c-Fos-driven transcriptional activation of transforming growth factor beta-1: inhibition of high glucose-induced promoter activity by thiazolidinediones.
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.
Weigert
Cora
C
Department of Internal Medicine, Division of Endocrinology, Metabolism and Pathobiochemistry, University of Tübingen, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany.
Brodbeck
Katrin
K
Bierhaus
Angelika
A
Häring
Hans U
HU
Schleicher
Erwin D
ED
D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D005947:Glucose / Q000037:antagonists & inhibitors*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D000077154:Rosiglitazone; D013552:Swine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists; D015533:Transcriptional Activation / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000235:genetics*; D053773:Transforming Growth Factor beta1; D000077288:Troglitazone
D002839:Chromans; D016760:Proto-Oncogene Proteins c-fos; D018160:Receptors, Cytoplasmic and Nuclear; C508961:Tgfb1 protein, mouse; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000077154:Rosiglitazone; D006861:Hydrogen Peroxide; D000077288:Troglitazone; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate