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J. Biol. Chem., Vol. 280, Issue 26, 24356-24362, July 1, 2005

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Role of CREB1 and NFB-p65 in the Down-regulation of Renin Gene Expression by Tumor Necrosis Factor ^*

Vladimir T. Todorov, Simon Völkl, Jürgen Friedrich, Leoni A. Kunz-Schughart¶, Thomas Hehlgans||, Linda Vermeulen**, Guy Haegeman**, M. Lienhard Schmitz, and Armin Kurtz

From the Institute of Physiology, ^¶Institute of Pathology, and ^||Department of Immunology, Regensburg University, D-93040 Regensburg, Germany, ^**Department of Molecular Biology, Gent University, B-9000 Gent, Belgium, and Department of Chemistry and Biochemistry, University of Bern, CH-3012 Bern, Switzerland

Tumor necrosis factor- (TNF) is a potent inhibitor of renin gene expression in renal juxtaglomerular cells. We have found that TNF suppresses renin transcription via transcription factor NFB, which targets a cAMP responsive element (CRE) in the renin promoter. Here we aimed to further clarify the role of NFB and the canonical CRE-binding proteins of the CRE-binding protein/activating transcription factor (CREB/ATF) family in the inhibition of renin gene expression by TNF in the juxtaglomerular cell line As4.1. TNF caused a moderate decrease in the binding of CREB1 to its cognate CRE DNA binding site. On the other hand, NFB-p65 transcriptional activity was substantially reduced by TNF, which targeted a trans-activation domain at the very C terminus of the p65 molecule. Our results suggest that TNF inhibits renin gene expression by decreasing the transactivating capacity of NFB-p65 and partially by attenuating CREB1 binding to CRE.

Received for publication, March 17, 2005 , and in revised form, April 21, 2005.

^* This work was supported by the Deutsche Forschungsgemeinschaft. 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.

To whom correspondence should be addressed. Tel.: 49-941-943-2962; Fax: 49-941-943-4315; E-mail: vladimir.todorov{at}vkl.uniregensburg.de.

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