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AP-1 Proteins Mediate Hyperglycemia-Induced Activation of the Human TGF-ß1 Promoter in Mesangial Cells

CORA WEIGERT^*, ULRICH SAUER, KATRIN BRODBECK^*, ANDREAS PFEIFFER, HANS U. HÄRING^* and ERWIN D. SCHLEICHER^*

^* Department of Internal Medicine, Division of Endocrinology, Metabolism and Pathobiochemistry, University of Tübingen, Tübingen, Germany.
Institute of Pathology, University of Munich, Munich, Germany.
Medical Center Hospital Bergmannsheil, Bochum, Germany.

Correspondence to Dr. Erwin D. Schleicher, Department of Internal Medicine, Division of Endocrinology, Metabolism and Pathobiochemistry, University of Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany. Phone: + +49 7071 29 87599; Fax: + +49 7071 29 5974; E-mail: enschlei{at}med.unituebingen.de

Abstract. Hyperglycemia-induced overproduction of the prosclerotic cytokine transforming growth factor-ß1 (TGF-ß1) has been implicated in the pathogenesis of diabetic nephropathy. Because high glucose and phorbol esters (PMA) increase TGF-ß1 mRNA levels in mesangial cells, this study was designed to characterize these effects on the human TGF-ß1 promoter activity. With the use of luciferase reporter gene constructs containing TGF-ß1 5'-flanking sequence (from -453 to +11 bp) transfected into mesangial cells, it was found that 30 mM glucose induced a nearly twofold increase in TGF-ß1 promoter activity after 24 h of incubation in human and porcine mesangial cells. Stimulation by PMA was more effective (2.3-fold). Mutagenesis in either one of the two or both activating protein-1 (AP-1) binding sites abolished the high glucose and the PMA effect. Furthermore, addition of the AP-1 inhibitor curcumin obliterated the glucose response. Corresponding experiments revealed that the transcription factor stimulating protein 1 was not involved in mediating the glucose effect. The high glucose-induced TGF-ß1 promoter activation was also prevented by inhibitors of protein kinase C and p38 mitogen-activated proteinkinase. Electrophoretic mobility shift assays with oligonucleotides containing one of the two AP-1 binding sites showed that glucose treatment markedly enhanced the binding activity of nuclear proteins of mesangial cells, particularly to box B. Supershift assays demonstrated that JunD and c-Fos were present in the protein-DNA complexes under control and hyperglycemic conditions. The functional and structural results show that glucose regulates human TGF-ß1 gene expression through two adjacent AP-1 binding sites and gives rise to the involvement of protein kinase C and p38 mitogen-activated proteinkinase in hyperglycemia-induced TGF-ß1 gene expression.

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