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A chronic hypoxic response in photoreceptors alters the vitreous proteome in mice


Schori, Christian; Trachsel, Christian; Grossmann, Jonas; Barben, Maya; Klee, Katrin; Storti, Federica; Samardzija, Marijana; Grimm, Christian (2019). A chronic hypoxic response in photoreceptors alters the vitreous proteome in mice. Experimental Eye Research, 185:107690.

Abstract

Reduced oxygenation of the outer retina in the aging eye may activate a chronic hypoxic response in RPE and photoreceptor cells and is considered as a risk factor for the development of age-related macular degeneration (AMD). In mice, a chronically active hypoxic response in the retinal pigment epithelium (RPE) or photoreceptors leads to age-dependent retinal degeneration. To identify proteins that may serve as accessible markers for a chronic hypoxic insult to photoreceptors, we used proteomics to determine the protein composition of the vitreous humor in genetically engineered mice that lack the von Hippel-Lindau tumor suppressor (Vhl) specifically in rods (rod) or cones (all-cone). Absence of VHL leads to constitutively active hypoxia-inducible transcription factors (HIFs) and thus to a molecular response to hypoxia even in normal room air. To discriminate between the consequences of a local response in photoreceptors and systemic hypoxic effects, we also evaluated the vitreous proteome of wild type mice after exposure to acute hypoxia. 1'043 of the identified proteins were common to all three hypoxia models. 257, 258 and 356 proteins were significantly regulated after systemic hypoxia, in rod and in all-cone mice, respectively, at least at one of the analyzed time points. Only few of the regulated proteins were shared by the models indicating that the vitreous proteome is differentially affected by systemic hypoxia and the rod or cone-specific hypoxic response. Similarly, the distinct protein compositions in the individual genetic models at early and late time points suggest regulated, cell-specific and time-dependent processes. Among the proteins commonly regulated in the genetic models, guanylate binding protein 2 (GBP2) showed elevated levels in the vitreous that were accompanied by increased mRNA expression in the retina of both rod and all-cone mice. We hypothesize that some of the differentially regulated proteins at early time points may potentially be used as markers for the detection of a chronic hypoxic response of photoreceptors.

Abstract

Reduced oxygenation of the outer retina in the aging eye may activate a chronic hypoxic response in RPE and photoreceptor cells and is considered as a risk factor for the development of age-related macular degeneration (AMD). In mice, a chronically active hypoxic response in the retinal pigment epithelium (RPE) or photoreceptors leads to age-dependent retinal degeneration. To identify proteins that may serve as accessible markers for a chronic hypoxic insult to photoreceptors, we used proteomics to determine the protein composition of the vitreous humor in genetically engineered mice that lack the von Hippel-Lindau tumor suppressor (Vhl) specifically in rods (rod) or cones (all-cone). Absence of VHL leads to constitutively active hypoxia-inducible transcription factors (HIFs) and thus to a molecular response to hypoxia even in normal room air. To discriminate between the consequences of a local response in photoreceptors and systemic hypoxic effects, we also evaluated the vitreous proteome of wild type mice after exposure to acute hypoxia. 1'043 of the identified proteins were common to all three hypoxia models. 257, 258 and 356 proteins were significantly regulated after systemic hypoxia, in rod and in all-cone mice, respectively, at least at one of the analyzed time points. Only few of the regulated proteins were shared by the models indicating that the vitreous proteome is differentially affected by systemic hypoxia and the rod or cone-specific hypoxic response. Similarly, the distinct protein compositions in the individual genetic models at early and late time points suggest regulated, cell-specific and time-dependent processes. Among the proteins commonly regulated in the genetic models, guanylate binding protein 2 (GBP2) showed elevated levels in the vitreous that were accompanied by increased mRNA expression in the retina of both rod and all-cone mice. We hypothesize that some of the differentially regulated proteins at early time points may potentially be used as markers for the detection of a chronic hypoxic response of photoreceptors.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Ophthalmology Clinic
04 Faculty of Medicine > Functional Genomics Center Zurich
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Ophthalmology
Life Sciences > Sensory Systems
Life Sciences > Cellular and Molecular Neuroscience
Language:English
Date:August 2019
Deposited On:11 Sep 2019 11:06
Last Modified:29 Jul 2020 11:18
Publisher:Elsevier
ISSN:0014-4835
OA Status:Hybrid
Publisher DOI:https://doi.org/10.1016/j.exer.2019.107690
PubMed ID:31181196

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