Role of CREB1 and NFκB-p65 in the down-regulation of renin gene expression by tumor necrosis factor α

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