Department of Ophthalmology, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan.
School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
Int J Mol Sci. 2022 Jun 27;23(13):7142. doi: 10.3390/ijms23137142.
Chronic hyperglycemia triggers an abnormal rise in reactive oxygen species (ROS) that leads to blindness in patients with diabetes mellitus (DM) and cataracts. In this study, the effects of dapagliflozin, metformin and resveratrol on ROS production were investigated in lens epithelial cells (LECs) of animals with fructose-induced DM. LECs were isolated from patients without DM, or with DM devoid of diabetic retinopathy. Animals were treated with 10% fructose for 8 weeks to induce DM, which was verified by monitoring blood pressure and serum parameters. For drug treatments, 1.2 mg/day of dapagliflozin was given for 2 weeks, 500 mg/kg/day of metformin was given, and 10 mg/kg/day of resveratrol was given. Dihydroethidium was used to stain endogenous O˙ production in vivo of the LECs. Superoxide production was expressed in the cataract of DM, or patients without DM. Sodium-glucose cotransporter 2 (SGLT2), glucose transporter 1 (GLUT1), GLUT5, the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47/p67-phox, NOX4 and RAGE were significantly increased in LECs with DM. In addition, the dapagliflozin treatment reduced GLUT5, p47/p67-phox, NADPH oxidase 4 (NOX4) and receptor for advanced glycation end products (RAGE) expressions. On the contrary, metformin or resveratrol inhibited p47-phox, GLUT5, and SGLT2 expressions, but not nuclear factor erythroid 2-related factor 2 (NRF2). In summary, dapagliflozin, metformin or resveratrol down-regulated p47-phox expression through SGLT2 inactivation and ROS reduction. These important findings imply that SGLT2 can be blocked to ameliorate oxidative stress in the cataracts of DM patients.
慢性高血糖会引发活性氧（ROS）异常升高，导致糖尿病（DM）患者失明和白内障。在这项研究中，研究人员研究了达格列净、二甲双胍和白藜芦醇对果糖诱导的糖尿病动物晶状体上皮细胞（LEC）中 ROS 产生的影响。LEC 从无糖尿病患者或无糖尿病性视网膜病变的糖尿病患者中分离出来。用 10%果糖处理动物 8 周以诱导 DM，通过监测血压和血清参数来验证。对于药物治疗，给予 1.2mg/天达格列净治疗 2 周，给予 500mg/kg/天二甲双胍，给予 10mg/kg/天白藜芦醇。使用二氢乙啶在体染色 LEC 内源性 O˙产生。超氧化物产生在 DM 或无 DM 患者的白内障中表达。钠-葡萄糖共转运蛋白 2（SGLT2）、葡萄糖转运蛋白 1（GLUT1）、GLUT5、还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶亚基 p47/p67-phox、NOX4 和晚期糖基化终产物受体（RAGE）在 DM 患者的 LEC 中显著增加。此外，达格列净治疗降低了 GLUT5、p47/p67-phox、NADPH 氧化酶 4（NOX4）和晚期糖基化终产物受体（RAGE）的表达。相反，二甲双胍或白藜芦醇抑制了 p47-phox、GLUT5 和 SGLT2 的表达，但不抑制核因子红细胞 2 相关因子 2（NRF2）。总之，达格列净、二甲双胍或白藜芦醇通过 SGLT2 失活和 ROS 减少下调 p47-phox 表达。这些重要发现表明，SGLT2 可以被阻断以改善 DM 患者白内障的氧化应激。
