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Lalit P. Singh, Takhellambam S. Devi; TXNIP Regulates Oxidative/Nitrosative Stress and Apoptosis of Retinal Pericytes under Chronic Hyperglycemia: Implications for Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5429.
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Diabetic retinopathy (DR) is the most common cause of blindness among the working age group people in the US. Early defects at the onset of DR include capillary basement membrane thickening, pericyte apoptosis and vessel leakage. The purpose of this study is to investigate molecular mechanism(s) of retinal pericyte apoptosis under chronic high glucose.
We recently showed that thioredoxin interacting/inhibiting protein (TXNIP), which is a pro-oxidative stress and pro-apoptotic protein, is significantly increased in the retina of diabetic rats in vivo and in vitro by high glucose (HG, 25 mM) in retinal cells in culture and induces oxidative stress and pro-inflammatory gene expression. Here, we investigate cellular responses of pericytes to sustained HG exposure (HG vs. 5 mM glucose for 5 days) in culture using a temperature-sensitive conditionally immortalized rat retinal pericyte cell line (TR-rPCT1).
We observe that HG increases TXNIP expression significantly in RT-rPCT1 and correlates positively with elevated ROS, protein-S-nitrosylation, and ATP depletion. These metabolic abnormalities are associated with nuclear DNA-break, pro-apoptotic caspase-3 activation, and a reduction in MTT activity suggesting pericyte cell death. Treatment of TR-rPCT1 cells with azaserine (0.2 mM), which inhibits hexosamine pathway and TXNIP, blocks HG-induced ROS generation, ATP reduction and restores MTT activity. Interestingly, we observe that retinal pericytes, unlike Muller cells, have modest autophagic response (LC3BII expression), which is a survival mechanism for cells under metabolic stress.
TXNIP overexpression, oxidative/nitrosative stress and a lack of autophagic/mitophagic response in retinal pericytes under chronic hyperglycemia may render them susceptible to early pre-mature demise and vasculopathy in DR. We propose that TXNIP plays a critical role in oxidative/nitrosative stress and pericyte loss in DR.
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