Increased O-GlcNAcylation of NF-κB Enhances Retinal Ganglion Cell Death in Streptozotocin-induced Diabetic Retinopathy

Curr Eye Res. 2016;41(2):249-57. doi: 10.3109/02713683.2015.1006372. Epub 2015 Apr 2.


Purpose: Hyperglycemia results in increased flux through the hexoxamine biosynthetic pathway. We examined whether hyperglycemia increases O-GlcNAcylation in the diabetic retina and whether elevated O-GlcNAcylation of nuclear factor (NF)-κB increases apoptosis of retinal ganglion cells (RGCs) in diabetic retinopathy (DR).

Materials and methods: Diabetes was induced in C57BL/6 mice by five consecutive intraperitoneal injections of 55 mg/kg streptozotocin. All mice were killed 2 months after injections and expression levels of O-GlcNAcylated proteins, O-linked N-acetylglucosamine transferase (OGT), β-d-N-acetylglucosaminidase and NF-κB, and the extent of RGC death were examined. Immunoprecipitations were performed to investigate whether O-GlcNAcylation of NF-κB led to its activation and RGC death in DR.

Results: The expression levels of O-GlcNAcylated proteins and OGT were markedly higher in diabetic retinas than in control retinas. OGT colocalized with NeuN, a RGC-specific marker, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells in the ganglion cell layer of diabetic retinas. The p65 subunit of NF-κB was O-GlcNAcylated and the level of O-GlcNAcylated p65 was higher in diabetic retinas than in control retinas.

Conclusion: The present data suggest that hyperglycemia increases O-GlcNAcylation in DR and that O-GlcNAcylation of the p65 subunit of NF-κB is involved in hyperglycemia-induced NF-κB activation and RGC death in DR.

Keywords: Diabetes; NF-κB; O-GlcNAcylation; ganglion cell death; retinopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosaminidase / metabolism*
  • Acylation
  • Animals
  • Apoptosis*
  • Blood Glucose / metabolism
  • Blotting, Western
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Retinopathy / metabolism*
  • Diabetic Retinopathy / pathology
  • Hyperglycemia / metabolism
  • Immunoprecipitation
  • In Situ Nick-End Labeling
  • Male
  • Mice
  • Mice, Inbred C57BL
  • N-Acetylglucosaminyltransferases / metabolism*
  • Retinal Ganglion Cells / pathology*
  • Transcription Factor RelA / metabolism*


  • Blood Glucose
  • Rela protein, mouse
  • Transcription Factor RelA
  • N-Acetylglucosaminyltransferases
  • UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase
  • Acetylglucosaminidase