Absence of DJ-1 causes age-related retinal abnormalities in association with increased oxidative stress.
Absence of DJ-1 causes age-related retinal abnormalities in association with increased oxidative stress.
复制标题
DOI：
10.1016/j.freeradbiomed.2017.01.018
复制
发表时间：
2017-03
影响因子：
7.4
通讯作者：
Cai H
中科院分区：
文献类型：
--
作者：
Bonilha VL;Bell BA;Rayborn ME;Samuels IS;King A;Hollyfield JG;Xie C;Cai H
氧化应激改变了大多数生物组织的生理功能，并可导致细胞死亡。在视网膜中，氧化应激引发一系列事件，导致RPE和光感受器的局灶性丧失，这被认为是地图状萎缩的主要促成因素。尽管存在这些影响，但在正常和病理条件下RPE氧化应激的分子调控仍然在很大程度上未知。更好地了解参与调节RPE和光感受器氧化应激反应的机制是非常必要的。为此，我们评估了缺乏DJ-1的小鼠中光感受器和RPE的变化，DJ-1是一种被认为在保护细胞免受氧化应激方面很重要的蛋白质。检查了年轻（3个月）和老年（18个月）DJ-1敲除（DJ-1 KO）和年龄匹配的野生型小鼠。在这两个老年小鼠扫描激光检眼镜检查（SLO）显示存在一些自发荧光灶。18个月大的DJ-1 KO视网膜的特征还在于与野生型相比RPE荧光显著增加。光学相干断层扫描（OCT）成像表明，所有视网膜层都存在于两个DJ-1 KO组的眼睛中。ERG比较显示，与年龄匹配的对照组相比，年龄较大的DJ-1 KO小鼠在黑暗和光适应条件下的敏感性降低。组织学上，年轻DJ-1 KO组的RPE含有明显的空泡，而老年组的RPE细胞则增大，形状不规则。这些在OCT和用鬼笔环肽标记的整装RPE/脉络膜制备物中也是明显的。与野生型对照组相比，老年DJ-1 KO小鼠中的光感受器显示出对视紫红质的免疫反应性降低和视锥标记物的局部减少。与野生型对照水平相比，在年轻和年老DJ-1 KO小鼠组中的视网膜/RPE裂解物中较低水平的活化Nrf 2是明显的。相反，在年轻和年老的DJ-1 KO小鼠的视网膜/RPE裂解物中检测到更高水平的蛋白质羰基衍生物和iNOS免疫反应性。这些结果表明，DJ-1 KO小鼠显示与较高水平的氧化应激标志物相关的视网膜/RPE变性的进行性体征。总的来说，该分析表明DJ-1在保护光感受器和RPE免受衰老过程中的氧化损伤方面起着重要作用。
Oxidative stress alters physiological function in most biological tissues and can lead to cell death. In the retina, oxidative stress initiates a cascade of events leading to focal loss of RPE and photoreceptors, which is thought to be a major contributing factor to geographic atrophy. Despite these implications, the molecular regulation of RPE oxidative stress under normal and pathological conditions remains largely unknown. A better understanding of the mechanisms involved in regulating RPE and photoreceptors oxidative stress response is greatly needed. To this end we evaluated photoreceptor and RPE changes in mice deficient DJ-1, a protein that is thought to be important in protecting cells from oxidative stress. Young (3 months) and aged (18 months) DJ-1 knockout (DJ-1 KO) and age-matched wild-type mice were examined. In both aged mice scanning laser ophthalmoscopy (SLO) showed the presence of a few autofluorescent foci. The 18 month-old DJ-1 KO retinas were also characterized by a noticeable increase in RPE fluorescence to wild-type. Optical coherence tomography (OCT) imaging demonstrated that all retinal layers were present in the eyes of both DJ-1 KO groups. ERG comparisons showed that older DJ-1 KO mice had reduced sensitivity under dark- and light-adapted conditions compared to age-matched control. Histologically, the RPE contained prominent vacuoles in young DJ-1 KO group with the appearance of enlarged irregularly shaped RPE cells in the older group. These were also evident in OCT and in whole mount RPE/choroid preparations labeled with phalloidin. Photoreceptors in the older DJ-1 KO mice displayed decreased immunoreactivity to rhodopsin and localized reduction in cone markers compared to the wild-type control group. Lower levels of activated Nrf2 were evident in retina/RPE lysates in both young and old DJ-1 KO mouse groups compared to wild-type control levels. Conversely, higher levels of protein carbonyl derivatives and iNOS immunoreactivity were detected in retina/RPE lysates from both young and old DJ-1 KO mice. These results demonstrate that DJ-1 KO mice display progressive signs of retinal/RPE degeneration in association with higher levels of oxidative stress markers. Collectively this analysis indicates that DJ-1 plays an important role in protecting photoreceptors and RPE from oxidative damage during aging.