ALBERT

Description: by Pei-Yi Chu, Chih-Jen Cheng, Yi-Chang Wu, Yu-Wei Fang, Tom Chau, Shinichi Uchida, Sei Sasaki, Sung-Sen Yang, Shih-Hua Lin Stimulation of the OSR1 (Oxidative stress-responsive kinase-1)/SPAK [STE20 (sterile 20)/SPS1-related proline/alanine-rich kinase]-NCC (Na + -Cl − cotransporter) signaling cascade plays an important role in the WNK [With-No-Lysine (K)] kinase 4 D561A knock-in mouse model of pseudohypoaldosteronism type II (PHA II) characterized by salt-sensitive hypertension and hyperkalemia. The aim of this study was to investigate the respective roles of Osr1 and Spak in the pathogenesis of PHA II in vivo . Wnk4 D561A/+ mice were crossed with kidney tubule-specific (KSP) Osr1 knockout (KSP- Osr1 −/− ) and Spak knockout ( Spak −/− ) mice. Blood pressure, plasma and urine biochemistries, and the relevant protein expression in the kidneys were examined. Wnk4 D561A/+ , KSP- Osr1 −/− , and Spak −/− mice recapitulated the phenotypes of PHA II, Bartter-like syndrome, and Gitelman syndrome, respectively. Wnk4 D561A/+ .KSP- Osr1 −/− remained phenotypically PHA II while Wnk4 D561A/+ . Spak −/− mice became normotensive and lacked the PHA II phenotype. Phosphorylated Spak and Ncc were similarly increased in both Wnk4 D561A/+ and Wnk4 D561A/+ .KSP- Osr1 −/− mice while phosphorylated Ncc normalized in Wnk4 D561A/+ . Spak −/− mice. Furthermore, Wnk4 D561A/+ .KSP- Osr1 −/− mice exhibited exaggerated salt excretion in response to thiazide diuretics while Wnk4 D561A/+ . Spak −/− mice exhibited normal responses. Wnk4D561A/+.Spak −/− . KSP-Osr1 −/− triple mutant mice had low blood pressure and diminished phosphorylated Ncc. Both SPAK and OSR1 are important in the maintenance of blood pressure but activation of SPAK-NCC plays the dominant role in PHA II. SPAK may be a therapeutic target for disorders with salt-sensitive hypertension related to WNK4 activation.