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 journalArticle

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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

Fingerprint

Gene Expression Regulation
Gene expression
Vitamin D Response Element
Podocytes
Calcitriol Receptors
Vitamin D
Acetylation
Luciferases
Histones
Mediator Complex Subunit 1
Assays
Glomerular Filtration Barrier
nephrin
1,25-dihydroxyvitamin D
Retinoid X Receptors
Messenger RNA
RNA Polymerase II
Diaphragms
Diaphragm
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Molecular mechanism underlying 1,25-dihydroxyvitamin D regulation of nephrin gene expression. / Deb, Dilip K.; Wang, Youli; Zhang, Zhongyi; Nie, Hongguang; Huang, Xueshi; Yuan, Zhengwei; Chen, Yunzi; Zhao, Qun; Li, Yan Chun.

In: Journal of Biological Chemistry, Vol. 286, No. 37, 16.09.2011, p. 32011-32017.

Research output: Contribution to journalArticle

Deb, DK, Wang, Y, Zhang, Z, Nie, H, Huang, X, Yuan, Z, Chen, Y, Zhao, Q & Li, YC 2011, 'Molecular mechanism underlying 1,25-dihydroxyvitamin D regulation of nephrin gene expression', Journal of Biological Chemistry, vol. 286, no. 37, pp. 32011-32017. https://doi.org/10.1074/jbc.M111.269118
Deb, Dilip K. ; Wang, Youli ; Zhang, Zhongyi ; Nie, Hongguang ; Huang, Xueshi ; Yuan, Zhengwei ; Chen, Yunzi ; Zhao, Qun ; Li, Yan Chun. / Molecular mechanism underlying 1,25-dihydroxyvitamin D regulation of nephrin gene expression. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 37. pp. 32011-32017.
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