title: Chronic Metabolic Acidosis Activates Renal Tubular Sodium Chloride Cotransporter through Angiotension II-dependent WNK4-SPAK Phosphorylation Pathway.
abstract: The mechanism by which chronic metabolic acidosis (CMA) regulates sodium (Na(+))-chloride (Cl(-)) cotransporter (NCC) in the renal distal convoluted tubules remains unexplored. We examined the role of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and with-no-lysine kinase 4 (WNK4) on expression of NCC in mouse models of CMA. CMA was induced by NH4Cl in wild type mice (WTA mice), SPAK, and WNK4 knockout mice. The quantities of Ncc mRNA, expression of total NCC, phosphorylated (p)-NCC, SPAK and WNK4 in the kidneys as well as NCC inhibition with hydrochlorothiazide and Na(+) balance were evaluated. Relative to WT mice, WTA mice had similar levels of Ncc mRNA, but increased expression of total and p-NCC, SPAK, and WNK4 and an exaggerated response to hydrochlorothiazide which could not be observed in SPAK or WNK4 knockout mice with CMA. In WTA mice, increased plasma renin activity, aldosterone and angiotensin II concentrations accompanied by a significantly negative Na(+) balance. High Na(+) diet abolished the enhanced NCC expression in WTA mice. Furthermore, an angiotensin II type 1 receptor blocker rather than a mineralocorticoid receptor antagonist exerted a marked inhibition on Na(+) reabsorption and NCC phosphorylation in WTA mice. CMA increases WNK4-SPAK-dependent NCC phosphorylation and appears to be secondary to previous natriuresis with volume-dependent angiotensin II activation.
authors.affiliation: Division of Nephrology, Department of Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.|Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Fang
authors.affiliation: Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan.|Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Taipei, Taiwan.
authors.forename: Sung-Sen
authors.initials: SS
authors.lastname: Yang
authors.affiliation: Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Taipei, Taiwan.
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan.|Division of Pediatric Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Min-Hua
authors.initials: MH
authors.lastname: Tseng
authors.affiliation: Division of Nephrology, Department of Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan.|Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Taipei, Taiwan.
authors.forename: Shih-Hua
authors.initials: SH
authors.lastname: Lin
mesh_terms: D000138:Acidosis / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001774:Blood Chemical Analysis; D004195:Disease Models, Animal; D004232:Diuretics / Q000494:pharmacology; D015870:Gene Expression; D006852:Hydrochlorothiazide / Q000494:pharmacology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D049992:Sodium Chloride Symporters / Q000235:genetics / Q000378:metabolism*; D016482:Urinalysis
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D004232:Diuretics; D049992:Sodium Chloride Symporters; D006852:Hydrochlorothiazide; D000804:Angiotensin II; D012964:Sodium; C499024:Prkwnk4 protein, mouse; C486407:Stk39 protein, mouse; D017346:Protein Serine-Threonine Kinases