黄芪甲苷通过抑制mTORC1信号通路调控自噬改善糖尿病肾病的研究  

AS-IV Slows the Progression of Diabetic Nephropathy by Inhibitting mTORC1 and Enhancing Autophagic Flux

作　　者：王增四 高文[2] 何达 谢小行 WANG Zengsi;GAO Wen;HE Da(Traditional Chinese and Western Medicine Hospital of Wuhan,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430022)

机构地区：[1]华中科技大学同济医学院附属武汉中西医结合医院肾病内科,武汉430022 [2]华中科技大学同济医学院附属同济医院健康管理中心,武汉430030

出　　处：《中国中西医结合肾病杂志》2024年第10期854-857,I0001,共5页Chinese Journal of Integrated Traditional and Western Nephrology

基　　金：国家自然科学基金资助项目(No.81503432);湖北省自然科学基金资助项目(No.2015CFB395)。

摘　　要：目的:观察黄芪甲苷CAS-IV对链脲佐菌素(STZ)诱导的糖尿病肾病大鼠肾脏自噬活性及mTOR1信号通路的影响,阐明黄芪甲苷肾保护作用的潜在分子机制。方法:SD大鼠随机分为正常组(Normal)和造模组,采用STZ腹腔注射诱导的糖尿病肾病大鼠为动物模型,造模成功后分为模型组(Model),AS-IV组,AS-IV+巴佛洛霉素A1(BA)组,4-苯基丁酸(PBA)组和雷帕霉素(RAPA)组。治疗第8周末检测大鼠肾脏功能和肾脏损伤指标;HE和PAS观察肾脏病理学改变;Western blotting检测肾脏组织LC3Ⅱ/Ⅰ、p62/SQSTMi表达评估大鼠肾组织自噬活性,检测mTOR和Raptor磷酸化水平及mTOR1信号下游靶点S6K1和4EBP磷酸化的水平评估mTOR1信号通路活性。结果:经黄芪甲苷干预后,大鼠尿蛋白排出率显著降低,肾功能改善,肾脏病理变化减轻;肾组织LC3Ⅱ/Ⅰ表达增加,P62/SQSTM1的表达下降;mTOR及Raptor磷酸化水平下调,S6K1和4EBP的磷酸化水平明显减少。联合使用黄芪甲苷及巴弗洛霉素A1处理后,黄芪甲苷的上述肾保护效应被完全阻断。结论:黄芪甲苷可降低糖尿病肾病大鼠尿白蛋白排泄率,改善肾脏病理变化,其机制可能与黄芪甲苷抑制mTOR1活性,上调大鼠肾组织自噬活性有关。Objective:We investigated the effect of AS-IV on the progression of diabetic nephropathy(DN)in rats induced with streptozotocin(STZ)and the underlying mechanism involving autophagy.Methods:Male SD rats were divided into normal control group(Normal group)and diabetic nephropathy rats group,diabetic nephropathy rats treated with AS-IV(AS-IV group)or 4-phenylbutyrate(PBA group)or rapamycin(RAPA group)or AS-IV plus bafilomycin A1(AS-IV+BA group).After 8 weeks of treatment,the renal function and renal injury indicators were detected by HITACHI automatically,morphology change of kidney was examined by histological evaluation(HE)and periodic acid-Schiff(PAS),The express of LC3Ⅱ/Ⅰand p62 were tested to evaluate the autophagy activity,the phosphorylation level of mTOR,Raptor,and the main downstream signal targets of S6K1 and 4EBP were measured to evaluate the activity of mTOR1 signaling pathway.Results:AS-IV treated animals had less histological glomerular injury.A remarkable restoration of impaired autophagy,as indicated by altered expression and activity of p62 and LC3Ⅱ/Ⅰ,and significant suppressed the mTOR1 signal pathway activity,as evidenced by decreasing of phosphorylation of Raptor and mTOR,and the downstream targets of S6 kinase and eukaryotic initiation factor 4B.Inhibiting autophagic flux with bafilomycin A1 abolished the renoprotection effect of AS-IV under diabetes conditions.Conclusion:AS-IV attenuates the progression of DN,which is mediated at least in part by inhibition of mTOR1,with increased autophagy flux.

关 键 词：黄芪甲苷 糖尿病肾病 自噬 哺乳动物雷帕霉素靶蛋白 

分 类 号：R285.5[医药卫生—中药学]