:Protein Serine-Threonine Kinases