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Renu Kowluru, Julia M Santos; Protein Deacetylases Sirt1 and Epigenetic Modification of Matrix Metalloproteinase-9 in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5834.
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In the pathogenesis of diabetic retinopathy, increased matrix metalloproteinase-9 (MMP-9) accelerates retinal cell death via damaging the mitochondria. The transcription of MMP-9 is considered to be mediated by the binding of the nuclear transcriptional factor-kB (p65 subunit) at its promoter region. The process is facilitated by the acetylation of p65, which is controlled by a NAD-dependent deacetylase sirtuin-1 (Sirt1). The objective of this study is to investigate the role of Sirt1 in epigenetic modification of MMP-9 promoter in the development of diabetic retinopathy.
Retinal endothelial cells were incubated in normal (5mM) or high (20mM) glucose for 4 days in presence or absence of Sirt1 activator resveratrol. The activities of Sirt1 and MMP-9, p65 acetylation and its binding at MMP-9 promoter (by chromatin immunoprecipitation), and the mitochondria damage were quantified. The results were confirmed in the retina from human donors with diabetic retinopathy.
High glucose decreased Sirt1 activity and increased acetylation of p65 in retinal endothelial cells. This was accompanied by increased binding of p65 at MMP-9 promoter, and compromised mitochondria transcription. Inclusion of resveratrol prevented glucose-induced increase in acetylation of p65, and also it’s binding at the MMP-9 promoter. In the same cells, increase in the activity of MMP-9 and mitochondria damage was also ameliorated. Consistent with the results from isolated retinal endothelial cells, the activity of Sirt1 was also compromised in the retina from human donors with diabetic retinopathy.
Due to decrease in Sirt1 activity in diabetes, p65 acetylation is increased, and this facilitates its recruitment at MMP-9 promoter resulting in increased MMP-9 and mitochondrial damage. Thus, the regulation of Sirt1 by pharmacological means could serve as a potential target to prevent/delay the development of diabetic retinopathy.
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