Regulation of vascular endothelial growth factor expression by advanced glycation end products

J Biol Chem. 2001 Nov 23;276(47):43836-41. doi: 10.1074/jbc.M106534200. Epub 2001 Sep 24.


Advanced glycation end products (AGEs) are generated during long term diabetes and are correlated with the development of diabetic complications, such as retinopathy. Diabetic retinopathy is characterized by an increased retinal neovascularization due to the action of the angiogenic factor, vascular endothelial growth factor (VEGF). In this report, we show that injection of insulin and glycated albumin (Alb-AGE) to mice increases VEGF mRNA expression in eyes. Insulin and Alb-AGE stimulate VEGF mRNA and protein expression in retinal epithelial cells (ARPE-19). Alb-AGE-induced VEGF expression is not modulated by the use of antioxidants, N-acetyl-l-cysteine or pyrrolidinedithiocarbamate, or by an inhibitor of phosphatidylinositol 3-kinase (PI3K), wortmannin. However, using an inhibitor of ERK activation, U0126, we show that Alb-AGE stimulates VEGF expression through an ERK-dependent pathway. Accordingly, we found that Alb-AGE activated mitogen-activate protein kinase, ERK1/2, JNK1/2, but not p38, and that Alb-AGE did not activate PI3K and PKB. Moreover, Alb-AGE activated the transcription factor, hypoxia inducible factor-1 (HIF-1) DNA binding activity. This activation is mediated by an increase in accumulation of the HIF-1alpha protein through an ERK-dependent pathway. Thus, stimulation of VEGF expression by Alb-AGE, through the activation of HIF-1, could play an important role in the development of diabetic retinopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albumins / physiology
  • Animals
  • Base Sequence
  • Cell Line
  • DNA Primers
  • Endothelial Growth Factors / genetics*
  • Endothelial Growth Factors / metabolism
  • Enzyme Activation
  • Epithelial Cells / metabolism
  • Gene Expression Regulation / physiology*
  • Glycation End Products, Advanced / physiology*
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lymphokines / genetics*
  • Lymphokines / metabolism
  • Male
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger / genetics
  • Retina / cytology
  • Retina / metabolism
  • Signal Transduction
  • Transcription Factors / metabolism
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Albumins
  • DNA Primers
  • Endothelial Growth Factors
  • Glycation End Products, Advanced
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lymphokines
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases