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Divya Ail, Christina Lange, Christian Grimm; HIF1 dependend upregulation of Stanniocalcin-2 in chronic and acute hypoxia in the retina. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1176. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
A hallmark of retinal blinding diseases is degeneration of photoreceptors. Often, oxidative stress influences cell survival and the disease process. Hypoxia may differentially affect retinal integrity-chronic hypoxia leads to cell death but acute hypoxia is neuroprotective. Hypoxia stabilizes hypoxia inducible transcription factors (HIFs) expressing several target genes involved in diverse physiological processes. In normoxia HIF-alpha subunits are rapidly degraded by a Von Hippel Lindau (VHL) protein complex dependent pathway. To elucidate molecular mechanisms involved in hypoxia - mediated degeneration and / or protection, we aimed at the identification of the gene network controlled by HIF1 in rod photoreceptors in vivo.
Mice with a Cre-mediated deletion of Vhl specifically in rod photoreceptors were generated (VhlΔrod). These showed a hypoxia-like response with the stabilization of HIF1α and HIF2α in normoxia. The retinal transcriptome of these mice was compared with the transcriptome of mice that additionally lack HIF1A in their rods (Vhl;Hif1aΔrod). Expression of individual genes and proteins was analyzed an by qPCR and western bloting, respectively. Retinal function was tested by ERG and morphology analyzed by light microscopy and immunofluorescence (IF).
Retinal morphology of VhlΔrod and Vhl;Hif1aΔrod mice did not grossly differ from controls at 11 weeks of age, but at 1 year of age VhlΔrod mice lost about 75% of photoreceptors, indicating that long term stabilization of HIF1A results in an age-dependent degeneration. IF stainings for markers of Müller glia cells, rods, cones and microglia at 11 weeks of age showed slight variations in the knockdown mice. Gene chip analysis indicated that HIF1 directly or indirectly controls expression of a large number of genes in rod photoreceptors. One of those, stanniocalcin-2 (Stc2), showed a 14 fold upregulation on stabilization of HIF1A. Retinal Stc2 expression was also elevated in acute hypoxia, with a fast return to basal levels upon reoxygenation. Surprisingly, IF results suggests a strong expression of STC2 in Müller glia cells and in nerve fibres.
STC2 is a secreted glycoprotein, which has been shown to be regulated by HIF1A in other systems. Its role in the retina remains to be explored. The localization of STC2 in Muller glia cells may suggest a cross-talk between stressed photoreceptors and Muller glia cells.
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