The precise mechanism by which cytokines such as IL-1 negatively modulate expression of the renin gene remains incomplete. IL-1 can repress renin transcription under both baseline and retinoic acid-stimulated conditions in As4.1 cells, a renin-expressing cell line derived from the kidney. This repression does not require a negative regulatory element present in the renin enhancer, but is optimal in the presence of the entire renin enhancer. Three tandem copies of the a retinoic acid response element is sufficient to attenuate the retinoic acid-response by IL-1. The decrease in retinoic acid-induced renin promoter activity in response to IL-1 was blocked with the general tyrosine kinase inhibitor Genistein. IL-1 caused an increase in the phosphorylation of extracellular signal-regulated protein kinase (ERK), but not p38MAP kinase or JNK. PD98059, an Erk kinase inhibitor, significantly decreased IL-1-mediated phosphorylation of ERK1/2, and attenuated the repression of baseline renin transcription in response to IL-1. PD98059 partially reversed the IL-1 effect on retinoic acid-mediated transcription. To further investigate this mechanism, we searched the downstream effectors of ERK1/2 pathway. Although there was no effect of IL-1 on the phosphorylation of ELK, JAK2 or STAT1, IL-1 significantly increased tyrosine-phosphorylation of signal transducers and activators of transcription 3 (STAT3), an effect attenuated by PD98059. STAT3 overexpression significantly repressed transcription of the renin gene, whereas siRNA-mediated knockdown of STAT3 increased renin at baseline and attenuated the IL-1 response. We conclude that in As4.1 cells, IL-1 down regulates renin gene expression via a mechanism involving the Erk-STAT3 pathway.