Interleukin-1β Attenuates Renin Gene Expression Via a Mitogen-Activated Protein Kinase Kinase-Extracellular Signal-Regulated Kinase and Signal Transducer and Activator of Transcription 3-Dependent Mechanism in As4.1 Cells

Abstract

The precise mechanism by which cytokines such as IL-1beta negatively modulate expression of the renin gene remains incomplete. IL-1beta 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 retinoic acid response element is sufficient to attenuate the retinoic acid-response by IL-1beta. The decrease in retinoic acid-induced renin promoter activity in response to IL-1beta was blocked with the general tyrosine kinase inhibitor Genistein. IL-1beta caused an increase in the phosphorylation of ERK, but not p38MAPK or c-Jun N-terminal kinase. PD98059, an Erk kinase inhibitor, significantly decreased IL-1beta-mediated phosphorylation of ERK1/2, and attenuated the repression of baseline renin transcription in response to IL-1beta. PD98059 partially reversed the IL-1beta 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-1beta on the phosphorylation of ELK, Janus kinase 2, or signal transducers and activators of transcription (STAT) 1, IL-1beta significantly increased tyrosine-phosphorylation of STAT3, an effect attenuated by PD98059. STAT3 overexpression significantly repressed transcription of the renin gene, whereas small interfering RNA-mediated knockdown of STAT3 increased renin at baseline and attenuated the IL-1beta response. We conclude that in As4.1 cells, IL-1beta down-regulates renin gene expression via a mechanism involving the Erk-STAT3 pathway.