Tumor necrosis factor-α (TNFα) 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 TNFα signaling to renin gene in the mouse juxtaglomerular cell line As4.1. TNFα was found to activate NFκB, which is one of the principal intracellular mediators of TNFα signal transduction. Constitutive activation of NFκB suppressed renin gene transcription, but NFκB appeared not to target the NFκB binding sites in the renin promoter. Thus, NFκB, but not the canonical NFκB binding sequences in the renin promoter, seemed to be involved in the suppression of renin transcription by TNFα. Deletion/mutation analysis revealed that the effect of TNFα 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 NFκB proteins in the complex that binds to mouse renin CRE. Our results strongly suggest that NFκB mediates the effect of TNFα on renin transcription targeting a CRE in the mouse renin promoter.