Role of CREB1 and NFκB-p65 in the Down-regulation of Renin Gene Expression by Tumor Necrosis Factor α

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