Abstract
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.
Highlights
Given that photoreceptors receive their oxygen largely from the choroidal blood with its reduced flow in older eyes, it is plausible that photoreceptors contribute to the upregulation of hypoxia-induced hypoxia-inducible transcription factors (HIFs) target genes in response to a mild but chronic hypoxia that may develop during ageing
Tissue hypoxia is relevant for many pathologies affecting the retinal and choroidal vasculature in diseases such as diabetic retinopathy and neovascular age-related macular degeneration (AMD)
Targeting the HIF-regulated growth factor vascular endothelial growth factor (VEGF) shows great benefit for patients suffering from wet AMD
Summary
Reduced choroidal blood flow in the ageing eye [7, 8] and in the foveolar region of AMD patients [9], choroidal ischemia in dry AMD [9–11] and the correlation between drusen accumulation and decreased choroidal blood volume in AMD [12] has led to the hypothesis that reduced oxygen availability to retinal cells might be a significant factor that contributes—likely together with other factors—to disease development and progression [4, 13]. Since both rods and cones have an. We show that the ageing human retina may experience increased hypoxic stress, identify HIF1 as the factor being mainly responsible for photoreceptor degeneration in a model of chronic hypoxia-like conditions and demonstrate that AAV-mediated RNA interference targeting Hif1a mitigates the degenerative phenotype
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