April 2010
Volume 51, Issue 13
ARVO Annual Meeting Abstract  |   April 2010
Metabolic Memory Phenomenon in Diabetic Retinopathy: Epigenetic Regulation of Manganese Superoxide Dismutase
Author Affiliations & Notes
  • Q. Zhong
    Ophthalmology, Kresge Eye Institute, Detroit, Michigan
  • M. Kanwar
    Ophthalmology, Wayne State Univ/Kresge Eye Inst, Detroit, Michigan
  • R. A. Kowluru
    Ophthalmology, Wayne State Univ/Kresge Eye Inst, Detroit, Michigan
  • Footnotes
    Commercial Relationships  Q. Zhong, None; M. Kanwar, None; R.A. Kowluru, None.
  • Footnotes
    Support  NIH-R011EY017313
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 5638. doi:
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      Q. Zhong, M. Kanwar, R. A. Kowluru; Metabolic Memory Phenomenon in Diabetic Retinopathy: Epigenetic Regulation of Manganese Superoxide Dismutase. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5638.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : Diabetic retinopathy resists reversal after hyperglycemia is terminated suggesting a metabolic memory phenomenon. The retina continues to experience increased oxidative stress, and the activity of antioxidant defense enzyme manganese superoxide dismutase (MnSOD), which is encoded by sod2 gene, continues to be compromised for some time after re-institution of good glycemia. The mechanism responsible for this continued inhibition of retinal MnSOD is unclear. Histone modifications affect gene expression and have been linked to the metabolic memory in vascular smooth muscle cells. The aim of this study is to investigate the role of epigenetic regulation of MnSOD in the resistance of diabetic retinopathy to arrest after re-institution of normal glycemia.

Methods: : Wistar rats made diabetic by streptozotocin were maintained either in poor glycemic control (PC, glycated hemoglobin GHb >11%) or in good glycemic control (GC, GHb <5.5%) for four months, or allowed to be in PC for two months followed by two months of GC (PC-GC). Age-matched normal rats served as control. Chromatin immunoprecipitation (CHIP) was conducted in retina with anti trimethylated histone H4 lysine 20 (tri me H4K20) and nuclear transcriptional factor NFkB p50 antibodies, and CHIP-DNA was amplified by quantitative real-time PCR.

Results: : Tri me H4K20 was increased at the promoter and enhancer of sod2 in the retina obtained from rats in PC group, possibly making chromatin compact and inaccessible to other transcription activators. NFkB p50 was increased at the enhancer of sod2 inPC further repressing the transcription of MnSOD. Reversal of hyperglycemia after two months of PC (PC-GC group) failed to reverse the increases in tri me H4K20 and NFkB p50 at the promoter/enhancer of sod2 respectively, and the activity of MnSOD continued to be compromised. However, if the rats were maintained in GC for the entire four months, tri me H4K20 and NFkB p50 were comparable to the values obtained from the age-matched normal rats, and these values were significantly different from those obtained from rats in PC group.

Conclusions: : Increased tri me H4K20 appears as one of the factor responsible for decreased retinal MnSOD in diabetes, and the failure to normalize tri me H4K20 after reversal hyperglycemia suggests its role in the metabolic memory phenomenon associated with the progression of diabetic retinopathy. Thus, histone methylation may serve as a potential target to be modulated to inhibit the development and progression of retinopathy in diabetic patients.

Keywords: diabetic retinopathy • oxidation/oxidative or free radical damage • antioxidants 

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