Molecular mechanism underlying 1,25-dihydroxyvitamin D regulation of nephrin gene expression

Dilip K. Deb, Youli Wang, Zhongyi Zhang, Hongguang Nie, Xueshi Huang, Zhengwei Yuan, Yunzi Chen, Qun Zhao, Yan Chun Li

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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) 2D 3). Here we showed that in podocytes 1,25(OH) 2D 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) 2D 3 treatment, and the induction was abolished by mutations within -312VDRE. ChIP assays showed that, upon 1,25(OH) 2D 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) 2D 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) 2D 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.

Original languageEnglish (US)
Pages (from-to)32011-32017
Number of pages7
JournalJournal of Biological Chemistry
Volume286
Issue number37
DOIs
StatePublished - Sep 16 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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