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From the Institute of Nephrology,* University of Wales College of Medicine, Heath Park Cardiff, Wales, United Kingdom; and the Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland
Proximal tubular renal epithelial cells may contribute to the pathogenesis of renal interstitial fibrosis in diabetes by generation of cytokines such as transforming growth factor (TGF)-ß1. We have previously demonstrated that proximal tubular renal epithelial cell TGF-ß1 synthesis may be modulated by elevated glucose concentration and by cytokines such as platelet-derived growth factor (PDGF). The aim of the current study was to characterize the mechanism by which glucose and PDGF synergistically stimulate the generation of TGF-ß1. Addition of either 25 mmol/L of D-glucose or low-dose PDGF increased TGF-ß1 mRNA expression without stimulation of TGF-ß1 protein synthesis. In contrast sequential stimulation with 25 mmol/L of D-glucose for 48 hours followed by low-dose (25 ng/ml) PDGF led to a significant increase in TGF-ß1 synthesis. Elevated glucose concentration stimulated de novo gene transcription as assessed by stimulation of a TGF-ß1 promoter-luciferase construct. This led to induction of a poorly translated TGF-ß1 transcript determined by polysome analysis. PDGF at low dose did not influence TGF-ß1 transcription, but led to alteration in TGF-ß1 mRNA stability and translation. Without a previous glucose-induced increase in the amount of TGF-ß1 transcript, PDGF did not stimulate significant TGF-ß1 protein synthesis. At a high dose (100 ng/ml) PDGF stimulated TGF-ß1 synthesis independent of glucose concentration. This was associated with increased TGF-ß1 gene transcription and alteration in TGF-ß1 mRNA translational efficiency. In conclusion the data suggests that in diabetic nephropathy, the role of glucose is to lower the threshold at which a stimulus such as PDGF stimulates TGF-ß1 protein synthesis. The data also suggest that independent regulation of TGF-ß1 transcription and translation by glucose and PDGF account for their synergistic effect on TGF-ß1 protein synthesis. We hypothesize that the role of glucose in diabetic nephropathy is to prime the kidney for an injurious response to other stimuli.
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