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(American Journal of Pathology. 2003;163:2565-2574.)
© 2003 American Society for Investigative Pathology

Long-Term Exposure of Proximal Tubular Epithelial Cells to Glucose Induces Transforming Growth Factor-ß1 Synthesis via an Autocrine PDGF Loop

Donald Fraser^*, Nigel Brunskill, Takafumi Ito^* and Aled Phillips^*

From the Institute of Nephrology,^* University of Wales College of Medicine, Heath Park, Cardiff, Wales; and the Department of Cell Physiology and Pharmacology and Department of Nephrology, Leicester University School of Medicine, Leicester, United Kingdom

We have recently reported increased transforming growth factor (TGF)-ß1 gene transcription in proximal tubular cells within 12 hours of exposure to 25 mmol/L D-glucose, with a requirement for a second stimulus such as platelet-derived growth factor (PDGF) to increase its translation in short-term experiments. In the current study we investigated the effect on TGF-ß1 production of prolonged exposure of proximal tubular cells to high glucose concentrations. Enzyme-linked immunosorbent assay of cell culture supernatant showed significant increase in latent TGF-ß1 only after 7 days exposure to high glucose. Radiolabeling of glucose-stimulated cells with ³H amino acids and subsequent immunoprecipitation of TGF-ß1 demonstrated de novo synthesis from day 5 of high glucose exposure onwards. Similarly, polysome analysis showed enhanced translation of TGF-ß mRNA after 4 or more days of high glucose exposure. TGF-ß1 synthesis, following addition of glucose, was inhibited by blockade of the PDGF- receptor subunit. Glucose did not alter PDGF expression, nor expression of PDGF -receptors. Activation of the receptor following addition of 25 mm D-glucose could be demonstrated suggesting increased sensitivity to endogenous PDGF. Exposure to glucose activated p38MAP kinase, and inhibition of this activation abrogated both glucose induced TGF-ß1 transcriptional activation and TGF-ß1 synthesis. Inhibition of p38MAP kinase did not influence the effect of exogenous PDGF when cells were stimulated sequentially by glucose and PDGF. We postulate that glucose induces an early increase in TGF-ß1 transcription via activation of p38MAP kinase. In addition, glucose causes a late increase in PDGF-dependent TGF-ß1 translation by enhancing cellular sensitivity to PDGF. This provides a potential explanation for the clinical observation that prolonged poor glycemic control may contribute to progression of diabetic nephropathy.

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