RETINAL CAPILLARY PERICYTE CELL DEATH IN DIABETIC RETINOPATHY

视网膜毛细血管周细胞选择性变性已被公认为糖尿病视网膜病变的标志。由于这种周细胞的丢失会导致任何其他形态的变化，所以防止这种周细胞的死亡可能是预防糖尿病视网膜病变整个过程的关键。类似的周细胞丢失也发生在喂食半乳糖的狗身上。由于醛糖还原酶抑制剂阻止了这些早期的毛细血管改变，因此，人们认为醛糖还原酶参与了周细胞退化的早期阶段。本课题研究了抑制醛糖还原酶能否阻止高血糖或半乳糖血症所致的视网膜毛细血管周细胞死亡。在高浓度(50 MM)D-半乳糖的条件下，狗视网膜毛细血管细胞迅速积累糖醇、半乳糖。高半乳糖培养2周后，细胞形态未见明显变化。然而，尽管形态正常，但许多细胞在原位隧道染色中显示出凋亡阳性染色。这些细胞还表现出明显的DNA片段化，称为阶梯形成。醛糖还原酶抑制剂AL1576可完全阻止上述DNA改变。有趣的是，在类似的高半乳糖培养液中，在醛糖还原酶水平极低的狗视网膜毛细血管内皮细胞中，没有出现任何凋亡的变化。醛糖还原酶的存在在高糖环境诱导细胞凋亡过程中起着至关重要的作用。-糖尿病、视网膜病变、醛糖还原酶、周细胞、内皮细胞、细胞凋亡

The selective degeneration of retinal capillary pericytes has been well established as the hallmark of diabetic retinopathy. Because this pericyte loss proceeds to any other morphological changes, preventing this pericyte death can be a key to prevent the whole process of diabetic retinopathy. The similar pericyte loss also occurs in dog fed with galactose. Since aldose reductase inhibitors prevent these early capillary changes, aldose reductase has been suggested to involve in this early stage of pericyte degeneration. In this project, we investigated whether inhibition of aldose reductase can prevent the cell death (apoptosis) of retinal capillary pericytes induced by hyperglycemia or galactosemia.When cultured in the medium containing a high concentration (50 mM) of D-galactose, dog retinal capillary cells quickly accumulated sugar alcohol, galactitol. Although the culture in high galactose media was continued for 2 weeks, these cells developed no obvious morphological changes. However, despite of normal morphology, many of the cells displayed positive staining for apoptosis with in situ TUNNEL staining. These cells also displayed the obvious DNA fragmentation called ladder formation. Aldose reductase inhibitor AL 1576 completely prevented all these DNA changes. Interestingly, the similar culture in high galactose medium did not develop any apoptotic changes in dog retinal capillary endothelial cells where the aldose reductase level is extremely low. The presence of aldose reductase appears to be crucial for the induction of apoptosis by the exposure to high sugar environment. - diabetes, retinopathy, aldose reductase, pericyte, endothelial cells, apoptosis