Shivashankar Gaganashree, Lim Julie C, Acosta Monica L
School of Optometry and Vision Science, New Zealand National Eye Centre and Centre for Brain Research, University of Auckland, Auckland, New Zealand.
Department of Physiology, School of Medical and Health Sciences and New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand.
J Ophthalmol. 2023 Feb 28;2023:7893104. doi: 10.1155/2023/7893104. eCollection 2023.
Recent evidence has shown that retinal inflammation is a key player in diabetic retinopathy (DR) pathogenesis. To further understand and validate the metabolic biomarkers of DR, we investigated the effect of intravitreal proinflammatory cytokines on the retinal structure, function, and metabolism in an in vivo hyperglycemic mouse model.
C57Bl/6 mice were rendered hyperglycemic within one week of administration of a single high-dose intraperitoneal injection of streptozotocin, while control mice received vehicle injection. After confirming hyperglycemia, the mice received an intravitreal injection of either proinflammatory cytokines (TNF- and IL-1) or vehicle. Similarly, control mice received an intravitreal injection of either proinflammatory cytokines or vehicle. The retinal structure was evaluated using fundus imaging and optical coherence tomography, and retinal function was assessed using a focal electroretinogram (ERG), two days after cytokine injection. Retinas were collected for biochemical analysis to determine key metabolite levels and enzymatic activities.
Hyperglycemic mice intraocularly injected with cytokines developed visible retinal vascular damage and intravitreal and intraretinal hyper-reflective spots two days after the cytokines injection. These mice also developed a significant functional deficit with reduced a-wave and b-wave amplitudes of the ERG at high light intensities compared to control mice. Furthermore, metabolic disruption was evident in these mice, with significantly higher retinal glucose, lactate, ATP, and glutamine levels and a significant reduction in glutamate levels compared with control mice. Minimal or no metabolic changes were observed in hyperglycemic mice without intraocular cytokines or in control mice with intraocular cytokines at 2 days post hyperglycemia.
Proinflammatory cytokines accelerated the development of vascular damage in the eyes of hyperglycemic mice. Significant changes were observed in retinal structure, function, and metabolic homeostasis. These findings support the idea that with the onset of inflammation in DR, there is a deficit in metabolism. Therefore, early intervention to prevent inflammation-induced retinal changes in diabetic patients may improve the disease outcome.
近期证据表明，视网膜炎症是糖尿病视网膜病变（DR）发病机制中的关键因素。为了进一步理解和验证DR的代谢生物标志物，我们在体内高血糖小鼠模型中研究了玻璃体内促炎细胞因子对视网膜结构、功能和代谢的影响。
通过单次高剂量腹腔注射链脲佐菌素，在一周内使C57Bl/6小鼠血糖升高，而对照小鼠接受溶剂注射。确认血糖升高后，小鼠接受玻璃体内注射促炎细胞因子（TNF-和IL-1）或溶剂。同样，对照小鼠接受玻璃体内注射促炎细胞因子或溶剂。在细胞因子注射两天后，使用眼底成像和光学相干断层扫描评估视网膜结构，使用焦点视网膜电图（ERG）评估视网膜功能。收集视网膜进行生化分析，以确定关键代谢物水平和酶活性。
细胞因子注射两天后，眼内注射细胞因子的高血糖小鼠出现明显的视网膜血管损伤以及玻璃体内和视网膜内高反射点。与对照小鼠相比，这些小鼠在高光强度下还出现了明显的功能缺陷，ERG的a波和b波振幅降低。此外，这些小鼠的代谢紊乱明显，与对照小鼠相比，视网膜葡萄糖、乳酸、ATP和谷氨酰胺水平显著升高，谷氨酸水平显著降低。在高血糖小鼠中，未进行眼内细胞因子注射或在高血糖两天后进行眼内细胞因子注射的对照小鼠中，观察到最小或无代谢变化。
促炎细胞因子加速了高血糖小鼠眼部血管损伤的发展。在视网膜结构、功能和代谢稳态方面观察到显著变化。这些发现支持了DR炎症发作时存在代谢缺陷的观点。因此，早期干预以预防糖尿病患者炎症诱导的视网膜变化可能会改善疾病结局。
