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C. Lange, M. Thiersch, S. Joly, M. Samardzija, C. Grimm; Normoxic Activation of Hifs in Photoreceptors Provides Transient Protection Against Light Induced Degeneration. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4520.
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Hypoxic preconditioning protects the retina against light induced photoreceptor degeneration. Transcription factors like hypoxia inducible factors (HIFs) are activated during hypoxia and regulate the expression of target genes that may play an important role in the protection of photoreceptors from damage. This study was performed to analyze whether normoxic activation of HIFs in photoreceptors could protect these cells similar to hypoxic preconditioning.
Von Hippel Lindau (VHL) protein was knocked down specifically in photoreceptors and after the development of the eye by breeding Vhlh flox/flox mice to mice expressing Cre-recombinase under the opsin promotor. 10-week-old Vhlh flox/flox;opsin-cre mice were analyzed for HIF stabilization by Western blot and target gene expression by real-time PCR. Mice were exposed to bright white light and photoreceptor cell death was assessed 36 hours and 10 days post exposure.
In 10-week-old Vhlh flox/flox;opsin-cre HIF-1α and HIF-2α were stabilized and expression of target genes like adrenomedullin, STAT3 or metallothioneins was induced. However, expression of erythropoietin (EPO), that was thought to play a major role in hypoxia mediated neuroprotection, was not induced. Nevertheless light exposed Vhlh flox/flox;opsin-cre mice showed a protection of photoreceptors at 36 hours after the insult. However, this protection was lost 10 days after light.
Normoxic activation of HIF transcription factors in photoreceptors transiently protects against light induced retinal degeneration. The lack of full protection as observed after hypoxic preconditioning indicates that hypoxia may induce protective factors in cells other than rod photoreceptors. These factors may include EPO and may act in a paracrine fashion to protect against degeneration. Alternatively, artificial activation of HIF transcription factors is not sufficient for a complete ‘hypoxic’ response in normoxia.
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