小檗碱类似物Y53在STZ诱导的糖尿病C57BL/6J小鼠中抗糖尿病肾病的作用研究  

Study of anti-diabetic nephropathy efficacy of berberine analogue Y53 in STZ-induced diabetic C57BL /6J mice

作　　者：李峥[1] 王灿[1] 宋丹青[1] 蒋建东[2] 孔维佳[1] LI Zheng WANG Can SONG Dan-qing JIANG Jian-dong KONG Wei-jia(Institute of Medicinal Biotechnology Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China)

机构地区：[1]中国医学科学院医药生物技术研究所,北京100050 [2]中国医学科学院药物研究所,北京100050

出　　处：《中国药理学通报》2016年第9期1236-1242,共7页Chinese Pharmacological Bulletin

基　　金：国家科技重大专项重大新药创制子课题(No 2014ZX09101005-008)

摘　　要：目的研究小檗碱(BBR)类似物假BBR(Y53)在链脲佐菌素(STZ)诱导的糖尿病(DM)小鼠中改善糖尿病肾病(DN)的作用。方法采用腹腔注射STZ 120 mg·kg^(-1)的方法诱发C57BL/6J小鼠的DM。建模成功的动物被分为4组,每天分别灌胃给予生理盐水、BBR 50 mg·kg^(-1)、Y53 50mg·kg^(-1)或罗格列酮(ROSI)5 mg·kg^(-1)。实验过程中和结束后,收集动物的尿液、全血、血清和肾脏,使用试剂盒检测相关指标。以苏木精-伊红(HE)染色对肾组织进行病理学检验,分别以实时荧光定量反转录-PCR(qRT-PCR)和Western blot检测肾脏中靶基因的mRNA和蛋白的表达水平。结果与DM对照组比较,Y53能够明显降低DM动物的空腹血糖(FBG)和糖化血红蛋白(GHb),改善多食和多尿等DM症状(P<0.01)。与DM对照组比较,Y53还可明显降低血尿素氮(BUN)、血清肌酐(Scr)、24 h尿蛋白、肾指数、血清和肾组织中的晚期糖基化终末产物(AGEs)和一氧化氮(NO)、以及肾脏胆固醇(CHO)和三酰甘油(TG)含量(P<0.05或P<0.01)。在病理检测中,与DM对照组比较,Y53可明显改善DM小鼠肾组织的形态并抑制肾小球硬化(P<0.001)。另外,与DM对照组比较,Y53还能明显下调DM小鼠肾脏中纤维化相关基因,如转化生长因子-β1(TGF-β1)和smad2的表达(P<0.01)。该研究中Y53的肾脏保护效果明显优于BBR和ROSI(P<0.05或P<0.01)。结论BBR类似物Y53在STZ诱导的DM小鼠中具有明显的改善肾脏损伤、恢复肾功能的作用,该化合物在未来有可能被开发成为治疗DN的新型药物。Aim To investigate the ameliorative effects pseudoberberine（ Y53）,a berberine（ BBR） analogue,on diabetic nephropathy（ DN） in streptozotocin（ STZ）-induced diabetic mice. Methods Diabetes mellitus（ DM） of the C57BL/6J mice was induced by intraperitoneal injection of STZ at 120 mg·kg^（-1）. The diabetic animals were divided into 4 groups,which were orallytreated with saline,50 mg · kg^（-1）of BBR,50 mg ·kg^（-1）of Y53 or 5 mg · kg^（-1）of rosiglitazone（ ROSI）,respectively. During and after the experiment,the urine,blood,serum and kidney of the animals were harvested for determination of relevant parameters by kits. Kidney tissues of the mice were subjected to pathological examination by hematoxylin eosin（ HE）staining; mRNA and protein expression levels of target genes in the kidney were determined by quantitative real-time reverse transcriptase-polymerase chain reaction（ qRT-PCR） and Western blot,respectively. Results Y53 greatly reduced the fasting blood glucose（ FBG）and glycosylated hemoglobin（ GHb）,improved diabetic symptoms such as polyphagia and polyuria in the diabetic mice（ P 0. 01 vs DM control group）. Y53 potently reduced the blood urea nitrogen（ BUN）,serum creatinine（ Scr）,24 h urinary protein,kidney index,serum and kidney advanced glycation end-products（ AGEs） and nitric oxide（ NO）,as well as kidney cholesterol（ CHO） and triglyceride（ TG） contents（ P 0. 05 or P 0. 01 vs DM control group）. In the pathological examination,Y53 greatly restored kidney mor-phology and suppressed glomerular sclerosis（ P 0. 001 vs DM control group）. In addition,Y53 significantly reduced the renal expression of fibrosis-related genes,such as the transforming growth factor-β1（ TGF-β1）and smad2（ P 0. 01 vs DM control group）. The renoprotective efficacies of Y53 were superior to those of BBR and ROSI in our study（ P 0. 05 or P 0. 01）.Conclusions The BBR analogue Y53 has potent activities in ameliorating renal injury and restorin

关 键 词：糖尿病肾病 假小檗碱 肾脏保护 晚期糖基化终末产物 一氧化氮 转化生长因子-Β1 

分 类 号：R332[医药卫生—人体生理学] R322.61[医药卫生—基础医学]