小檗碱对糖尿病肾病小鼠肾脏中FXR和SHP表达的影响  

Effects of berberine on expression of FXR and SHPin kidney of mice with diabetic nephropathy

作　　者：邓礼娟 黄洁瑶 胡彦君 崔威 方伟 肖亚平 DENG Li-juan;HUANG Jie-yao;HU Yan-jun;CUI Wei;FANG Wei;XIAO Ya-ping(Dept of Pharmacy,Chongqing University Three Gorges Hospital,School of Medicine,Chongqing University,Chongqing 404000,China)

机构地区：[1]重庆大学附属三峡医院药学部,重庆大学医学院,重庆404000

出　　处：《中国药理学通报》2024年第12期2269-2276,共8页Chinese Pharmacological Bulletin

基　　金：中国博士后科学基金第71批面上项目(No 2022MD713718);重庆市博士后科学基金项目(No CSTB2022NSCQBHX0709);重庆万州区博士“直通车”项目(No wzstc-20220124);重庆大学附属三峡医院人才科研项目(No ZX-50010101-2022-331)。

摘　　要：目的 基于转录组学探究小檗碱(berberine,BBR)对糖尿病肾病(diabetic nephropathy,DN)小鼠的改善作用及其潜在机制。方法 8周龄db/db小鼠随机分为模型组(DN组)、BBR 50 mg·kg^(-1)组(BBR-L组)、BBR 100 mg·kg^(-1)组(BBR-H组)和恩格列净10 mg·kg^(-1)组(EMPA组);同时以同龄db/m小鼠作为对照组(NC组),每组8只,灌胃1次/d,连续8周。给药结束后,采集血清、尿液和肾脏样本,评估肾功能指标并观察肾脏病理变化。通过转录组学检测各组小鼠肾组织差异表达基因(DEGs),并进行KEGG和GO富集分析。最后,利用分子对接、分子动力学模拟、Western blot和免疫组化验证潜在靶点。结果 BBR和EMPA均明显降低DN小鼠的空腹血糖水平,改善肾功能,减轻肾损伤和纤维化。与NC组相比,DN组共有855个DEGs;与DN组相比,BBR-H组共有194个DEGs。KEGG富集分析表明,BBR治疗DN的作用机制主要与1型糖尿病和胆汁分泌等信号通路有关。分子对接结果表明BBR与FXR具有强烈的结合活性,与SHP具有较好的结合活性。分子动力学模拟结果与分子对接结果基本一致。与NC组比,DN组FXR和SHP蛋白表达明显降低;而与DN组相比,BBR组FXR和SHP蛋白表达明显升高。结论 BBR可能通过上调FXR、SHP的表达调控胆汁酸和脂质稳态,减轻DN引起的肾脏损伤。Aim To explore the ameliorative effects of berberine(BBR)on diabetic nephropathy(DN)in mice and investigate its potential mechanisms through transcriptomic analysis.Methods 8-week-old db/db mice were randomly assigned into four groups:model group(DN group),BBR 50 mg·kg^(-1) group(BBR-L group),BBR 100 mg·kg^(-1) group(BBR-H group),and empagliflozin 10 mg·kg^(-1) group(EMPA group).Age-matched db/m mice were used as the control group(NC group),with eight mice in each group.Each group received intragastric administration once daily for eight weeks.After the treatment,serum,urine,and kidney samples were collected to evaluate renal function indicators and observe renal pathological changes.Differentially expressed genes(DEGs)in kidney tissue were identified through transcriptomic analysis,followed by KEGG and GO enrichment analysis.Potential targets were further validated using molecular docking,molecular dynamics simulations,Western blot,and immunohistochemistry.Results Both BBR and EMPA significantly reduced fasting blood glucose levels in DN mice,improved renal function,and alleviated renal injury and fibrosis.Compared to the NC group,855 DEGs were identified in the DN group,while 194 DEGs were identified in the BBR-H group compared to the DN group.KEGG enrichment analysis indicated that the mechanisms underlying BBR′s effects on DN were primarily related to type 1 diabetes and bile secretion pathways.Molecular docking results demonstrated a strong binding affinity between BBR and FXR and a moderate binding affinity with SHP.Molecular dynamics simulations corroborated the docking results.FXR and SHP protein expression significantly decreased in the DN group compared to the NC group.At the same time,BBR treatment significantly increased the expression of these proteins compared to the DN group.Conclusion BBR may mitigate DN-induced renal injury by modulating bile acid and lipid homeostasis through the FXR-SHP pathway.

关 键 词：小檗碱 糖尿病肾病 转录组学 分子动力学模拟 法尼醇X受体 小异二聚体伴侣受体 

分 类 号：R-332[医药卫生] R284.1R322.61R392.11R394R692.39