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J. Biol. Chem., Vol. 279, Issue 2, 1458-1467, January 9, 2004

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Tumor Necrosis Factor- Activates NFB to Inhibit Renin Transcription by Targeting cAMP-responsive Element^*

Vladimir T. Todorov, Simon Völkl, Markus Müller¶, Alexander Bohla, Jürgen Klar, Leoni A. Kunz-Schughart||, Thomas Hehlgans**, and Armin Kurtz

From the Institutes of Physiology and ^||Pathology and ^**Department of Immunology, Regensburg University, Regensburg D-93040, Germany

Tumor necrosis factor- (TNF) is known to inhibit renin gene expression in juxtaglomerular cells, which are the main source of renin in vivo. In the present study we aimed to characterize the intracellular mechanisms of TNF signaling to renin gene in the mouse juxtaglomerular cell line As4.1. TNF was found to activate NFB, which is one of the principal intracellular mediators of TNF signal transduction. Constitutive activation of NFB suppressed renin gene transcription, but NFB appeared not to target the NFB binding sites in the renin promoter. Thus, NFB, but not the canonical NFB binding sequences in the renin promoter, seemed to be involved in the suppression of renin transcription by TNF. Deletion/mutation analysis revealed that the effect of TNF on renin gene is transmitted by a cAMP-responsive element (CRE) located at -2697 to -2690. Mobility shift/supershift assays evidenced for the presence of NFB proteins in the complex that binds to mouse renin CRE. Our results strongly suggest that NFB mediates the effect of TNF on renin transcription targeting a CRE in the mouse renin promoter.

Received for publication, August 6, 2003 , and in revised form, October 14, 2003.

^* 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.

^¶ Present address: Sanofi-Synthelabo Group, Berlin, Germany.

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

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