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C. G. Besirli, N. D. Chinskey, Q.-D. Zheng, D. N. Zacks; Autophagy and the Control of Photoreceptor Apoptosis. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5207.
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To determine the role of autophagy activation during retinal detachment-induced photoreceptor apoptosis.
Retina-RPE separation was created in Brown Norway rats by subretinal injection of 1% hyaluronic acid. The expression of LC3 in the retina and the time course of LC3B-I to LC3B-II conversion after retinal detachment were determined with Western blots and immunohistochemistry. LC3B-I to LC3B-II conversion was examined in the presence of Met12, a small molecule inhibitor of the Fas/FasL signaling. The activation of cathepsin B and cathepsin D in photoreceptors after retinal detachment was measured with Western blots. In some animals, retinal detachments were created with or without subretinal injection of 3-methyladenine (3-MA) or vehicle alone. Caspase-8 activation was examined with immunohistochemistry after retinas were harvested. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) was performed in retinal sections 1, 3, and 7 days after separation.
Retina-RPE separation resulted in increased conversion of LC3B-I to LC3B-II in detached photoreceptors. This increase in LC3B-II levels was Fas-dependent as it was reduced in the presence of Met12. Detached retinas had increased levels of autophagosome-associated lysosomal proteases, cathepsin B and cathepsin D. Inhibition of autophagy by 3-MA in detached retinas accelerated the time course of photoreceptor caspase 8 activation and TUNEL labeling.
Fas-receptor activation after retina-RPE separation results in activation of both autophagy and apoptosis cascades. The autophagy cascade appears to function as a negative regulator (inhibitor) of the Fas-mediated apoptosis cascade.
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