title: Hypoxic preconditioning protects photoreceptors against light damage independently of hypoxia inducible transcription factors in rods.
abstract: Hypoxic preconditioning protects photoreceptors against light-induced degeneration preserving retinal morphology and function. Although hypoxia inducible transcription factors 1 and 2 (HIF1, HIF2) are the main regulators of the hypoxic response, photoreceptor protection does not depend on HIF1 in rods. Here we used rod-specific Hif2a single and Hif1a;Hif2a double knockout mice to investigate the potential involvement of HIF2 in rods for protection after hypoxic preconditioning. To identify potential HIF2 target genes in rods we determined the retinal transcriptome of hypoxic control and rod-specific Hif2a knockouts by RNA sequencing. We show that rods do not need HIF2 for hypoxia-induced increased survival after light exposure. The transcriptomic analysis revealed a number of genes that are potentially regulated by HIF2 in rods; among those were Htra1, Timp3 and Hmox1, candidates that are interesting due to their connection to human degenerative diseases of the retina. We conclude that neither HIF1 nor HIF2 are required in photoreceptors for protection by hypoxic preconditioning. We hypothesize that HIF transcription factors may be needed in other cells to produce protective factors acting in a paracrine fashion on photoreceptor cells. Alternatively, hypoxic preconditioning induces a rod-intrinsic response that is independent of HIF transcription factors.
authors.affiliation: Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zürich, Zürich, Switzerland.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Kast
authors.affiliation: Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zürich, Zürich, Switzerland; Center for Integrative Human Physiology (ZIHP), University of Zürich, Zürich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Schori
authors.affiliation: Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zürich, Zürich, Switzerland; Center for Integrative Human Physiology (ZIHP), University of Zürich, Zürich, Switzerland; Neuroscience Center (ZNZ), University of Zürich, Zürich, 8057, Switzerland. Electronic address: cgrimm@opht.uzh.ch.
authors.forename: Christian
authors.initials: C
authors.lastname: Grimm
mesh_terms: D000818:Animals; D016923:Cell Death; D004247:DNA / Q000235:genetics*; D004596:Electroretinography; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics*; D019194:Ischemic Preconditioning / Q000379:methods*; D008027:Light / Q000009:adverse effects; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D012162:Retinal Degeneration / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004247:DNA
keywords: HIF; Hypoxia-inducible factors; Hypoxic preconditioning; Light damage; Neuroprotection; Photoreceptors; Retinal degeneration