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Cagri G. Besirli, Nicholas D. Chinskey, Qiong-Duan Zheng, David N. Zacks; Autophagy Activation in the Injured Photoreceptor Inhibits Fas-Mediated Apoptosis. Invest. Ophthalmol. Vis. Sci. 2011;52(7):4193-4199. doi: 10.1167/iovs.10-7090.
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© 2016 Association for Research in Vision and Ophthalmology.
To examine the activation of autophagy and its relationship to Fas-mediated photoreceptor apoptosis during experimental retinal detachment.
Retina–retinal pigment epithelium (RPE) separation was created in Brown-Norway rats by subretinal injection of 1% hyaluronic acid and the intraretinal levels of the autophagy proteins LC3 and Atg5, the time course of LC3-I to LC3-II conversion, and the activation of cathepsins B and D were assayed with Western blot analysis and immunohistochemistry. We measured the ability of a Fas-activating antibody to induce LC3-I to LC3-II conversion in 661W cells, and the in vivo effect of Met12, a small molecule inhibitor of the Fas receptor, on LC3-I to LC3-II conversion and Atg5 expression. Autophagy activation was inhibited using 3-methyladenine (3-MA) or siRNA knockdown of Atg5 and the effect on apoptosis was measured using a caspase 8 activity assay, caspase 8 immunoblots, and photoreceptor TUNEL staining.
Retina–RPE separation resulted in a Fas-dependent activation of autophagy, with increased Atg5 levels and intraphotoreceptor conversion of LC3-I to LC3-II. Detached retinas had increased levels of autophagosome-associated lysosomal proteases, cathepsins B and D. Inhibition of autophagy by 3-MA or siAtg5 accelerated the time course of caspase 8 activation and photoreceptor TUNEL staining.
Autophagy activation occurs in the photoreceptors after retina–RPE separation. This appears to be, at least in part, dependent on Fas receptor activation, and plays a role in regulating the level of photoreceptor apoptosis.
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