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Manish Mishra, Renu A Kowluru; A novel role of poly(ADP-ribose) polymerase 1 in mitochondrial damage in diabetic retinopathy.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3204.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetes damages retinal mitochondria, and this accelerates capillary cell apoptosis. Our previous work has shown that the activation of retinal matrix metalloproteinase 9 (MMP-9) in diabetes degrades the extracellular matrix and damages the mitochondria. Transcription of MMP-9 is controlled by a number of transcriptional factors including nuclear factor-kB and activator protein 1 (AP-1). MMP-9 promoter has two distinct AP-1 binding sites (proximal and distal region), and in diabetes, its binding at both the sites is increased. Transcription factor regulatory enzyme, poly(ADP-ribose) polymerase 1 (PARP-1), is also activated in diabetes, and its inhibition prevents the development of retinopathy in diabetic rodents. Our aim is to understand the role of PARP-1 in transcriptional regulation of MMP-9 and mitochondrial damage in the development of diabetic retinopathy.
Human retinal endothelial cells, incubated in normal or high glucose, were analyzed for PARP-1 interaction with AP-1 using co-immunoprecipitation and western blot techniques. To understand the role of PARP-1, cells incubated with PARP-1 inhibitor (PJ34, 1µM) were analyzed for the interactions of MMP-9 promoter with PARP-1 and AP-1 by chromatin immunoprecipitation technique. In same cell preparations, mitochondrial damage was evaluated by measuring electron transport complex III activity and mitochondrial membrane permeability.
PARP-1 interactions with AP-1 were increased by high glucose, and in the same cell preparations, binding of PARP-1 at MMP-9 promoter was also elevated. Regulation of PARP-1 by PJ34 ameliorated glucose-induced increase in AP-1 binding at MMP-9 promoter. PJ34 also prevented increase in MMP-9 expression and mitochondrial damage experienced by the cells in high glucose.
PARP-1, via manipulating the binding of AP-1 at the MMP-9 promoter, upregulates MMP-9 expression, and this accelerates mitochondrial dysfunction. Thus, regulation of PARP-1 activation will maintain mitochondrial homeostasis and inhibit/retard the development of diabetic retinopathy.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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