Independent regulation of transforming growth factor-beta1 transcription and translation by glucose and platelet-derived growth factor

Fraser, Donald James ORCID: https://orcid.org/0000-0003-0102-9342, Phillips, Aled Owain ORCID: https://orcid.org/0000-0001-9744-7113 and Wakefield, Lalage 2002. Independent regulation of transforming growth factor-beta1 transcription and translation by glucose and platelet-derived growth factor. American Journal of Pathology 161 (3) , pp. 1039-1049.

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Abstract

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)-beta1. We have previously demonstrated that proximal tubular renal epithelial cell TGF-beta1 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-beta1. Addition of either 25 mmol/L of D-glucose or low-dose PDGF increased TGF-beta1 mRNA expression without stimulation of TGF-beta1 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-beta1 synthesis. Elevated glucose concentration stimulated de novo gene transcription as assessed by stimulation of a TGF-beta1 promoter-luciferase construct. This led to induction of a poorly translated TGF-beta1 transcript determined by polysome analysis. PDGF at low dose did not influence TGF-beta1 transcription, but led to alteration in TGF-beta1 mRNA stability and translation. Without a previous glucose-induced increase in the amount of TGF-beta1 transcript, PDGF did not stimulate significant TGF-beta1 protein synthesis. At a high dose (100 ng/ml) PDGF stimulated TGF-beta1 synthesis independent of glucose concentration. This was associated with increased TGF-beta1 gene transcription and alteration in TGF-beta1 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-beta1 protein synthesis. The data also suggest that independent regulation of TGF-beta1 transcription and translation by glucose and PDGF account for their synergistic effect on TGF-beta1 protein synthesis. We hypothesize that the role of glucose in diabetic nephropathy is to prime the kidney for an injurious response to other stimuli.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Publisher:	American Society for Investigative Pathology
ISSN:	0002-9440
Last Modified:	17 Oct 2022 08:32
URI:	https://orca.cardiff.ac.uk/id/eprint/393

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