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H. Lee, H. Arnouk, R. Zhang, F. Lamoke, R. C. Hunt, W. J. M. Hrushesky, P. A. Wood, L. Wu, W. Jahng; Neuroprotecitve and Pro-Angiogenic Roles of Erythropoietin in Retina Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4944.
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The glycoprotein hormone erythropoietin (EPO) was found as a regulator of erythropoiesis by inhibiting apoptosis and by stimulating the proliferation and differentiation of erythroid precursor cells. Recently, EPO is known to have neuroprotective effect on ischemic brain by preventing neuronal cell apoptosis and differentiating neuronal precursor cell. Here we investigate regulation mechanism of neuroprotection through EPO in RPE and retina cells at hyperoxic, hypoxic condition or light exposure.
Angiogenic and neuroprotective effects of Epo were investigated in vitro (retina and RPE cell culture), ex vivo (bovine and mouse eye), in vivo (mouse) using Western blot, RT-PCR, cell viability assasy, immunohistochemistry. Survival of the RPE and retinal cells were assessed chemically by measuring cellular DNA contents using DNA-binding fluorescent dye. Cells were exposed to bright light exposure (10,000 lux of diffuse white fluorescent light) for 15, 30, and 60 min, or 1% O2 (hypoxic) or 50 % O2 (hyperoxic) for 30 min, 1,3,6, and 12 h at 37°C in a humidified 5% CO2 incubator, respectively. Changes in the level of EPO, janus kinase 2 (JAK2), hypoxia inducible factor-1α (Hif1α), RPE65, heme oxygenase-1 (HO-1), thioredoxin, c-Fos, or BCL-xl were investigated.
EPO is increased in light exposure, hypoxic and hyperoxic conditions. The anti-apoptotic factor (Bcl-XL) as well as another death signal factor (c-Fos) was increased in high dose of H2O2. Because RPE cell contains abundant anti-stress factors, the death threshold of RPE cell against oxidative stress seems to be higher than the other cells. Epo is up-regulated in 50% hyperoxic, 1% hypoxic, and bright light conditions. Further, the level of its downstream regulator, JAK2, and upstream regulators, Hif1α, and VEGF were also increased. Interestingly, treatment with EPO (50 unit) significantly increased the viability of human RPE cells and rat retinal cells exposed to bright light.
Hyperoxic and hypoxic environment or in the light, there is up-regulation of EPO in RPE and retinal cells. In the light and the oxidative stress, up-regulation of EPO confers neuroprotection against retinal degeneration. Our results show that Epo has dual functions such as neuroprotection by anti-apoptosis and neovascularization by pro-angiogenesis.
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