Lieth E, Barber A J, Xu B, Dice C, Ratz M J, Tanase D, Strother J M
Department of Neuroscience and Anatomy, Pennsylvania State University College of Medicine, Hershey Medical Center, 17033, USA.
Diabetes. 1998 May;47(5):815-20. doi: 10.2337/diabetes.47.5.815.
The early pathophysiology of diabetic retinopathy and the involvement of neural and vascular malfunction are poorly understood. Glial cells provide structural and metabolic support for retinal neurons and blood vessels, and the cells become reactive in certain injury states. We therefore used the streptozotocin rat model of short-term diabetic retinopathy to study glial reactivity and other glial functions in the retina in the first months after onset of diabetes. With a two-site enzyme-linked immunosorbent assay, we measured the expression of the intermediate filament glial fibrillary acidic protein (GFAP). After 1 month, GFAP was largely unchanged, but within 3 months of the beginning of diabetes, it was markedly induced, by fivefold (P < 0.04). Immunohistochemical staining showed that the GFAP induction occurred both in astrocytes and in Müller cells. Consistent with a glial cell malfunction, the ability of retinas to convert glutamate into glutamine, assayed chromatographically with an isotopic method, was reduced in diabetic rats to 65% of controls (P < 0.01). Furthermore, retinal glutamate, as determined by luminometry, increased by 1.6-fold (P < 0.04) after 3 months of diabetes. Taken together, these findings indicate that glial reactivity and altered glial glutamate metabolism are early pathogenic events that may lead to elevated retinal glutamate during diabetes. These data are the first demonstration of a specific defect in glial cell metabolism in the retina during diabetes. These findings suggest a novel understanding of the mechanism of neural degeneration in the retina during diabetes, involving early and possibly persistent glutamate excitotoxicity.
糖尿病视网膜病变的早期病理生理学以及神经和血管功能障碍的参与情况目前尚不清楚。神经胶质细胞为视网膜神经元和血管提供结构和代谢支持，并且在某些损伤状态下这些细胞会发生反应。因此，我们使用链脲佐菌素诱导的短期糖尿病视网膜病变大鼠模型，来研究糖尿病发病后头几个月视网膜中的神经胶质细胞反应性和其他神经胶质细胞功能。通过双位点酶联免疫吸附测定法，我们测量了中间丝神经胶质纤维酸性蛋白（GFAP）的表达。1个月后，GFAP基本未发生变化，但在糖尿病开始后的3个月内，其表达显著诱导增加，达到了五倍（P < 0.04）。免疫组织化学染色显示，GFAP的诱导在星形胶质细胞和Müller细胞中均有发生。与神经胶质细胞功能障碍一致，采用同位素方法通过色谱分析测定，糖尿病大鼠视网膜将谷氨酸转化为谷氨酰胺的能力降至对照组的65%（P < 0.01）。此外，通过荧光测定法测定，糖尿病3个月后视网膜谷氨酸增加了1.6倍（P < 0.04）。综上所述，这些发现表明神经胶质细胞反应性和神经胶质细胞谷氨酸代谢改变是早期致病事件，可能导致糖尿病期间视网膜谷氨酸水平升高。这些数据首次证明了糖尿病期间视网膜神经胶质细胞代谢存在特定缺陷。这些发现提示了对糖尿病期间视网膜神经变性机制的新认识，涉及早期且可能持续的谷氨酸兴奋性毒性。
