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Role of oxidative stress in epigenetic modification of MMP-9 promoter in the development of diabetic retinopathy

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An Erratum to this article was published on 28 February 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.

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Acknowledgements

We thank Mangayarkarasi ThandampallayamAjjeya for her help with the maintenance of animal colony and Dr. Arul J. Duraisamy for immunohistochemical analysis. This study was supported in part by grants from the National Institutes of Health (EY014370, EY017313 and EY022230) and from the Thomas Foundation to RAK, and an unrestricted grant to the Ophthalmology Department from Research to Prevent Blindness. The sponsor had no role in the design or conduct of this research.

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Authors and Affiliations

  1. Kresge Eye Institute, Wayne State University, Detroit, MI, 48201, USA

    Renu A. Kowluru & Yang Shan

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  1. Renu A. Kowluru
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  2. Yang Shan
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Correspondence to Renu A. Kowluru.

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Conflict of interest

RAK and YS have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/s00417-017-3625-x.

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Kowluru, R.A., Shan, Y. Role of oxidative stress in epigenetic modification of MMP-9 promoter in the development of diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 255, 955–962 (2017). https://doi.org/10.1007/s00417-017-3594-0

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  • DOI: https://doi.org/10.1007/s00417-017-3594-0

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