Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone.
Pseudohypoaldosteronism type II (PHAII) is caused by mutations in the WNK1 and WNK4 genes (WNK with-no-lysine kinase). In a mouse model of this disease where a mutant of Wnk4 D561A was knocked in, increased phosphorylation of the sodium chloride cotransporter (NCC) was found and the transporter was concentrated on the apical membrane of the distal tubules. In addition, we recently found that other kinases, such as the oxidative stress response kinase-1/STE20/SPS1-related proline alanine-rich kinase (OSR1/SPAK), also showed increased phosphorylation in these mice. Here we determined whether this kinase cascade is regulated by dietary salt intake. We found that the phosphorylation states of NCC and OSR1/SPAK were increased by low-salt diets and decreased by high-salt diets; a regulation completely lost in the knock-in mice. Increased phosphorylation was reversed by spironolactone and this decreased phosphorylation was reversed by administration of exogenous aldosterone. These studies suggest that that the WNK-OSR1/SPAK-NCC cascade may be a novel effector system of aldosterone action in the kidney.
Chiga
Motoko
M
Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Rai
Tatemitsu
T
Yang
Sung-Sen
SS
Ohta
Akihito
A
Takizawa
Toichiro
T
Sasaki
Sei
S
Uchida
Shinichi
S
D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011546:Pseudohypoaldosteronism; D049993:Sodium Chloride Symporter Inhibitors; D049992:Sodium Chloride Symporters / Q000378:metabolism*; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*
D049993:Sodium Chloride Symporter Inhibitors; D049992:Sodium Chloride Symporters; D017673:Sodium Chloride, Dietary; D000450:Aldosterone; D011494:Protein Kinases; C499024:Prkwnk4 protein, mouse; C486407:Stk39 protein, mouse; C534421:OXSR1 protein, mouse; D017346:Protein Serine-Threonine Kinases