Inhibition of oxygen-induced retinopathy in RTP801-deficient mice
Inhibition of oxygen-induced retinopathy in RTP801-deficient mice
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DOI：
10.1167/iovs.04-0052
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发表时间：
2004-10-01
影响因子：
4.4
通讯作者：
Shoshani, T
中科院分区：
文献类型：
--
作者：
Brafman, A;Mett, I;Shoshani, T
目的.缺血性增殖性视网膜病变是糖尿病、早产儿或视网膜静脉阻塞的并发症，是世界范围内致盲的主要原因。除了视网膜新生血管外，它还涉及视网膜变性，其中细胞凋亡是主要原因。先前的报道已经描述了一种新的HIF-1应答基因RTP 801的克隆，其在体外和体内均在神经元来源的缺血细胞中显示出强烈的缺氧依赖性上调。此外，RTP 801的诱导性过表达促进分化的神经元样PC 12细胞的凋亡，并增加其对缺血损伤和氧化应激的敏感性。本研究的目的是使用RTP 801缺陷小鼠来检查RTP 801在视网膜病变发病机制中的潜在作用。将野生型和RTP 801敲除小鼠用于早产儿视网膜病变（ROP）模型中。分别于出生后14天和17天取视网膜。通过荧光素血管造影和VEGF表达、新生血管形成和血管增生的分析来检查。RTP 801的表达在缺氧处理后的野生型视网膜中被诱导。转移到正常含氧条件后，野生型和基因敲除小鼠的视网膜VEGF表达也类似地上调。然而，在ROP模型中，RTP 801基因敲除小鼠的视网膜显示出视网膜新生血管的显著减少（P < 0.0001）和内核层中凋亡细胞的数量显著减少（P < 0.0001）。在不存在RTP 801表达的情况下，ROP小鼠模型中视网膜病变的发展显著减弱，因此暗示RTP 801在ROP的发病机制中的重要作用。
PURPOSE. Ischemic proliferative retinopathy, which occurs as a complication of diabetes mellitus, prematurity, or retinal vein occlusion, is a major cause of blindness worldwide. In addition to retinal neovascularization, it involves retinal degeneration, of which apoptosis is the main cause. A prior report has described the cloning of a novel HIF-1- responsive gene, RTP801, which displays strong hypoxia-dependent upregulation in ischemic cells of neuronal origin, both in vitro and in vivo. Moreover, inducible overexpression of RTP801 promotes the apoptotic death of differentiated neuron-like PC12 cells and increases their sensitivity to ischemic injury and oxidative stress. The purpose of the study was to examine the potential role of RTP801 in the pathogenesis of retinopathy, using RTP801-deficient mice.METHODS. Wild-type and RTP801-knockout mice were used in a model of retinopathy of prematurity (ROP). Their retinas were collected at postnatal day (P) 14 and P17. They were examined by fluorescein angiography and by analysis of VEGF expression, neovascularization, and apoptosis.RESULTS. The expression of RTP801 was induced in the wildtype retina after hypoxia treatment. The retinal expression of VEGF after transfer to normoxic conditions was similarly upregulated in both wild-type and knockout mice. Nevertheless, the retinas of the RTP801-knockout mice in an ROP model showed a significant reduction in retinal neovascularization ( P < 0.0001) and in the number of apoptotic cells in the inner nuclear layer ( P < 0.0001).CONCLUSIONS. In the absence of RTP801 expression, development of retinopathy in the mouse model of ROP was significantly attenuated, thus implying an important role of RTP801 in the pathogenesis of ROP.