Vitamin D Activates the Nrf2-Keap1 Antioxidant Pathway and Ameliorates Nephropathy in Diabetic Rats
Vitamin D Activates the Nrf2-Keap1 Antioxidant Pathway and Ameliorates Nephropathy in Diabetic Rats
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DOI：
10.1093/ajh/hpt160
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发表时间：
2014-04-01
影响因子：
3.2
通讯作者：
Nishi, Shinichi
中科院分区：
文献类型：
--
作者：
Nakai, Kentaro;Fujii, Hideki;Nishi, Shinichi
背景：糖尿病肾病是终末期肾脏疾病的主要危险因素。许多复杂的因素与糖尿病肾病的进展有关。使用非肥胖2型糖尿病模型大鼠，我们证实氧化应激是一个关键因素。由于最近的研究表明维生素D可以抑制氧化应激，我们探索了活性维生素D类似物maxacalcitol是否也可以减轻氧化应激并预防糖尿病肾病的进展。方法20周龄糖尿病大鼠随机分为3组，分别给予胰岛素、美沙骨化醇和载药治疗。在30周龄时，进行血液和尿液分析、肾脏组织学、免疫组织化学、实时聚合酶链反应和免疫印迹。结果3个治疗组间血压和肌酐清除率无显著差异，但maxacalcitol可降低蛋白尿和肾小球系膜基质扩张。maxacalcitol治疗可减轻全身和肾内氧化应激。核因子- κ B和烟酰胺腺嘌呤二核苷酸磷酸氧化酶的表达在胰岛素处理组和max calcit醇处理组也有所下降，但在单独给药组有所增加。此外，核因子红细胞2相关因子2 （Nrf2）表达降低，kelch样红细胞衍生蛋白与CNC同源性（ECH）相关蛋白1 （Keap1）表达升高；然而，这些表达在maxacalcitol和胰岛素处理组恢复。结论maxacalcitol通过抑制非肥胖型2型糖尿病患者的氧化应激和改善Nrf2-Keap1通路来减缓糖尿病肾病的进展，但未对血压和肾小球滤过率产生显著影响。
BACKGROUNDDiabetic nephropathy is a major risk of end-stage kidney disease. Many complex factors relate to the progression of diabetic nephropathy. Using nonobese type 2 diabetes model rats, we confirmed that oxidative stress was a crucial factor. Because recent studies suggest that vitamin D could suppress oxidative stress, we explored whether the active vitamin D analog, maxacalcitol, could also attenuate oxidative stress and prevent the progression of diabetic nephropathy.METHODSDiabetic rats aged 20 weeks were divided into 3 groups and treated with insulin, maxacalcitol, and vehicle. At age 30 weeks, blood and urine analyses, renal histology, immunohistochemistry, real-time polymerase chain reaction, and western blot were performed.RESULTSAlthough maxacalcitol reduced albuminuria and mesangial matrix expansion, no significant differences were observed in blood pressure and creatinine clearance among the 3 treatment groups. Systemic and intrarenal oxidative stress was reduced by maxacalcitol therapy. Expressions of nuclear factor-kappa B and nicotinamide adenine dinucleotide phosphate oxidase in the kidney also decreased in the insulin-treated and maxacalcitol-treated groups but increased in the vehicle-alone group. In addition, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) decreased and Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1) increased in the vehicle-treated group; however, these expressions were restored in the maxacalcitol- and insulin-treated groups.CONCLUSIONSIt is suggested that maxacalcitol attenuates the progression of diabetic nephropathy by suppression of oxidative stress and amelioration of the Nrf2-Keap1 pathway in nonobese type 2 diabetes without significant changes in blood pressure and glomerular filtration rate.