title: Aldosterone modulates thiazide-sensitive sodium chloride cotransporter abundance via DUSP6-mediated ERK1/2 signaling pathway.
abstract: Thiazide-sensitive sodium chloride cotransporter (NCC) plays an important role in maintaining blood pressure. Aldosterone is known to modulate NCC abundance. Previous studies reported that dietary salts modulated NCC abundance through either WNK4 [with no lysine (k) kinase 4]-SPAK (Ste20-related proline alanine-rich kinase) or WNK4-extracellular signal-regulated kinase-1 and -2 (ERK1/2) signaling pathways. To exclude the influence of SPAK signaling pathway on the role of the aldosterone-mediated ERK1/2 pathway in NCC regulation, we investigated the effects of dietary salt changes and aldosterone on NCC abundance in SPAK knockout (KO) mice. We found that in SPAK KO mice low-salt diet significantly increased total NCC abundance while reducing ERK1/2 phosphorylation, whereas high-salt diet decreased total NCC while increasing ERK1/2 phosphorylation. Importantly, exogenous aldosterone administration increased total NCC abundance in SPAK KO mice while increasing DUSP6 expression, an ERK1/2-specific phosphatase, and led to decreasing ERK1/2 phosphorylation without changing the ratio of phospho-T53-NCC/total NCC. In mouse distal convoluted tubule (mDCT) cells, aldosterone increased DUSP6 expression while reducing ERK1/2 phosphorylation. DUSP6 Knockdown increased ERK1/2 phosphorylation while reducing total NCC expression. Inhibition of DUSP6 by (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one increased ERK1/2 phosphorylation and reversed the aldosterone-mediated increments of NCC partly by increasing NCC ubiquitination. Therefore, these data suggest that aldosterone modulates NCC abundance via altering NCC ubiquitination through a DUSP6-dependent ERK1/2 signal pathway in SPAK KO mice and part of the effects of dietary salt changes may be mediated by aldosterone in the DCTs.
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: Xiuyan
authors.initials: X
authors.lastname: Feng
authors.affiliation: Renal Division, the Second Affiliated Hospital, Wenzhou Medical University, Zhejiang, China; Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: Yiqian
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Renal Division, the Second Affiliated Hospital, Wenzhou Medical University, Zhejiang, China;
authors.forename: Ningjun
authors.initials: N
authors.lastname: Shao
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Renal Division, the First Affiliated Hospital, Wenzhou Medical University, Zhejiang, China;
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Renal Division, the Second Affiliated Hospital, Wenzhou Medical University, Zhejiang, China; Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: Zhizhi
authors.initials: Z
authors.lastname: Zhuang
authors.affiliation: Renal Division, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China;
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: Yingli
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Renal Division, the Second Affiliated Hospital, Wenzhou Medical University, Zhejiang, China;
authors.forename: Jieqiu
authors.initials: J
authors.lastname: Zhuang
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee; and.
authors.forename: Eric
authors.initials: E
authors.lastname: Delpire
authors.affiliation: Renal Division, the Second Affiliated Hospital, Wenzhou Medical University, Zhejiang, China;
authors.forename: Dingying
authors.initials: D
authors.lastname: Gu
authors.affiliation: Renal Division, the Second Affiliated Hospital, Wenzhou Medical University, Zhejiang, China; Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Section of Nephrology, Atlanta Veterans Administration Medical Center, Decatur, Georgia hcai3@emory.edu.
authors.forename: Hui
authors.initials: H
authors.lastname: Cai
mesh_terms: D000450:Aldosterone / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D054642:Dual Specificity Phosphatase 6 / Q000378:metabolism*; D004573:Electrolytes / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D049992:Sodium Chloride Symporters / Q000187:drug effects* / Q000378:metabolism*; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D049971:Thiazides / Q000494:pharmacology*; D054875:Ubiquitination / Q000187:drug effects / Q000502:physiology
chemical_list: D004573:Electrolytes; D049992:Sodium Chloride Symporters; D017673:Sodium Chloride, Dietary; D049971:Thiazides; D000450:Aldosterone; C486407:Stk39 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse
keywords: ERK1/2; SPAK KO mice; aldosterone; dietary salt; dual-specificity protein phosphatase 6; sodium chloride cotransporter