Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zürich, Zürich, Switzerland.
Neuroscience Center Zurich (ZNZ), University of Zürich, Zürich, Switzerland.
Cell Death Differ. 2018 Dec;25(12):2071-2085. doi: 10.1038/s41418-018-0094-7. Epub 2018 Apr 17.
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.
随着年龄的增长，人眼脉络膜血流减少和组织变化会损害感光细胞和视网膜色素上皮的供氧。因此，可能会出现轻微但慢性的缺氧，并扰乱细胞代谢、功能，最终导致细胞死亡，这可能导致与年龄相关的黄斑变性（AMD）等视网膜病变。在这里，我们表明，几种缺氧诱导基因在老年人类视网膜中表达水平更高，这表明在生理衰老过程中缺氧诱导转录因子（HIFs）的活性增加。为了模拟慢性升高的 HIF 活性，并研究其对感光细胞的后续影响，我们在视杆细胞中缺失了 von Hippel Lindau（VHL）蛋白。这激活了 HIF 转录因子，并导致老年小鼠视网膜中进行性缓慢的视网膜变性。重要的是，这个过程主要依赖于 HIF1，而 HIF2 的贡献较小。通过使用 AAV 介导的 RNA 干扰（anti-Hif1a shRNA）的基因治疗方法显著减轻了变性，这表明可能适用于人类患者的潜在干预策略。
