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C Grimm, A Wenzel, M Groszer, H Mayser, M Seeliger, M Gassmann, CE Remé; Erythropoietin in the Retina: Protection Against Light-induced Retinal Apoptosis . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1888.
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Purpose: Due to their high metabolic activity, photoreceptors encounter borderline hypoxia during darkness and hypoxic areas play significant roles in retinal disorders such as diabetic retinopathy. Low levels of oxygen stabilize HIF-1α which, upon heterodimerization responds by upregulating erythropoietin (Epo) and VEGF among others. Epo promotes survival of cells during ischemia in brain and erythropoiesis in bone marrow by signaling through its receptor (EpoR) and interfering with apoptosis. We investigated Epo in the retina to analyze its function and potential activity as a neuroprotective agent in retinal degenerations. Methods: Mice were exposed to low oxygen levels (6% O2, 6h), allowed to reoxygenate in room air for 4 or 16 hours, analyzed immediately or exposed to high intensity visible light. Western blots and real time PCR were used to determine levels of various retinal proteins and mRNAs, respectively. Light microscopy, TUNEL staining and ERG recordings revealed extent of photoreceptor light damage. EpoR was detected by immunohistochemistry. Recombinant human (rh) Epo was injected intraperitoneally. Results: Hypoxic preconditioning protected retinas against light damage and preserved retinal morphology and function. Hypoxia-stabilized HIF-1α protein led to increased production of VEGF and Epo in the retina. EpoR localized to photoreceptors. Induction of AP-1 was not affected but hypoxic preconditioning prevented activation of caspase-1 gene expression, a late step in light induced apoptosis. Intraperitoneally injected rhEpo accumulated in the retina and protected photoreceptors against light damage even when applied 2 hours after light exposure. Conclusion: Hypoxia induces HIF-1α and Epo in the retina which protects photoreceptors against light damage by interfering with a late step in the apoptotic cascade. The rescue of photoreceptors by injection of rhEpo even after light exposure suggests a therapeutic potential for Epo. Proper function of this oxygen sensing system in the retina may be highly relevant for health and disease in the retina.
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