Epigenetic Changes in Mitochondrial Superoxide Dismutase in the Retina and the Development of Diabetic Retinopathy

  1. Renu A. Kowluru
  1. Kresge Eye Institute, Wayne State University, Detroit, Michigan
  1. Corresponding author: Renu A. Kowluru, rkowluru{at}med.wayne.edu.

Abstract

OBJECTIVE To investigate the role of epigenetic regulation of the manganese superoxide dismutase gene (sod2) in the development of diabetic retinopathy and the metabolic memory phenomenon associated with its continued progression after hyperglycemia is terminated.

RESEARCH DESIGN AND METHODS Streptozotocin-induced diabetic rats were maintained in poor glycemic control (PC, GHb ∼12%) or in good glycemic control (GC, GHb ∼7.0%) for 4 months, or were allowed to maintain PC for 2 months, followed by GC for 2 additional months (PC-Rev). For experimental galactosemia, a group of normal rats were fed a 30% galactose diet for 4 months or for 2 months, followed by a normal diet for 2 additional months. Trimethyl histone H4 lysine 20 (H4K20me3), acetyl histone H3 lysine 9 (H3K9), and nuclear transcriptional factor NF-κB p65 and p50 at the retinal sod2 promoter and enhancer were examined by chromatin immunoprecipitation.

RESULTS Hyperglycemia (diabetes or galactosemia) increased H4K20me3, acetyl H3K9, and NF-κB p65 at the promoter and enhancer of retinal sod2, upregulated protein and gene expression of SUV420h2, and increased the interactions of acetyl H3K9 and NF-κB p65 to H4K20me3. Reversal of hyperglycemia failed to prevent increases in H4K20me3, acetyl H3K9, and NF-κB p65 at sod2, and sod2 and SUV420h2 continued to be abnormal. Silencing SUV420h2 by its small interfering RNA in retinal endothelial cells prevented a glucose-induced increase in H4K20me3 at the sod2 enhancer and a decrease in sod2 transcripts.

CONCLUSIONS Increased H4K20me3 at sod2 contributes to its downregulation and is important in the development of diabetic retinopathy and in the metabolic memory phenomenon. Targeting epigenetic changes may serve as potential therapeutic targets to retard the development and progression of diabetic retinopathy.

  • Received January 26, 2010.
  • Accepted January 27, 2011.

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  1. Diabetes vol. 60 no. 4 1304-1313
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