Activation of nuclear factor-kappaB induced by diabetes and high glucose regulates a proapoptotic program in retinal pericytes

Diabetes. 2002 Jul;51(7):2241-8. doi: 10.2337/diabetes.51.7.2241.


To reconstruct the events that may contribute to the accelerated death of retinal vascular cells in diabetes, we investigated in situ and in vitro the activation of nuclear factor-kappaB (NF-kappaB), which is triggered by cellular stress and controls several programs of gene expression. The retinal capillaries of diabetic eye donors showed an increased number of pericyte nuclei positive for NF-kappaB, when compared with nondiabetic donors, whereas endothelial cells were negative. Microvascular cell apoptosis and acellular capillaries were increased only in the diabetic donors with numerous NF-kappaB-positive pericytes. Likewise, high glucose in vitro activated NF-kappaB in retinal pericytes but not in endothelial cells, and increased apoptosis only in pericytes. Studies with NF-kappaB inhibitors suggested that in pericytes, basal NF-kappaB has prosurvival functions, whereas NF-kappaB activation induced by high glucose is proapoptotic. Pericytes exposed to high glucose showed increased expression of Bax and of tumor necrosis factor-alpha, which were prevented by the NF-kappaB inhibitors and mimicked by transfection with the p65 subunit of NF-kappaB, and failed to increase the levels of the NF-kappaB-dependent inhibitors of apoptosis. Colocalization of activated NF-kappaB and Bax overexpression was observed in the retinal pericytes of diabetic donors. A proapoptotic program triggered by NF-kappaB selectively in retinal pericytes in response to hyperglycemia is a possible mechanism for the early demise of pericytes in diabetic retinopathy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Apoptosis*
  • Capillaries / pathology
  • Capillaries / physiopathology
  • Cause of Death
  • Cyclophilins / genetics
  • Diabetes Mellitus / physiopathology*
  • Endothelium, Vascular / pathology
  • Endothelium, Vascular / physiology
  • Endothelium, Vascular / physiopathology
  • Female
  • Humans
  • Hyperglycemia / physiopathology*
  • Male
  • Microcirculation / physiology*
  • Middle Aged
  • NF-kappa B / genetics*
  • NF-kappa B / metabolism*
  • Pericytes / cytology*
  • Pericytes / physiology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-bcl-2*
  • Reference Values
  • Retina / pathology
  • Retina / physiopathology*
  • Retinal Vessels / pathology
  • Retinal Vessels / physiology
  • Retinal Vessels / physiopathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / genetics
  • bcl-2-Associated X Protein


  • BAX protein, human
  • NF-kappa B
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Necrosis Factor-alpha
  • bcl-2-Associated X Protein
  • Cyclophilins