Hif1a inactivation rescues photoreceptor degeneration induced by a chronic hypoxia-like stress
| Autor: | Katrin Klee, Frank Blaser, Marijana Samardzija, Daniel Barthelmes, Isabelle Meneau, Federica Storti, Christian Schori, Maya Barben, Martin Biel, Christian Grimm, Stylianos Michalakis, Divya Ail |
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| Přispěvatelé: | University of Zurich, Grimm, Christian |
| Rok vydání: | 2018 |
| Předmět: |
10018 Ophthalmology Clinic
0301 basic medicine Retinal degeneration genetic structures 610 Medicine & health Retinal Pigment Epithelium Degeneration (medical) Biology Article 1307 Cell Biology Mice 03 medical and health sciences chemistry.chemical_compound 1312 Molecular Biology medicine Animals Humans 10064 Neuroscience Center Zurich Hypoxia Molecular Biology Retina Retinal pigment epithelium Retinal Degeneration Retinal Cell Biology Macular degeneration Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease eye diseases Cell biology Oxidative Stress 030104 developmental biology HIF1A medicine.anatomical_structure chemistry Ageing 10076 Center for Integrative Human Physiology NIH 3T3 Cells sense organs Photoreceptor Cells Vertebrate |
| Zdroj: | Cell Death and Differentiation |
| ISSN: | 1476-5403 1350-9047 |
| Popis: | Reduced choroidal blood flow and tissue changes in the ageing human eye impair oxygen delivery to photoreceptors and the retinal pigment epithelium. As a consequence, mild but chronic hypoxia may develop and disturb cell metabolism, function and ultimately survival, potentially contributing to retinal pathologies such as age-related macular degeneration (AMD). Here, we show that several hypoxia-inducible genes were expressed at higher levels in the aged human retina suggesting increased activity of hypoxia-inducible transcription factors (HIFs) during the physiological ageing process. To model chronically elevated HIF activity and investigate ensuing consequences for photoreceptors, we generated mice lacking von Hippel Lindau (VHL) protein in rods. This activated HIF transcription factors and led to a slowly progressing retinal degeneration in the ageing mouse retina. Importantly, this process depended mainly on HIF1 with only a minor contribution of HIF2. A gene therapy approach using AAV-mediated RNA interference through an anti-Hif1a shRNA significantly mitigated the degeneration suggesting a potential intervention strategy that may be applicable to human patients. |
| Databáze: | OpenAIRE |
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