Yu Jeremy Y, Du Mei, Elliott Michael H, Wu Mingyuan, Fu Dongxu, Yang Shihe, Basu Arpita, Gu Xiaowu, Ma Jian-Xing, Aston Christopher E, Lyons Timothy J
Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK.
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Diabetologia. 2016 Sep;59(9):2026-35. doi: 10.1007/s00125-016-4012-6. Epub 2016 Jun 15.
AIMS/HYPOTHESIS: We aimed to determine whether plasma lipoproteins, after leakage into the retina and modification by glycation and oxidation, contribute to the development of diabetic retinopathy in a mouse model of type 1 diabetes.
To simulate permeation of plasma lipoproteins into retinal tissues, streptozotocin-induced mouse models of diabetes and non-diabetic mice were challenged with intravitreal injection of human 'highly-oxidised glycated' low-density lipoprotein (HOG-LDL), native- (N-) LDL, or the vehicle PBS. Retinal histology, electroretinography (ERG) and biochemical markers were assessed over the subsequent 14 days.
Intravitreal administration of N-LDL and PBS had no effect on retinal structure or function in either diabetic or non-diabetic animals. In non-diabetic mice, HOG-LDL elicited a transient inflammatory response without altering retinal function, but in diabetic mice it caused severe, progressive retinal injury, with abnormal morphology, ERG changes, vascular leakage, vascular endothelial growth factor overexpression, gliosis, endoplasmic reticulum stress, and propensity to apoptosis.
CONCLUSIONS/INTERPRETATION: Diabetes confers susceptibility to retinal injury imposed by intravitreal injection of modified LDL. The data add to the existing evidence that extravasated, modified plasma lipoproteins contribute to the propagation of diabetic retinopathy. Intravitreal delivery of HOG-LDL simulates a stress known to be present, in addition to hyperglycaemia, in human diabetic retinopathy once blood-retinal barriers are compromised.
目的/假设：我们旨在确定血浆脂蛋白渗漏至视网膜并经糖基化和氧化修饰后，是否会在1型糖尿病小鼠模型中促使糖尿病视网膜病变的发生。
为模拟血浆脂蛋白渗透至视网膜组织的过程，对链脲佐菌素诱导的糖尿病小鼠模型和非糖尿病小鼠进行玻璃体内注射人“高度氧化糖基化”低密度脂蛋白（HOG-LDL）、天然（N-）LDL或溶剂磷酸缓冲盐溶液（PBS）。在随后的14天内评估视网膜组织学、视网膜电图（ERG）和生化标志物。
玻璃体内注射N-LDL和PBS对糖尿病和非糖尿病动物的视网膜结构或功能均无影响。在非糖尿病小鼠中，HOG-LDL引发短暂的炎症反应，但未改变视网膜功能；而在糖尿病小鼠中，它会导致严重的进行性视网膜损伤，伴有形态异常、ERG改变、血管渗漏、血管内皮生长因子过度表达、胶质细胞增生、内质网应激和凋亡倾向。
结论/解读：糖尿病使小鼠对玻璃体内注射修饰LDL所致的视网膜损伤易感。这些数据进一步证明，渗漏至视网膜的修饰血浆脂蛋白会促使糖尿病视网膜病变的发展。一旦血视网膜屏障受损，玻璃体内注射HOG-LDL可模拟人类糖尿病视网膜病变中除高血糖外已知存在的一种应激状态。
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