Based on the presence of functional retinoic acid receptor/retinoid X receptor (RAR/RXR) transcription factor binding sequences in the renin gene enhancer and on the fact that the peroxisome proliferator-activated receptors (PPARs) bind to DNA as heterodimers with RXRs we speculated that PPARs could be involved in the regulation of renin gene expression. To test this hypothesis we used the human renin-producing cell line CaLu-6. Among the PPAR isoforms only PPARgamma was transcriptionally active in CaLu-6 cells. PPARgamma was found to bind to renin gene enhancer. Endogenous or pharmacological PPARgamma agonists (unsaturated fatty acids and thiazolidinediones, respectively) stimulated up to 20-fold renin gene expression. The effect of PPARgamma agonists appeared also to potentiate the cAMP/protein kinase A signaling to renin gene, which is the main pathway involved in the stimulation of renin transcription. PPARgamma knock-down through RNA interference decreased renin mRNA levels in CaLu-6 cells and in the mouse renin-producing juxtaglomerular-like cell line As4.1. PPARgamma agonists stimulated both renin gene expression and renin secretion in juxtaglomerular cells which are the main source of renin in vivo. Thus, PPARgamma was identified as a novel intracellular mediator involved in the up-regulation of renin transcription.