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Maya Barben, Christian Schori, Christian Grimm, Marijana Samardzija; A chronic hypoxia-like response leads to cone degeneration. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4645.
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© ARVO (1962-2015); The Authors (2016-present)
The recently generated Rpe65R91W;Nrl-/- (R91W;Nrl-/-) double-mutant mice (Samardzija et al., IOVS, 2014, 55(8):5304-5313) express only cone photoreceptors in a well-layered and functional retina, and facilitate the investigation of cone-degenerative diseases, such as age-related macular degeneration (AMD). Since hypoxia has been postulated to be important in the etiology of AMD (Arjaama et al., Ageing Res Rev. 2009, 8(4):349-58), we analyzed the effect of a chronic hypoxia-like response on cone pathophysiology. We hypothesized that a cone-specific inactivation of von Hippel Lindau protein (VHL) in R91W;Nrl-/- mice leads to a long-term activation of HIF transcription factors enabling transcription of HIF target genes, and results in age-dependent retinal degeneration.
We ablated Vhl specifically in cones of the all-cone R91W;Nrl-/- mouse using the Cre-LoxP system (BPcre;R91W;Nrl-/-;Vhlf/f (=coneΔVhl)). ConeΔVhl mice were analyzed at 4, 6, 8, 12 and 26 weeks of age, and compared to age-matched R91W;Nrl-/-;Vhlf/f control mice. Stabilization of HIF1A and differential regulation of HIF1 target genes were tested by Western blotting and real-time PCR. Photoreceptor degeneration and cellular structure in the retina were evaluated by light microscopy and TUNEL staining, respectively.
Based on data from ZsGreen-reporter mice, recombination by BPcre led to the inactivation of the floxed Vhl gene in most S-cones, but also in M-cones, and few other retinal cells of coneΔVhl mice. HIF1A was stabilized and expression of HIF1 target genes such as adrenomedullin and vascular endothelial growth factor were induced in retinas of normoxic coneΔVhl mice. Importantly, cone-specific ablation of Vhl resulted in a strong retinal degeneration with most cones lost at 26 weeks of age.
<br /> Here, we employed the all-cone R91W;Nrl-/- mouse to analyze the reaction of cones to a chronic hypoxia-like response, a feature that may be part of AMD pathology. Our results indicate that chronic activation of HIF transcription factors induces cone degeneration leading to loss of vision. However, further analysis is required to understand the underlying molecular pathways that lead to cone cell death. Ultimately, these results could assist in the development of therapeutical approaches for the treatment of cone-related diseases that suffer from reduced oxygenation of photoreceptors.
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