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Role of oxidative stress in epigenetic modification of MMP-9 promoter in the development of diabetic retinopathy.
- Source :
-
Graefe's Archive of Clinical & Experimental Ophthalmology . May2017, Vol. 255 Issue 5, p955-962. 8p. - Publication Year :
- 2017
-
Abstract
- Background: In the pathogenesis of diabetic retinopathy, damaged retinal mitochondria accelerate apoptosis of retinal capillary cells, and regulation of oxidative stress by manipulating mitochondrial superoxide dismutase ( SOD2) protects mitochondrial homeostasis and prevents the development of diabetic retinopathy. Diabetes also activates matrix metalloproteinase-9 (MMP-9), and activated MMP-9 damages retinal mitochondria. Recent studies have shown a dynamic DNA methylation process playing an important role in regulation of retinal MMP-9 transcription in diabetes; the aim of this study is to investigate the role of oxidative stress in MMP-9 transcription. Methods: The effect of regulation of mitochondrial superoxide on DNA methylation of MMP-9 promoter region was investigated in retinal endothelial cells incubated in the presence or absence of a MnSOD mimetic MnTBAP, by quantifying the levels of 5 methyl cytosine (5mC) and hydroxyl-methyl cytosine (5hmC). The binding of DNA methylating, and of hydroxymenthylating enzymes (Dnmts and Tets, respectively), at MMP-9 promoter (by chromatin immunoprecipitation) was also evaluated. The in vitro results were confirmed in the retina of diabetic mice overexpressing SOD2. Results: MnTBAP attenuated glucose-induced decrease in 5mC levels and increase on Dnmt1 binding at the MMP-9 promoter region. MnTBAP also ameliorated alterations in 5hmC levels and Tet binding, regulated MMP-9 transcription, and prevented mitochondrial damage. Similarly, mice overexpressing SOD2 were protected from diabetes-induced alteration in MMP-9 promoter methylation, and its transcription. Conclusions: Thus, regulation of oxidative stress by pharmacologic/genetic approaches maintains retinal mitochondrial homeostasis by ameliorating epigenetic modifications in the MMP-9 promoter region. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 0721832X
- Volume :
- 255
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- Graefe's Archive of Clinical & Experimental Ophthalmology
- Publication Type :
- Academic Journal
- Accession number :
- 122540819
- Full Text :
- https://doi.org/10.1007/s00417-017-3594-0