利拉鲁肽抑制ERS改善高脂饮食诱导的DN肾损害  

Liraglutide alleviates high-fat diet-induced diabetic nephropathy by inhibiting endoplasmic reticulum stress

作　　者：梁日英 符畅 梁华[1] 徐芬[1] 王美君 蔡梦茵[1] Liang Riying;Fu Chang;Liang Hua;Xu Fen;Wang Meijun;Cai Mengyin(Department of Endocrinology and Metabolism,the Third Affiliated Hospital of Sun Yat-sen University,Guangzhou 510630,China)

机构地区：[1]中山大学附属第三医院内分泌与代谢病学科

出　　处：《新医学》2019年第11期826-831,共6页Journal of New Medicine

基　　金：国家自然科学基金（81670762）;广东省自然科学基金（2016A030313258）;广州市科技计划项目（201707010118）;中山大学高校基本科研业务费青年教师培育项目（13ykpy31）

摘　　要：目的探讨内质网应激(ERS)机制是否参与调节利拉鲁肽改善高脂饮食诱导的糖尿病肾病(DN)。方法采用高脂饮食喂养7~8周龄C56BL/6小鼠共12周以诱导早期DN,正常饮食喂养小鼠作为对照组。将高脂饮食小鼠分为高脂饮食(HFD)组及高脂饮食+利拉鲁肽干预(HFD+Lira)组,HFD+Lira组予腹腔注射利拉鲁肽400μg/(kg·d)8周。HFD组与对照组均予相对应体积的生理盐水。每2周监测小鼠体质量及血糖情况,干预8周后评估/观察小鼠胰岛功能、胰岛素抵抗、尿蛋白、肾脏组织形态结构以及肾脏组织ERS通路蛋白葡萄糖调节蛋白78(GRP78)与剪接型X-盒结合蛋白1(XBP1s)的表达水平。结果HFD组体质量、空腹血糖和体脂含量均高于对照组;利拉鲁肽干预8周后,与HFD组比较,HFD+Lira组体质量、空腹血糖和体脂含量均改善(P均<0.01)。HFD组血糖、尿蛋白高于对照组、胰岛素抵抗较对照组明显,HFD+Lira组血糖及尿蛋白均低于HFD组、胰岛素抵抗较HFD组改善(P均<0.017)。对照组肾小球、肾小管结构正常,HFD组可见肾小管区域大量空泡形成、肾小球囊腔扩大、大量脂质沉积,与HFD组相比,HFD+Lira组肾小管区域空泡减少、扩大的肾小球囊腔及脂质沉积腔改善。HFD组GRP78与XBP1s蛋白表达水平均较对照组高,HFD+Lira组XBP1s蛋白的表达水平低于HFD组(P均<0.017)。结论利拉鲁肽可能通过抑制ERS通路而改善高脂饮食喂养诱导的DN肾损害。Objective To investigate whether the mechanism of endoplasmic reticulum stress(ERS)is involved in the protective effect of liraglutide on diabetic nephropathy(DN)induced by high-fat diet.Methods The 7-8-week old C56BL/6 mice were subjected to a high fat diet(HFD)for 12 weeks to establish mouse models with early DN,and those mice given with normal diet were allocated into the control group.Then,mice in the HFD group were further divided into the HFD and HFD+Liraglutide(HFD+Lira)groups.Mice in the HFD+Lira group were given with liraglutide at a dose of 400μg/(kg·d)by intraperitoneal injection for 8 weeks.An equivalent amount of normal saline was administered in the HFD and control groups.During the period of animal experiment,body weight and fasting blood glucose were monitored every two weeks.At 8 weeks after intervention,the islet function,insulin resistance,urinary albumin,renal morphology and the expression levels of glucose regulatory protein 78(GRP78)and X-box binding protein 1 splicing(XBP1s)on the ERS signaling pathway in the renal tissues were evaluated or observed.Results The body weight,fasting blood glucose and body fat content in the HFD group were significantly higher compared with those in the control group.At 8 weeks after liraglutide intervention,body weight,fasting blood glucose and body fat content in the HFD+Lira group were significantly alleviated than those in the HFD group(all P<0.01).In the HFD group,the fasting blood glucose and urinary albumin were higher,whereas the insulin resistance was more evident compared with those in the control group.In the HFD+Lira group,the fasting blood glucose and urinary albumin were significantly lower,whereas the insulin resistance was ameliorated compared with those in the HFD group(all P<0.017).The structures of glomerulus and renal tubules were normal in the control group.A large quantity of vacuoles in the renal tubule,Bowman’s capsule space and a large amount of lipid deposition were observed in the HFD group.Compared with the HFD group,the amount

关 键 词：糖尿病肾病 胰高血糖素样肽1 内质网应激 葡萄糖调节蛋白78 剪接型X-盒结合蛋白1 利拉鲁肽 

分 类 号：R58[医药卫生—内分泌]