title: Molecular mechanism underlying 1,25-dihydroxyvitamin D regulation of nephrin gene expression.
abstract: Nephrin plays a key role in maintaining the structure of the slit diaphragm in the glomerular filtration barrier. Our previous studies have demonstrated potent renoprotective activity for 1,25-dihydroxyvitamin D (1,25(OH)(2)D(3)). Here we showed that in podocytes 1,25(OH)(2)D(3) markedly stimulated nephrin mRNA and protein expression. ChIP scan of the 6-kb 5' upstream region of the mouse nephrin gene identified several putative vitamin D response elements (VDREs), and EMSA confirmed that the VDRE at -312 (a DR4-type VDRE) could be bound by vitamin D receptor (VDR)/retinoid X receptor. Luciferase reporter assays of the proximal nephrin promoter fragment (-427 to +173) showed strong induction of luciferase activity upon 1,25(OH)(2)D(3) treatment, and the induction was abolished by mutations within -312VDRE. ChIP assays showed that, upon 1,25(OH)(2)D(3) activation, VDR bound to this VDRE leading to recruitment of DRIP205 and RNA polymerase II and histone 4 acetylation. Treatment of mice with a vitamin D analog induced nephrin mRNA and protein in the kidney, accompanied by increased VDR binding to the -312VDRE and histone 4 acetylation. 1,25(OH)(2)D(3) reversed high glucose-induced nephrin reduction in podocytes, and vitamin D analogs prevented nephrin decline in both type 1 and 2 diabetic mice. Together these data demonstrate that 1,25(OH)(2)D(3) stimulates nephrin expression in podocytes by acting on a VDRE in the proximal nephrin promoter. Nephrin up-regulation likely accounts for part of the renoprotective activity of vitamin D.
authors.affiliation: Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Deb
authors.forename: Youli
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhongyi
authors.initials: Z
authors.lastname: Zhang
authors.forename: Hongguang
authors.initials: H
authors.lastname: Nie
authors.forename: Xueshi
authors.initials: X
authors.lastname: Huang
authors.forename: Zhengwei
authors.initials: Z
authors.lastname: Yuan
authors.forename: Yunzi
authors.initials: Y
authors.lastname: Chen
authors.forename: Qun
authors.initials: Q
authors.lastname: Zhao
authors.forename: Yan Chun
authors.initials: YC
authors.lastname: Li
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002117:Calcitriol / Q000494:pharmacology*; D002461:Cell Line, Transformed; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056913:Mediator Complex Subunit 1 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009154:Mutation; D050199:Podocytes / Q000378:metabolism*; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018167:Receptors, Calcitriol / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D030181:Vitamin D Response Element
chemical_list: D050071:Bone Density Conservation Agents; D006657:Histones; C538856:Med1 protein, mouse; D056913:Mediator Complex Subunit 1; D008565:Membrane Proteins; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; C113267:nephrin; D012319:RNA Polymerase II; D002117:Calcitriol