TY - JOUR
T1 - Molecular mechanism underlying 1,25-dihydroxyvitamin D regulation of nephrin gene expression
AU - Deb, Dilip K.
AU - Wang, Youli
AU - Zhang, Zhongyi
AU - Nie, Hongguang
AU - Huang, Xueshi
AU - Yuan, Zhengwei
AU - Chen, Yunzi
AU - Zhao, Qun
AU - Li, Yan Chun
PY - 2011/9/16
Y1 - 2011/9/16
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M111.269118
DO - 10.1074/jbc.M111.269118
M3 - Article
C2 - 21803771
AN - SCOPUS:80052758537
SN - 0021-9258
VL - 286
SP - 32011
EP - 32017
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 37
ER -
