The peroxisome proliferator-activated receptor gamma activating compounds thiazolidinedione (TZD) have been shown to inhibit diabetes-induced glomerular transforming growth factor-beta1 (TGF-beta1) expression, thereby ameliorating diabetic nephropathy. Here we examined the hypothesis that TZDs block high glucose-induced TGF-beta1 gene activation by interaction with the activated protein kinase C-c-Fos-TGF-beta1 promoter cascade in mesangial cells. The TZD compounds troglitazone and rosiglitazone completely prevented the high glucose induction of both TGF-beta1 promoter activity and elevation in nuclear c-Fos protein levels. The scavenging properties of troglitazone were shown not to be responsible for this inhibitory action, because hydrogen peroxide-mediated stimulation of TGF-beta1 promoter activity was not blocked. TZD-treatment did not interfere with the transcriptional activity of c-Fos responsible for stimulation of the TGF-beta1 promoter. The findings suggest a molecular mechanism by which TZD-treatment reduces specifically high glucose-induced, c-Fos-mediated gene activation, since phorbol ester-induced c-Fos mRNA and protein expression and subsequent elevation of TGF-beta1 mRNA expression were not prevented by TZDs.