Angiotensin II induces human TGF-beta 1 promoter activation: similarity to hyperglycaemia

Diabetologia. 2002 Jun;45(6):890-8. doi: 10.1007/s00125-002-0843-4. Epub 2002 May 17.


Aims/hypothesis: Activation of the renal renin-angiotensin system has been implicated in the pathogenesis of diabetic nephropathy. Because previous in vitro studies demonstrated the angiotensin II (ang II)-mediated up-regulation of the prosclerotic transforming growth factor beta 1 (TGF) we studied the molecular mechanism of ang II-induced TGF-beta 1 gene activation.

Methods: Mesangial cells were stimulated with 100 nmol/l ang II with or without inhibitors of protein kinase C (PKC) and p38 MAPK and the TGF-beta 1 promoter activity was determined by promoter-reporter assays. The effect of ang II on the binding of nuclear proteins to the regulatory AP-1 site B, previously shown to mediate the high glucose-response of the TGF-beta 1 promoter, was studied by electrophoretic mobility shift assays.

Results: Ang II enhanced the activity of the TGF-beta1 promoter fragment -453/+11 approximately 1.6-fold. Mutation of each of two AP-1 binding sites or inhibition of the PKC- and p38 MAPK-dependent pathways blocked the ang II-stimulated activity completely. Furthermore, ang II activated the binding of nuclear proteins to the AP-1 box B of the TGF-beta 1 promoter. These effects were similar to those previously observed with high glucose. Co-incubation with ang II and high glucose had no additive effect on TGF-beta 1 promoter activity, protein binding to the AP-1 box B or activation of p38 MAPK.

Conclusion/interpretation: The findings indicate that ang II and hyperglycaemia stimulate the TGF-beta 1 gene activation through the same PKC- and p38 MAPK-dependent pathways by the same regulatory elements of the TGF-beta 1 promoter. Our data could also be relevant for e.g. hypertension-induced glomerulosclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology*
  • Animals
  • Base Sequence
  • Binding Sites
  • Cell Line
  • Gene Expression Regulation / drug effects
  • Genes, Reporter
  • Glomerular Mesangium / drug effects
  • Glomerular Mesangium / physiology*
  • Glucose / pharmacology
  • Humans
  • Hyperglycemia / genetics
  • Hyperglycemia / physiopathology*
  • Mitogen-Activated Protein Kinases / metabolism
  • Mutagenesis, Site-Directed
  • Oligodeoxyribonucleotides
  • Promoter Regions, Genetic*
  • Recombinant Proteins / biosynthesis
  • Swine
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • Transfection
  • Transforming Growth Factor beta / genetics*
  • Transforming Growth Factor beta1
  • beta-Galactosidase / genetics
  • p38 Mitogen-Activated Protein Kinases


  • Oligodeoxyribonucleotides
  • Recombinant Proteins
  • TGFB1 protein, human
  • Transcription Factors
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Angiotensin II
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • beta-Galactosidase
  • Glucose