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Shameka J Shelby, Pavan S Angadi, David N Zacks; Autophagy in retinal detachment is mediated by hypoxia-inducible factor. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1106.
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Retinal detachment results in a time-dependent death of the photoreceptor cells. This separation also results in a hypoxic environment for the photoreceptors. Previous studies from our lab have shown that autophagy becomes activated post separation, and serves to delay apoptotic photoreceptor death. In the present study we test the hypothesis that hypoxia leads to increased levels of hypoxia-inducible factor (HIF) in the photoreceptors, and secondary activation of autophagy.
Retina-RPE separation was created in Brown-Norway rats by injection of 1% hyaluronic acid into the subretinal space. Retinas were harvested 1-7 days after detachment, and assayed for HIF protein levels with attached retinas serving as controls. Cultured (661W) photoreceptor cells were subjected to hypoxic conditions (1% O2, 5% CO2) and assayed for induction of HIF and autophagy. The requirement of Hif1α in regulating photoreceptor autophagy was tested using siRNA in cultured cells.
Hif1α and Hif2α protein levels peak at 1 day post retina-RPE separation and gradually decrease over time. In cultured photoreceptor cells, hypoxia results in increased levels of HIF and activation of autophagy. Silencing of Hif1α by siRNA appears to reduce the hypoxia-induced increase in autophagy.
Photoreceptor hypoxia due to retina-RPE separation results in increased Hif1α and Hif2α protein levels which contribute, at least in part, to the activation of autophagy. Future studies will use inhibitors of HIF proteins in the rodent model of retinal detachment to confirm the mechanism in vivo.
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