目的 基于核因子 E2 相关因子 2（Nrf2）信号通路探讨活络效灵丹对糖尿病大鼠肾损伤的保护作用及机 制。方法 将 SD 大鼠随机分为正常组、模型组、科素亚组（10 mg·kg-1 ）及活络效灵丹低、高剂量组（5.4、 10.8 g·kg-1 ），每组各 6 只。采用高糖高脂喂养联合低剂量链脲佐菌素（35 mg·kg-1 ）腹腔注射诱导复制糖尿病大 鼠模型。各给药组按照上述剂量灌胃给药，每天 1 次，连续给药 8 周。药物干预第 0、2、4、6、8 周分别进行 体质量及空腹血糖检测；采用自动生化分析仪检测各组大鼠尿液中的 24 h 尿蛋白、尿肌酐，以及血清中的尿 素氮、血肌酐、总胆固醇及甘油三酯含量，计算肌酐清除率；HE 染色法观察肾脏组织病理变化；生化法检测 血清及肾脏中氧化应激指标超氧化物歧化酶（SOD）、丙二醛（MDA）水平；ELISA 法检测血清胰岛素及 Nrf2 水 平，计算胰岛素抵抗指数；Western Blot 法检测肾皮质中 Nrf2、血红素加氧酶 1（HO-1）、醌氧化还原酶 1 （NQO1）蛋白表达水平。结果 与正常组比较，模型组大鼠的体质量显著下降（P＜0.01）；空腹血糖水平显著升 高（P＜0.01）；血清总胆固醇水平及胰岛素抵抗指数显著升高（P＜0.01）；肾脏指数、尿素氮、24 h 尿蛋白及肌 酐清除率均显著升高（P＜0.05，P＜0.01）；血清及肾脏组织中 MDA 含量显著升高（P＜0.01），血清 SOD、Nrf2 水平显著降低（P＜0.01）；肾皮质中 Nrf2、HO-1、NQO1 蛋白表达均显著下调（P＜0.01）。与模型组比较，在药 物干预第 4、6 周活络效灵丹低剂量组大鼠的体质量明显升高（P＜0.05），药物干预第 6、8 周活络效灵丹高剂 量组大鼠的体质量显著升高（P＜0.01）；药物干预第 8 周活络效灵丹高剂量组大鼠的空腹血糖水平明显下降 （P＜0.05）；活络效灵丹低、高剂量组大鼠的血清总胆固醇水平及胰岛素抵抗指数显著降低（P＜0.05，P＜ 0.01）；活络效灵丹低剂量组大鼠的肾脏指数显著降低（P＜0.01），活络效灵丹低、高剂量组大鼠的尿素氮、 24 h 尿蛋白及肌酐清除率显著下降（P＜0.05，P＜0.01），血清及肾脏组织中 MDA 含量显著降低（P＜0.05，P＜ 0.01），血清 SOD、Nrf2 水平显著升高（P＜0.05，P＜0.001）；活络效灵丹低、高剂量组大鼠肾皮质中 Nrf2、 NQO1 蛋白表达显著上调（P＜0.05，P＜0.01），活络效灵丹低剂量组大鼠肾皮质中 HO-1 蛋白表达明显上调 （P＜0.05）。结论 活络效灵丹对糖尿病大鼠的肾脏病变具有一定改善作用，可能与调控 Nrf2 信号通路，改善 体内氧化应激有关。

Objective To explore the protective effect and mechanism of Huoluo Xiaoling Dan on renal injury in diabetic rats based on the nuclear factor erythroid 2-related factor 2（Nrf2） signaling pathway. Methods SD rats were randomly divided into the normal group，model group，Cozaar group （10 mg·kg-1 ），and low- and high-dose Huoluo Xiaoling Dan groups （5.4，10.8 g·kg-1 ），with 6 rats in each group. A diabetic rat model was induced by high-sugar and high-fat diet feeding combined with a single intraperitoneal injection of a low dose of streptozotocin （35 mg·kg-1 ）. Each treatment group received the corresponding dose by oral gavage once daily for 8 consecutive weeks. Body mass and fasting blood glucose （FBG） were measured at weeks 0， 2， 4， 6， and 8 of drug intervention. An automatic biochemical analyzer was used to detect 24-hour urinary protein and urinary creatinine in urine，as well as serum levels of blood urea nitrogen （BUN），serum creatinine （Scr），total cholesterol （TC），and triglycerides （TG）；creatinine clearance rate （CCr） was calculated. Renal histopathological changes were observed by HE staining. Biochemical methods were used to measure the levels of oxidative stress markers superoxide dismutase （SOD） and malondialdehyde （MDA） in serum and renal tissue. ELISA was used to detect serum insulin and Nrf2 levels，and the insulin resistance index （HOMA-IR） was calculated. Western Blot was performed to detect the protein expression levels of Nrf2，heme oxygenase-1（HO-1），and NAD（P）H quinone oxidoreductase 1（NQO1） in the renal cortex of rats. Results Compared with the normal group， the model group showed a significant decrease in body mass （P＜0.01）； FBG levels were significantly increased （P＜0.01）；serum TC levels and HOMA-IR were significantly increased （P＜0.01）；kidney index，BUN，24-hour urinary protein，and CCr were all significantly elevated （P＜0.05，P＜0.01）；MDA content in serum and renal tissue was significantly increased （P＜0.01），while serum SOD and Nrf2 levels were significantly decreased （P＜0.01）； protein expression of Nrf2， HO-1， and NQO1 in the renal cortex was significantly downregulated （P＜0.01）. Compared with the model group，body mass in the low-dose Huoluo Xiaoling Dan group was significantly increased at weeks 4 and 6 of intervention （P＜0.05），and in the high-dose group at weeks 6 and 8（P＜ 0.01）；FBG levels in the high-dose group were significantly decreased at week 8（P＜0.05）；serum TC levels and HOMA-IR were significantly reduced in both the low- and high-dose groups （P＜0.05，P＜0.01）；kidney index was significantly decreased in the low-dose group （P＜0.01）；BUN，24-hour urinary protein，and CCr were significantly decreased in both the low- and high-dose groups （P＜0.05，P＜0.01）；MDA content in serum and renal tissue was significantly reduced （P＜0.05，P＜0.01），while serum SOD and Nrf2 levels were significantly increased （P＜0.05， P＜0.001）；protein expression of Nrf2 and NQO1 in the renal cortex was significantly upregulated in both the low- and high-dose groups （P＜0.05，P＜0.01），and HO-1 protein expression was significantly upregulated in the low-dose group （P＜0.05）. Conclusion Huoluo Xiaoling Dan has a certain ameliorative effect on renal lesions in diabetic rats， which may be related to regulating the Nrf2 signaling pathway and improving oxidative stress in the body.

R285.5

上海市卫生健康委员会科研发展基金项目（202150030）；浦东新区国家中医药改革示范区项目（YC-2023-0605）；浦东新区国家 中医药传承创新发展试验区建设项目（PDZY-2025-0919）