title: 1,25-Dihydroxyvitamin D3 suppresses high glucose-induced angiotensinogen expression in kidney cells by blocking the NF-{kappa}B pathway.
abstract: The renin-angiotensin system (RAS) is a major mediator of renal injury in diabetic nephropathy. Our previous studies demonstrated that 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] plays a renoprotective role by suppressing the RAS, with renin and angiotensinogen (AGT) as the main targets. The mechanism whereby 1,25(OH)(2)D(3) transcriptionally suppresses renin gene expression has been elucidated; however, how vitamin D regulates AGT remains unknown. Exposure of mesangial cells or podocytes to high glucose (HG; 30 mM) markedly stimulated AGT expression. In mesangial cells, the stimulation was inhibited by 1,25(OH)(2)D(3) (20 nM) or NF-kappaB inhibitor BAY 11-7082, suggesting the involvement of NF- kappaB in HG-induced AGT expression and the interaction between 1,25(OH)(2)D(3) and NF-kappaB in the regulation. Plasmid pNF-kappaB-Luc luciferase reporter assays showed that 1,25(OH)(2)D(3) blocked HG-induced NF-kappaB activity. EMSA and ChIP assays demonstrated increased p65/p50 binding to a NF-kappaB binding site at -1734 in the AGT gene promoter upon high glucose stimulation, and the binding was disrupted by 1,25(OH)(2)D(3) treatment. Overexpression of p65/p50 overcame 1,25(OH)(2)D(3) suppression, and mutation of this NF-kappaB binding site blunted 1,25(OH)(2)D(3) suppression of the promoter activity. In mice lacking the vitamin D receptor, AGT mRNA expression in the kidney was markedly increased compared with wild-type mice, and AGT induction in diabetic mice was suppressed by treatment with a vitamin D analog. These data indicate that 1,25(OH)(2)D(3) suppresses hyperglycemia-induced AGT expression by blocking NF-kappaB-mediated pathway.
authors.affiliation: Department of Medicine and Committee on Molecular Metabolism and Nutrition, Division of Biological Sciences, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Deb
authors.forename: Yunzi
authors.initials: Y
authors.lastname: Chen
authors.forename: Zhongyi
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Frances L
authors.initials: FL
authors.lastname: Szeto
authors.forename: Kari E
authors.initials: KE
authors.lastname: Wong
authors.forename: Juan
authors.initials: J
authors.lastname: Kong
authors.forename: Yan Chun
authors.initials: YC
authors.lastname: Li
mesh_terms: D000808:Angiotensinogen / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D002460:Cell Line; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000378:metabolism; D004347:Drug Interactions; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000494:pharmacology*; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014815:Vitamins / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D014815:Vitamins; D000808:Angiotensinogen; D002117:Calcitriol; D005947:Glucose