title: SPAK deficiency corrects pseudohypoaldosteronism II caused by WNK4 mutation.
abstract: 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. Wnk4(D561A/+).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.
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chu
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Cheng
authors.forename: Yi-Chang
authors.initials: YC
authors.lastname: Wu
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Fang
authors.forename: Tom
authors.initials: T
authors.lastname: Chau
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchida
authors.forename: Sei
authors.initials: S
authors.lastname: Sasaki
authors.forename: Sung-Sen
authors.initials: SS
authors.lastname: Yang
authors.forename: Shih-Hua
authors.initials: SH
authors.lastname: Lin
mesh_terms: D000818:Animals; D002712:Chlorides / Q000652:urine; D004195:Disease Models, Animal; D004232:Diuretics / Q000494:pharmacology; D017353:Gene Deletion; D056726:Genetic Association Studies; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D011546:Pseudohypoaldosteronism / Q000235:genetics* / Q000378:metabolism; D012964:Sodium / Q000652:urine; D064466:Solute Carrier Family 12, Member 1 / Q000378:metabolism; D064486:Solute Carrier Family 12, Member 3 / Q000378:metabolism
chemical_list: D002712:Chlorides; D004232:Diuretics; C578875:Slc12a3 protein, mouse; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D012964:Sodium; C499024:Prkwnk4 protein, mouse; C486407:Stk39 protein, mouse; C534421:OXSR1 protein, mouse; D017346:Protein Serine-Threonine Kinases
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