Evidence for a novel TGF-β1 - Independent mechanism of fibronectin production in mesangial cells overexpressing glucose transporters

Cora Weigert, Katrin Brodbeck, Frank C. Brosius, Matthias Huber, Rainer Lehmann, Ulrich Friess, Sonia Facchin, Steffen Aulwurm, Hans U. Häring, Erwin D. Schleicher, Charles W. Heilig

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Recent experimental work indicates that the hyperglycemia-induced increase in mesangial matrix production, which is a hallmark in the development of diabetic nephropathy, is mediated by increased expression of GLUT1. Mesangial cells stably transfected with human GLUT1 mimic the effect of hyperglycemia on the production of the extracellular matrix proteins, particularly fibronectin, when cultured under normoglycemic conditions. Our investigation of the molecular mechanism of this effect has revealed that the enhanced fibronectin production was not mediated by the prosclerotic cytokine transforming growth factor (TGF)-β1. We found markedly increased nuclear content in Jun proteins, leading to enhanced DNA-binding activity of activating protein 1 (AP-1). AP-1 inhibition reduced fibronectin production in a dosage-dependent manner. Moreover, inhibition of classic protein kinase C (PKC) isoforms prevented both the activation of AP-1 and the enhanced fibronectin production. In contrast to mesangial cells exposed to high glucose, no activation of the hexosamine biosynthetic, p38, or extracellular signal-related kinase 1 and 2 mitogen-activated protein kinase pathways nor any increase in TGF-β1 synthesis could be detected, which could be explained by the absence of oxidative stress in cells transfected with the human GLUT1 gene. Our data indicate that increased glucose uptake and metabolism induce PKC-dependent AP-1 activation that is sufficient for enhanced fibronectin production, but not for increased TGF-β1 expression.

Original languageEnglish (US)
Pages (from-to)527-535
Number of pages9
JournalDiabetes
Volume52
Issue number2
DOIs
StatePublished - Feb 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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