Small Molecule Inhibiting Nuclear Factor-kB Ameliorates Oxidative Stress and Suppresses Renal Inflammation in Early Stage of Alloxan-Induced Diabetic Nephropathy in Rat
Small Molecule Inhibiting Nuclear Factor-kB Ameliorates Oxidative Stress and Suppresses Renal Inflammation in Early Stage of Alloxan-Induced Diabetic Nephropathy in Rat
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DOI：
10.1111/bcpt.12718
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发表时间：
2017-05-01
影响因子：
3.1
通讯作者：
Choubey, Abhinav
中科院分区：
文献类型：
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作者：
Borgohain, Manash P.;Lahkar, Mangala;Choubey, Abhinav
糖尿病肾病是糖尿病的主要微血管并发症之一，最终导致心血管疾病。长期高血糖和慢性肾脏炎症是糖尿病肾病发生和发展的两个关键因素。核因子-kB（NF-kB）介导的炎症级联反应是糖尿病肾病肾血管炎症的重要因素。本实验研究了一种有效的NF-κ B抑制剂Piceatannol对四氧嘧啶（ALX）诱导的糖尿病大鼠各种氧化应激标志物和NF-κ B依赖性肾脏炎症级联反应的影响。实验性糖尿病在雄性Wistar大鼠中通过单次腹腔内剂量，150 mg/kg体重（b.w.）关于ALX糖尿病大鼠用30和50 mg/kg b.w.剂量的Piceatannol（PCTNL）治疗。口服PCTNL 14天后，血糖水平、肾小球滤过率、血清标志物和血脂均明显恢复。PCTNL管理也扭转了细胞的抗氧化机制，即超氧化物歧化酶和谷胱甘肽的活性下降和丙二醛和一氧化氮的水平升高。此外，云杉醇治疗组显示出对肾脏促炎细胞因子和NF-kB p65/p50与DNA结合的显着抑制。肾组织病理学研究也支持其对糖尿病肾损害的改善作用。重要的是，在50毫克/千克的剂量下，效果更为显著，就体重增加而言，五氯三硝柳胺未能产生显著效果。然而，总体研究结果清楚地表明，PCTNL通过消除氧化应激和NF-κ B活化在糖尿病中提供了显着的肾脏保护-并且可能在糖尿病肾病的早期阶段有帮助。
Diabetic nephropathy is one of the major microvascular complications of diabetes mellitus which ultimately gives rise to cardiovascular diseases. Prolonged hyperglycaemia and chronic renal inflammation are the two key players in the development and progression of diabetic nephropathy. Nuclear factor kB (NF-kB)-mediated inflammatory cascade is a strong contributor to the renovascular inflammation in diabetic nephropathy. Here, we studied the effects of piceatannol, a potent NF-kB inhibitor, on various oxidative stress markers and NF-kB dependent diabetic renoinflammatory cascades in rat induced by alloxan (ALX). Experimental diabetes was induced in male Wistar rats by a single intraperitoneal dose, 150 mg/kg body-weight (b.w.) of ALX. Diabetic rats were treated with Piceatannol (PCTNL) at a dose of 30 and 50 mg/kg b.w. After 14 days of oral treatment, PCTNL significantly restored blood sugar level, glomerular filtration rate, serum markers and plasma lipids. PCTNL administration also reversed the declined activity of cellular antioxidant machineries namely superoxide dismutase and glutathione and the elevated levels of malondialdehyde and nitric oxide. Moreover, piceatannol-treated groups showed marked inhibition of renal pro-inflammatory cytokines and NF-kB p65/p50 binding to DNA. Renal histopathological investigations also supported its ameliorative effects against diabetic kidney damage. Importantly, effects were more prominent at a dose of 50 mg/kg, and in terms of body-weight gain, PCTNL failed to effect significantly. However, overall findings clearly demonstrated that PCTNL provides remarkable renoprotection in diabetes by abrogating oxidative stress and NF-kB activation - and might be helpful in early stage of diabetic nephropathy.