Influence of dapagliflozin on renal oxidant stress in high-fat-diet induced obese mice
- Author:
- No author available
- Journal Title:
- China Medicine
- Issue:
- 2
- DOI:
- 10.3760/j.issn.1673-4777.2023.02.017
- Key Word:
- 糖尿病;达格列净;肥胖;肾损伤;氧化应激
Abstract： 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.
- [1]Norgaard, Sisse Andersen,Briand, Francois,Sand, Fredrik Wolfhagen,etc.Nephropathy in diabetic db/db mice is accelerated by high protein diet and improved by the SGLT2 inhibitor dapagliflozin[J].2019,860.
- [2]Tao Zhang,Yanqing Chi,Yingli Kang,etc.Resveratrol ameliorates podocyte damage in diabetic mice via SIRT1/PGC‐1α mediated attenuation of mitochondrial oxidative stress[J].2019,234(4).
- [3]Artunc, Ferruh,Schleicher, Erwin,Weigert, Cora,etc.The impact of insulin resistance on the kidney and vasculature[J].2016,12(12).
- [4]Neuen, Brendan L.,Young, Tamara,Heerspink, Hiddo J. L.,etc.SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis[J].2019,7(11).
- [5]郭立新.2021年糖尿病领域年度重大进展回顾[J].2022,14(1).
- [6]Arab, Hany H.,Al-Shorbagy, Muhammad Y.,Saad, Muhammed A..Activation of autophagy and suppression of apoptosis by dapagliflozin attenuates experimental inflammatory bowel disease in rats: Targeting AMPK/mTOR, HMGB1/RAGE and Nrf2/HO-1 pathways[J].2021,335.
- [7]Baird, Liam,Yamamoto, Masayuki.The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway[J].2020,40(13).
- [8]Yoh Keigyou,Hirayama Aki,Ishizaki Kazusa,etc.Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2-deficient mice[J].2008,13(11).
- [9]Choi Hoon-In,Kim Hye-Jin,Park Jung-Sun,etc.PGC-1α attenuates hydrogen peroxide-induced apoptotic cell death by upregulating Nrf-2 via GSK3β inactivation mediated by activated p38 in HK-2 Cells[J].2017,7(1).
- [10]Wang, Liming,Chang, Jae-Hyung,Buckley, Anne F.,etc.Knockout of TRPC6 promotes insulin resistance and exacerbates glomerular injury in Akita mice[J].2019,95(2).
- [11]Sharma,K.,Karl,B.,Mathew,A.V.,etc.Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease[J].2013,24(11).
- [12]Packer, Milton.Role of ketogenic starvation sensors in mediating the renal protective effects of SGLT2 inhibitors in type 2 diabetes[J].2020,34(9).
- [13]van Bommel, Erik J. M.,Muskiet, Marcel H. A.,van Baar, Michael J. B.,etc.The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial[J].2020,97(1).