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

J Biol Chem. 2011 Sep 16;286(37):32011-7. doi: 10.1074/jbc.M111.269118. Epub 2011 Jul 29.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Animals
  • Bone Density Conservation Agents / pharmacology*
  • Calcitriol / pharmacology*
  • Cell Line, Transformed
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Gene Expression Regulation / drug effects*
  • HEK293 Cells
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Mediator Complex Subunit 1 / genetics
  • Mediator Complex Subunit 1 / metabolism
  • Membrane Proteins / biosynthesis*
  • Membrane Proteins / genetics
  • Mice
  • Mutation
  • Podocytes / metabolism*
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Receptors, Calcitriol / agonists
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / metabolism
  • Retinoid X Receptors / genetics
  • Retinoid X Receptors / metabolism
  • Vitamin D Response Element*


  • Bone Density Conservation Agents
  • Histones
  • Med1 protein, mouse
  • Mediator Complex Subunit 1
  • Membrane Proteins
  • RNA, Messenger
  • Receptors, Calcitriol
  • Retinoid X Receptors
  • nephrin
  • RNA Polymerase II
  • Calcitriol