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R. S. Singh, C. J. Barnstable, S. K. Bronson, T. W. Gardner; Autophagy: Neuroprotective Response to Stress in Mammalian Retina. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3310.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetes upregulates retinal autophagy and ischemic preconditioning protects retina from subsequent ischemic injury by increased expression of autophagy protein Apg3p. We hypothesized that autophagy is a neuroprotective adaptive response of retina to stress.
Retinas from diabetic Ins2Akita mice and age-matched controls were analyzed for evidence of autophagy using electron microscopy. Retinal sections from diabetic GFP-LC3 mice and age-matched controls were evaluated for fluorescence patterns using confocal microscopy. The role of autophagy on retinal neuronal survival was evaluated by blocking autophagy with chloroquine treatment and measuring response to cell death-inducing stimuli. R28 cells were treated with 10 µM chloroquine for 24 hours and subjected to brief serum deprivation. Male Sprague Dawley rats were treated with subconjunctival chloroquine (10 µL of 100 µM in 1x PBS) for 24 hours followed by 30 min of ischemia and 6 hours of reperfusion injury. Apoptosis was measured using DNA fragmentation ELISA.
Diabetic mouse retina shows increased cytoplasmic vacuolization consistent with upregulated macroautophagy. Diabetic GFP-LC3 mice also exhibited altered GFP staining pattern after 3 months of diabetes consistent with autophagic vacuole trafficking. Blocking autophagy with chloroquine in R28 cells induced a 3-fold increase in cell death over non-treated controls after 2 hours of serum deprivation (p<0.01E-7). Retinas from chloroquine treated rats showed a 2-fold increase in retinal cell death compared to controls after ischemia reperfusion injury (p<0.005).
These findings suggest that autophagy is an adaptive neuroprotective response in retinal ischemia-reperfusion and early diabetic retinopathy.
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