糖尿病肾病（DN）是1型糖尿病（T1DM）的主要微血管并发症。已经表明，腺苷酸一磷酸激活蛋白激酶（AMPK）活性的损害参与了DN潜在的增强氧化应激和炎症机制。从甜菊叶中分离得到的异青蒿内酯（ISV）具有抗氧化和抗炎性能，并通过激活AMPK缓解非酒精性脂肪肝和致命性败血性休克。ISV对DN的影响尚不清楚。本研究旨在调查ISV是否通过激活AMPK缓解T1DM成年雄性大鼠的DN。通过单次腹腔注射链脲佐菌素（STZ）（65mg/kg）诱导大鼠糖尿病，设计了5组大鼠（每组n=8），包括：对照组、ISV组（口服20mg/kg）、STZ组（糖尿病组）、STZ+ISV组（口服20mg/kg）、STZ+ISV+CC组（化合物C/AMPK抑制剂，腹腔注射0.2mg/kg）。进行空腹血糖和胰岛素水平测定、肾功能检测、血脂谱分析、氧化应激和炎症标志物测定、PCR和Western blotting分析以及肾脏的组织学研究。ISV对空腹血糖或胰岛素水平没有影响（p>0.05），但显著降低血清胆固醇、甘油三酯（TGs）和低密度脂蛋白胆固醇（LDL-c）的水平（p<0.01）。ISV还增加了尿肌酐排泄量，降低了尿白蛋白水平，并减轻了STZ诱导的糖尿病肾脏的小管和肾小球损伤。ISV还降低了肾组织丙二醛（MDA）（p<0.01）、肿瘤坏死因子α（TNF-α）（p<0.01）、白细胞介素6（IL-6）（p<0.01）的水平，以及控制和糖尿病大鼠的核因子κB（NF-κB）的mRNA和核蛋白水平。同时，ISV增加了控制组和糖尿病大鼠肾脏中AMPK的磷酸化（p<0.05）及超氧化物歧化酶（SOD）（p<0.01）、过氧化氢酶（CAT）（p<0.01）、总谷胱甘肽（GSH）（p<0.01）、核因子依赖的红细胞2相关因子（Nrf2）的mRNA和核蛋白水平（p<0.01）。CC的联合给药抵消了ISV的全部肾脏保护效应，并逆转了所有这些效应。总之，ISV的抗NF-κB作用和Nrf2的激活是其在STZ诱导的糖尿病大鼠DN中的肾保护作用的机制。

Diabetic nephropathy (DN) is the major microvascular complication of type 1 diabetes mellitus (T1DM). Impairment in adenosine monophosphate-activated protein kinase (AMPK) activity was shown to mediate the pro-oxidant and inflammatory mechanisms underlying DN. Isosteviol (ISV), isolated from Stevia rebaudiana, has antioxidant and anti-inflammatory properties and alleviates non-alcoholic fatty liver disease and lethal septic shock by activating AMPK. The effect of ISV on DN is unknown. This study examined if ISV alleviates DN in T1DM in adult male rats by activating AMPK. Diabetes was induced in rats by a single intraperitoneal (i.p.) injection of streptozotocin (STZ) (65 mg/kg). Five groups of rats (n=8 each) were designed and included: control, ISV (20 mg/kg orally), STZ (diabetic), STZ + ISV (20 mg/kg orally), STZ + ISV + CC (compound C/an AMPK inhibitor) (0.2 mg/kg, i.p). Fasting glucose and insulin levels, assessment of kidney function tests, lipid profile analysis, measurements of markers of oxidative stress and inflammation, PCR and Western blotting analysis, and histological studies of the kidneys were conducted. With no effect on fasting glucose or insulin levels (p>0.05), ISV reduced serum levels of cholesterol, triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-c) (p<0.01). ISV also increased urinary creatinine excretion, reduced urinary albumin levels, and alleviated tubular and glomerular damage of STZ-diabetic kidneys. ISV also lowered the renal levels of malondialdehyde (MDA) (p<0.01), tumor necrosis factor-alpha (TNF-α) (p<0.01), interleukin-6 (IL-6) (p<0.01), and mRNA and nuclear protein levels of nuclear factor kappaB (NF-κB) in both the control and diabetic rats. Concomitantly, ISV increased the phosphorylation of AMPK (p<0.05), levels of superoxide dismutase (SOD) (p<0.01), catalase (CAT) (p<0.01), total glutathione (GSH) (p<0.01), and mRNA and nuclear protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) (p<0.01) in the kidneys of the control and diabetic rats. Co-administration of CC prevented all renal protective effects of ISV and reversed all these effects. In conclusion, AMPK-induced inhibition of NF-κB and activation of Nrf2 entails the nephroprotective effect of ISV in STZ-diabetic rats.