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M Samardzija, C Grimm, A Wenzel, M Groszer, M Gassmann, CE Remé; Hypoxia-mediated Protection of Photoreceptors Against Light Damage: Signaling Mechanisms . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3730.
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Purpose: Low oxygen tension stabilizes hypoxia-inducible factor-1α (HIF-1α) which upon heterodimerization stimulates expression of erythropoietin (Epo). Through binding to its receptor (EpoR), Epo promotes cell survival by inhibiting apoptosis during erythropoiesis and in neurons after ischemia. Epo also protects photoreceptors from light damage (Abstract by Grimm et al.). Other known mechanisms protecting the retina against light damage involve induction of glucocorticoid receptor (GR) by stress and inhibition of rhodopsin regeneration. Intracellular signaling by Epo in other systems may involve phosphorylation of Akt and ERK1,2, stimulation of NF-KB and induction of XIAP and Bcl-XL as antiapoptotic measures. We investigated signaling mechanisms potentially involved in hypoxia-mediated protection of photoreceptors against light damage. Methods: Mice were exposed to low oxygen levels (6% O2, 6h), allowed to reoxygenate in room air for 4 hours and exposed to high intensity visible light. Levels of signaling proteins and nucleo-cytoplasmic distribution of GR were detected by Western blots. Rhodopsin content and regeneration was determined spectrophotometrically. Results: Hypoxic preconditioning induced HIF-1α and Epo gene expression leading to protection of photoreceptors against light damage. Hypoxia reduced phosphorylation of ERK1 but not of Akt. Hypoxia or light exposure did not influence levels of XIAP, Bcl-XL or EpoR. Nucleo-cytoplasmic distribution of RelA (regulatory subunit of NF-KB) was not altered. Hypoxia activated GR, but at the time point of light exposure after 4h of reoxygenation GR distribution was as in controls. Rhodopsin regeneration was normal after 4 hours of reoxygenation. Conclusion: The protective effect of hypoxia in the retina was not caused by activated GR or by reduced rhodopsin regeneration. Since hypoxia did not induce one of the known signaling pathways involved in Epo-mediated cell survival in other systems we propose that an alternative signaling mechanism may exist in the retina that mediates hypoxia-induced protection of photoreceptors against light damage.
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