2023 年第 2 期 第 18 卷

达格列净对高脂饮食诱导肥胖小鼠肾脏氧化应激的影响

Influence of dapagliflozin on renal oxidant stress in high-fat-diet induced obese mice

作者：王珺珺1方彭华2张真稳1

英文作者：Wang Junjun1 Fang Penghua2 Zhang Zhenwen1

单位：1扬州大学临床医学院，扬州225001；2南京中医药大学第一临床医学院临床医学实验研究中心，南京210023

英文单位：1Clinical Medical College of Yangzhou University  Yangzhou 225001 China; 2the Experimental Research Center of Clinical Medicine the First Medical School of Nanjing University of Chinese Medicine Nanjing 210023 China

关键词：糖尿病；达格列净；肥胖；肾损伤；氧化应激

英文关键词：Diabetesmellitus;Dapagliflozin;Obesity;Kidneyinjury;Oxidantstress

• 摘要：

• 目的 探讨达格列净调节高脂饮食诱导肥胖小鼠肾脏氧化应激的作用机制。方法 采用随机区组法将24只雄性健康C57BL/6小鼠随机分为正常对照（NC）组、模型对照（OC）组和达格列净组，每组8只。NC组小鼠予低脂饮食喂养，其他小鼠予高脂饲料喂养16周以建立肥胖小鼠模型。达格列净组小鼠予10 ml/（kg·d）达格列净连续灌胃21 d，NC组和OC组小鼠予等容积0.9%氯化钠注射液腹腔注射21 d。药物干预14 d后进行葡萄糖耐量试验和胰岛素耐量试验；药物干预结束后，检测小鼠体质量、空腹血糖、血浆胰岛素以及肾脏组织过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）、kelch样ECH关联蛋白1(Keap1)、核因子E2相关因子2（Nrf2）mRNA和蛋白水平。结果 药物干预结束后，OC组、达格列净组体质量均高于NC组，而达格列净组低于OC组（均P＜0.001）；OC组空腹血糖及血浆胰岛素水平均高于NC组，而达格列净组均低于OC组（均P＜0.05）。OC组葡萄糖耐量试验曲线下面积（AUC）、胰岛素耐量试验AUC均大于NC组，而达格列净组均小于OC组（均P＜0.05）。OC组肾脏组织PGC-1α、Nrf2 mRNA及蛋白水平均低于NC组，Keap1 mRNA及蛋白水平均高于NC组（均P＜0.05）。达格列净组肾脏组织PGC-1α mRNA及蛋白水平和Nrf2蛋白水平均高于OC组［（0.97±0.16）比（0.64±0.13）、（0.90±0.23）比（0.45±0.13）、（0.98±0.13）比（0.65±0.13）］，Keap1的mRNA及蛋白水平均低于OC组（均P＜0.05）。结论 达格列净可改善高脂饮食诱导肥胖小鼠的糖脂代谢和胰岛素抵抗，调节肾脏组织PGC-1α/Keap1/Nrf2抗氧化应激通路，并可能通过该通路减轻糖尿病肾损伤。

• Objective To investigate the mechanism of dapagliflozin regulating renal oxidant stress in high-fat-diet induced obese mice. Methods  Totally 24 healthy male C57BL/6 mice were randomly divided into control group (NC group), obesity control group (OC group) and dapagliflozin group, with 8 mice in each group. The NC group mice were fed with low-fat-diet, and other mice were fed with high-fat-diet for 16 weeks to establish obese mice model. Dapagliflozin group was treated with dapagliflozin 10 ml/（kg·d） by gavage for 21 d, and equal volumes of 0.9% sodium chloride injection were injected intraperitoneally in NC and OC groups, for 21 d. Glucose tolerance test and insulin tolerance test were performed 14 d after administration; levels of body mass, fasting plasma glucose, plasma insulin, and mRNA and protein of peroxisome proliferator activated receptor-γ co-activator-1α(PGC-1α), kelch-like ECH-associated protein 1(Keap1) and nuclear factor erythroid-2 related factor 2 (Nrf2) in kidney tissue were detected after administration. Results  After administration, the body mass of OC group and dapagliflozin group was higher than that of NC group, while the body mass of dapagliflozin group was lower than that of OC group(all P<0.001); levels of fasting plasma glucose and plasma insulin of OC group were higher than those of NC group, while the levels of dapagliflozin group were lower than those of OC group(all P<0.05). The area under the curve (AUC) of the glucose tolerance test and AUC of insulin tolerance test of OC group were larger than those of NC group, while both of dapagliflozin group were smaller than those of OC group (all P<0.05). The mRNA and protein levels of PGC-1α and Nrf2 in kidney tissue of OC group were lower than those of NC group, and mRNA and protein levels of Keap1 were higher than those of NC group（all P<0.05）. The mRNA and protein levels of PGC-1α and the protein level of Nrf2 in kidney tissue of dapagliflozin group were higher than those of OC group［（0.97±0.16）vs（0.64±0.13）,（0.90±0.23）vs（0.45±0.13）,（0.98±0.13）vs（0.65±0.13）］, and mRNA and protein levels of Keap1 were lower than those of OC group（all P<0.05）. Conclusions  Dapagliflozin can improve glycolipid metabolism and insulin resistance in high-fat-diet induced obese mice. It can regulate the antioxidative stress pathway PGC-1α/Keap1/Nrf2 in kidney tissue, which may alleviate diabetic kidney injury.