Ishibashi Yuji, Matsui Takanori, Matsumoto Takafumi, Kato Hiroshi, Yamagishi Sho-Ichi
Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, Osaka, Japan.
Diab Vasc Dis Res. 2016 Jul;13(4):312-5. doi: 10.1177/1479164116640220. Epub 2016 Apr 29.
Under diabetic conditions, glucose is converted to sorbitol via aldose reductase, whose process could contribute to diabetic vascular complications. However, effects of aldose reductase inhibitors are modest in diabetic patients. This may be attributed to weak inhibitory activity of aldose reductase inhibitors. We compared effects of ranirestat on endothelial cell damage with those of epalrestat.
Intracellular formations of sorbitol and superoxide were measured by liquid chromatography-mass spectrometry-mass spectrometry and dihydroethidium staining, respectively. Vascular cell adhesion molecule-1 gene expression was analysed by reverse transcription polymerase chain reaction. THP-1 cell adhesion to human umbilical vein endothelial cells was evaluated using a fluorescent probe.
High glucose significantly increased sorbitol levels, superoxide generation and vascular cell adhesion molecule-1 mRNA levels in, and THP-1 cell adhesion to, human umbilical vein endothelial cells, all of which were prevented by 500 nM ranirestat, but not epalrestat except for superoxide production.
Our present results suggest that ranirestat has a stronger inhibitory activity on aldose reductase than epalrestat and suppresses inflammatory reactions in high glucose-exposed human umbilical vein endothelial cells.
在糖尿病状态下，葡萄糖通过醛糖还原酶转化为山梨醇，这一过程可能导致糖尿病血管并发症。然而，醛糖还原酶抑制剂对糖尿病患者的疗效有限。这可能归因于醛糖还原酶抑制剂的抑制活性较弱。我们比较了雷尼司他与依帕司他对内皮细胞损伤的影响。
分别采用液相色谱 - 质谱 - 质谱法和二氢乙锭染色法测定山梨醇和超氧化物的细胞内生成情况。通过逆转录聚合酶链反应分析血管细胞黏附分子 -1 基因表达。使用荧光探针评估 THP -1 细胞与人脐静脉内皮细胞的黏附情况。
高糖显著增加人脐静脉内皮细胞中的山梨醇水平、超氧化物生成以及血管细胞黏附分子 -1 mRNA 水平，同时增加 THP -1 细胞与人脐静脉内皮细胞的黏附，所有这些均被 500 nM 雷尼司他抑制，但依帕司他除了对超氧化物生成有抑制作用外，对其他指标无抑制效果。
我们目前的结果表明，雷尼司他对醛糖还原酶的抑制活性比依帕司他更强，并能抑制高糖暴露的人脐静脉内皮细胞中的炎症反应。
