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Arul Joseph Duraisamy, Renu A Kowluru; Epigenetics and mitochondrial integrity in the metabolic memory associated with continued progression of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2652.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy continues to progress after termination of hyperglycemia, suggesting a metabolic memory phenomenon. Retinal mitochondria remain dysfunctional, and capillary cell apoptosis continues to progress. Mitochondrial integrity is maintained by continuous fusion and fission. In diabetes, mitochondrial fusion protein, Mitofusin 2 (Mfn2), is decreased leading to decreased mitochondrial DNA (mtDNA) instability. Gene expression is also regulated by epigenetic modifications, and the enzymes responsible for DNA methylation, DNA methyltransferases (Dnmts), continue to be activated even after re-institution of normal glycemia. The aim of this study is to investigate the role of epigenetic modifications of Mfn2 in the continued progression of diabetic retinopathy.
Streptozotocin-induced diabetic rats were divided into three groups; rats in group 1 were maintained in poor glycemic control (PC; GHb >10%) for four months followed by good glycemic control (GC, GHb <5.5%) for four additional months (PC-GC group). In groups 2 and 3, the rats remained in PC or GC respectively, for the entire 8 months. 5-methyl cytosine (5mC) levels at the Mfn2 promoter were measured in retinal microvessels (prepared by hypotonic shock) by MeDIP. Binding of Dnmt1, and transcription factor, SP1, was quantified by ChIP method and gene transcripts by qRT-PCR. mtDNA damage was evaluated by quantifying mtDNA-encoded cytochrome b (Cytb) expression.
Compared to normal rats, retinal microvessels from diabetic rats had decreased Mfn2 and increased 5-mC levels at its promoter. While the binding of Dnmt1 at the Mfn2 promoter was significantly elevated, that of SP1 was decreased. Reinstitution of GC failed to reverse the diabetes-induced increase in 5mC levels and Dnmt1 binding, and Mfn2 and Cytb continued to be suppressed.
Epigenetic modifications of the Mfn2 promoter, induced by prior hyperglycemic insult, do not benefit from re-institution of normal glycemia. Damaged mitochondrial structure and DNA continues to fuel into the vicious cycle of free radicals.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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