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J. Biol. Chem., Vol. 282, Issue 41, 29821-29830, October 12, 2007

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1,25-Dihydroxyvitamin D₃ Suppresses Renin Gene Transcription by Blocking the Activity of the Cyclic AMP Response Element in the Renin Gene Promoter^*

Weihua Yuan, Wei Pan, Juan Kong, Wei Zheng, Frances L. Szeto, Kari E. Wong, Ronald Cohen, Anna Klopot, Zhongyi Zhang, and Yan Chun Li¹

From the Department of Medicine and Committee on Molecular Metabolism and Nutrition, Division of Biological Sciences, the University of Chicago, Chicago, Illinois 60637

We have shown that 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) 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 –2725 to –2647 (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)₂D₃ inhibition of the transcriptional activity, suggesting the involvement of CRE in 1,25(OH)₂D₃-induced suppression. EMSA revealed that 1,25(OH)₂D₃ 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)₂D₃ suppresses renin gene expression at least in part by blocking the formation of CRE-CREB-CBP complex.

Received for publication, July 5, 2007 , and in revised form, August 8, 2007.

^* This work was supported in part by American Heart Association Grant-in-aid 0350503Z and National Institutes of Health Grants DK062072 and HL085793 (to Y. C. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Medicine, The University of Chicago, MC 4080, 5841 S. Maryland Ave., Chicago, IL 60637. Tel.: 773-702-2477; Fax: 773-702-5790; E-mail: cyan{at}medicine.bsd.uchicago.edu.

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