Vascular damage in a mouse model of diabetic retinopathy: Relation to neuronal and glial changes
Vascular damage in a mouse model of diabetic retinopathy: Relation to neuronal and glial changes
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DOI：
10.1167/iovs.04-1361
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发表时间：
2005-11-01
影响因子：
4.4
通讯作者：
Chen, DF
中科院分区：
文献类型：
--
作者：
Feit-Leichman, RA;Kinouchi, R;Chen, DF
目的.缺乏关于小鼠糖尿病视网膜病变发展的信息极大地阻碍了使用遗传小鼠模型研究疾病机制和开发治疗策略。本研究的目的是描述C57 Bl/6 J小鼠糖尿病视网膜病变的发生和病理进展。方法。糖尿病是通过连续5次注射链脲佐菌素（STZ）诱导的。在诱导糖尿病后的不同时间点（2周至22个月）收集视网膜，并通过分子、组织学、免疫组织化学技术和形态计量学分析进行检查。在糖尿病诱导的数天内，C57 Bl/6小鼠视网膜神经元中存在短暂的细胞凋亡诱导和半胱氨酸蛋白酶-3活化。胶质细胞酸性蛋白（GFAP），胶质细胞活化的标志物，同样是短暂上调，似乎在星形胶质细胞，但不是在穆勒细胞。这些异常很快恢复正常;最终，在糖尿病持续时间长达1年后，通过三种独立方法（视网膜横截面的神经节细胞层中的细胞数量、用荧光染料逆行标记视网膜神经节细胞或TUNEL染色）中的任何一种均未观察到视网膜神经节细胞（RGC）的可检测损失。尽管明显缺乏神经元和神经胶质细胞进行性损伤的证据，但糖尿病小鼠在发病后6个月开始出现糖尿病视网膜病变早期阶段的血管疾病特征。血管损伤-形成无细胞毛细血管和周细胞血影-继续增加，通过18个月的检查。糖尿病C57 Bl/6 J小鼠发生毛细血管病变，这是患者糖尿病视网膜病变早期阶段的特征。这些数据表明，糖尿病诱导的视网膜毛细血管变性可以独立于神经元损失或胶质细胞中的慢性GFAP上调而发展。
PURPOSE. Lack of information about the development of diabetic retinopathy in mice has greatly hindered the use of genetic mouse models for the study of disease mechanisms and the development of therapeutic strategies. The objective of this study was to characterize the occurrence and pathologic progression of diabetic retinopathy in C57Bl/6J mice.METHODS. Diabetes was induced with five consecutive injections of streptozotocin (STZ). The retinas were collected at different time points ( 2 weeks to 22 months) after the induction of diabetes and examined by using molecular, histologic, and immunohistochemical techniques and morphometric analysis.RESULTS. There was transient induction of cell apoptosis and caspase-3 activation in retinal neurons of C57Bl/6 mice within days of diabetes induction. Glial fibrillary acidic protein (GFAP), a marker of glial activation, likewise was transiently upregulated, seemingly in astrocytes but not in Muller cells. These abnormalities quickly returned to normal; ultimately, no detectable loss of retinal ganglion cells (RGCs) was noted by any of three independent methods ( number of cells in ganglion cell layer of retinal cross-sections, retrograde labeling of retinal ganglion cells with fluorescent dye, or TUNEL staining) after up to a 1-year duration of diabetes. Despite this apparent lack of evidence for progressive damage in neurons and glial cells, diabetic mice developed vascular disease characteristic of the early stage of diabetic retinopathy beginning at 6 months after the onset of disease. The vascular damage - formation of acellular capillaries and pericyte ghosts - continued to increase through the 18 months examined.CONCLUSIONS. Diabetic C57Bl/6J mice develop capillary lesion that are characteristic of the early stages of diabetic retinopathy in patients. The data suggest that diabetes-induced degeneration of retinal capillaries can develop independent of neuronal loss or chronic GFAP upregulation in glial cells.