Role of CREB1 and NF{kappa}B-p65 in the down-regulation of renin gene expression by tumor necrosis factor {alpha}.

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