Inhibition of SGLT2 alleviates diabetic nephropathy by suppressing high glucose-induced oxidative stress in type 1 diabetic mice.
Inhibition of SGLT2 alleviates diabetic nephropathy by suppressing high glucose-induced oxidative stress in type 1 diabetic mice.
复制标题
抑制 SGLT2 通过抑制 1 型糖尿病小鼠中高葡萄糖诱导的氧化应激来减轻糖尿病肾病。
DOI：
10.1002/prp2.239
复制
发表时间：
2016-08
影响因子：
2.6
通讯作者：
Wada J
中科院分区：
文献类型：
--
作者：
Hatanaka T;Ogawa D;Tachibana H;Eguchi J;Inoue T;Yamada H;Takei K;Makino H;Wada J
目前尚不清楚钠葡萄糖协同转运蛋白2（SGLT 2）抑制剂对糖尿病肾病的改善是由对SGLT 2的直接作用还是由高血糖的改善引起的。在这里，我们使用1型糖尿病小鼠模型和小鼠近端肾小管上皮细胞研究了达格列净对早期糖尿病肾病的影响。用达格列净或胰岛素治疗8周龄秋田小鼠12周。测量体重、尿白蛋白排泄量、血压以及血糖和血红蛋白A1c水平。通过组织学评估肾脏系膜基质扩张、间质纤维化和巨噬细胞浸润。在肾脏和培养的近端肾小管上皮细胞中评价氧化应激和凋亡。与未治疗的小鼠相比，达格列净和胰岛素同等降低血糖和血红蛋白A1c水平。与胰岛素治疗组相比，达格列净治疗组的尿量和饮水量显著增加，但两组之间的体重或血压无差异。与胰岛素组相比，达格列净组的巨噬细胞浸润和肾间质纤维化显著改善。达格列净可减弱氧化应激，抑制作用呈剂量依赖性。SGLT 2的RNAi敲低导致氧化应激降低。在秋田小鼠中，达格列净通过抑制高血糖诱导的氧化应激，以不依赖于高血糖改善的方式改善糖尿病肾病。我们的研究结果表明，达格列净可能是治疗糖尿病肾病的一种新的治疗方法。
It is unclear whether the improvement in diabetic nephropathy by sodium glucose cotransporter 2 (SGLT2) inhibitors is caused by a direct effect on SGLT2 or by the improvement in hyperglycemia. Here, we investigated the effect of dapagliflozin on early‐stage diabetic nephropathy using a mouse model of type 1 diabetes and murine proximal tubular epithelial cells. Eight‐week‐old Akita mice were treated with dapagliflozin or insulin for 12 weeks. Body weight, urinary albumin excretion, blood pressure, as well as levels of blood glucose and hemoglobin A1c were measured. Expansion of the mesangial matrix, interstitial fibrosis, and macrophage infiltration in kidneys were evaluated by histology. Oxidative stress and apoptosis were evaluated in kidneys and cultured proximal tubular epithelial cells. Compared with nontreated mice, dapagliflozin and insulin decreased blood glucose and hemoglobin A1c levels equally. Urine volume and water intake increased significantly in the dapagliflozin‐treated group compared with those in the insulin‐treated group, but there were no differences in body weight or blood pressure between the two groups. Macrophage infiltration and fibrosis in renal interstitium improved significantly in the dapagliflozin group compared with the insulin group. Oxidative stress was attenuated by dapagliflozin, and suppression occurred in a dose‐dependent manner. RNAi knockdown of SGLT2 resulted in reduced oxidative stress. Dapagliflozin ameliorates diabetic nephropathy by suppressing hyperglycemia‐induced oxidative stress in a manner independent of hyperglycemia improvement in Akita mice. Our findings suggest that dapagliflozin may be a novel therapeutic approach for the treatment of diabetic nephropathy.