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

Am J Pathol. 2002 Sep;161(3):1039-49. doi: 10.1016/s0002-9440(10)64265-4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Transformed
  • Drug Synergism
  • Glucose / pharmacology*
  • Humans
  • Kidney Tubules, Proximal / metabolism*
  • Platelet-Derived Growth Factor / pharmacology*
  • Protein Biosynthesis / drug effects*
  • Transcription, Genetic / drug effects*
  • Transforming Growth Factor beta / biosynthesis*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta1


  • Platelet-Derived Growth Factor
  • TGFB1 protein, human
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • platelet-derived growth factor A
  • Glucose