目的 研究盐酸小檗碱改善糖尿病肾病模型小鼠肾功能的作用及机制。方法 取8只C57BL/KS-db（db/m）雄性小鼠作为对照组，24只C57BL/KS-db（db/db）雄性小鼠随机分为模型组、盐酸二甲双胍（300 mg·kg^-1）组和盐酸小檗碱（300 mg·kg^-1）组，ig给药，每天给药1次，连续给药8周，对照组和模型组ig相同体积的蒸馏水。称体质量及肾脏质量，计算肾脏指数；采用全自动生化分析仪检测尿液中尿肌酐、24 h尿蛋白，以及血样中血肌酐、尿素氮的水平，计算肌酐清除率；采用苏木素-伊红（HE）染色、糖原过碘酸-雪夫（PAS）染色和马松（Masson）染色检测肾脏组织病理损伤程度；采用酶联免疫吸附剂测定（ELISA）法检测肾脏组织活性氧（ROS）、谷胱甘肽（GSH）、谷胱甘肽过氧化物酶（GSH-Px）、丙二醛（MDA）、超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、肿瘤坏死因子-α （TNF-α）、单核细胞趋化蛋白-1 （MCP-1）水平；采用实时荧光定量PCR （qRT-PCR）法检测肾脏组织LINC01619/miR-27a表达水平；采用Western blotting法检测肾脏组织叉头框蛋白O1 （FOXO1）/葡萄糖调节蛋白78（GRP78）/C/EBP同源蛋白（CHOP）蛋白表达情况。结果 与模型组比较，盐酸小檗碱组空腹血糖、体质量、肾脏指数、24 h尿蛋白、血肌酐和血尿素氮显著降低（P<0.01），尿肌酐和肌酐清除率显著升高（P<0.01）；肾脏组织病理损伤程度明显改善；肾脏组织ROS和MDA水平显著降低（P<0.001），GSH、GSH-Px、CAT和SOD活性显著升高（P<0.05）；肾脏组织中IL-1β、IL-6、TNF-α和MCP-1水平显著下降（P<0.05）；肾脏组织中LINC01619表达显著升高（P<0.01），miR-27a表达显著降低（P<0.01）；肾脏组织中FOXO1蛋白表达显著升高（P<0.01），而GRP78和CHOP蛋白表达显著降低（P<0.01）。结论 盐酸小檗碱可改善db/db小鼠的肾功能，其作用机制可能与调控LINC01619/miR-27a/FOXO1通路，改善内质网应激有关。

Objective To study the effect and mechanism of berberine hydrochloride on improving renal function in diabetic nephropathy mice.Methods Eight C57BL/KS-db (db/m) male mice were taken as control group. Twenty four C57BL/KS-db (db/db) male mice were randomly divided into model group, metformin (MET, 300 mg·kg^-1) group and berberine hydrochloride (300 mg·kg^-1) group. Drugs were ig given once a day for eight weeks. Body weight and kidney weight were weighed to calculate kidney index.Fasting blood glucose, urinary creatinine, 24 h urinary protein, blood creatinine and urea nitrogen were measured. HE staining, PAS staining and Masson staining were used to detect the degree of pathological injury of renal tissue. Reactive oxygen species (ROS), glutathione (GSH), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), interleukin-1 β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor -α (TNF-α), monocytes Chemotactic protein-1 (MCP-1) in renal tissue were detected by ELISA. The expression level of LINC01619/miR-27a in renal tissue were detected by real-time fluorescent quantitative PCR (qRT-PCR). The expression of FoxO1/GRP78/CHOP protein in renal tissue were detected by Western blotting. Results Compared with model group, fasting blood glucose, body mass, renal index, 24-hour urinary protein, blood creatinine and urea nitrogen in berberine hydrochloride group were significantly decreased (P<0.01), and urinary creatinine and creatinine clearance were significantly increased (P<0.01); The degree of pathological injury of renal tissue was significantly significantly improved; ROS and MDA in renal tissue were significantly decreased (P<0.001), GSH, GSH-Px, CAT and SOD were significantly increased (P<0.05). IL-1β, IL-6, TNF- α and MCP-1 were significantly decreased (P<0.05); The expression of LINC01619 was significantly increased (P<0.01), and the expression of miR-27a was significantly decreased (P<0.01). The expression of FOXO1 was significantly increased (P<0.01), while the expression of GRP78 and CHOP were significantly decreased (P<0.01). Conclusion Berberine hydrochloride can improve the renal function of db/db mice, and its mechanism may be related to regulating LINC01619/miR-27a/FOXO1 pathway and improving endoplasmic reticulum stress.

R285.5

国家自然科学基金资助项目（81803799）