1,25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter.
We have shown that 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) down-regulates renin expression. To explore the molecular mechanism, we analyzed the mouse Ren-1c gene promoter by luciferase reporter assays. Deletion analysis revealed two DNA fragments from -2,725 to -2,647 (distal fragment) and from -117 to +6 (proximal fragment) that are sufficient to mediate the repression. Mutation of the cAMP response element (CRE) in the distal fragment blunted forskolin stimulation as well as 1,25(OH)(2)D(3) inhibition of the transcriptional activity, suggesting the involvement of CRE in 1,25(OH)(2)D(3)-induced suppression. EMSA revealed that 1,25(OH)(2)D(3) markedly inhibited nuclear protein binding to the CRE in the promoter. ChIP and GST pull-down assays demonstrated that liganded VDR blocked the binding of CREB to the CRE by directly interacting with CREB with the ligand-binding domain, and the VDR-mediated repression can be rescued by CREB, CBP, or p300 overexpression. These data indicate that 1,25(OH)(2)D(3) suppresses renin gene expression at least in part by blocking the formation of CRE-CREB-CBP complex.
Yuan
Weihua
W
Department of Medicine, Division of Biological Sciences, the University of Chicago, Chicago, Illinois 60637, USA.
Pan
Wei
W
Kong
Juan
J
Zheng
Wei
W
Szeto
Frances L
FL
Wong
Kari E
KE
Cohen
Ronald
R
Klopot
Anna
A
Zhang
Zhongyi
Z
Li
Yan Chun
YC
D000818:Animals; D002117:Calcitriol / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D006801:Humans; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D012083:Renin / Q000096:biosynthesis / Q000235:genetics*; D020218:Response Elements; D015398:Signal Transduction
D002843:Chromatin; D008024:Ligands; D004247:DNA; D000242:Cyclic AMP; D012083:Renin; D002117:Calcitriol