利拉鲁肽通过抑制内质网应激介导的PERK/eIF2α/ATF4/CHOP通路改善糖尿病大鼠的肾组织损伤  

Liraglutide ameliorates renal tissue damage in diabetic rats by inhibiting the PERK/eIF2α/ATF4/CHOP pathway mediated by endoplasmic reticulum stress

作　　者：田颖 TIAN Ying(Department of Pharmacy,Beijing Stomatological Hospital Affiliated to Capital Medical University,Beijing 100050,China)

机构地区：[1]首都医科大学附属北京口腔医院药学部,北京100050

出　　处：《河北医科大学学报》2024年第7期823-831,共9页Journal of Hebei Medical University

基　　金：北京市卫生科技发展专项基金(2018-4-369)。

摘　　要：目的 探讨利拉鲁肽通过蛋白激酶R样内质网激酶(protein kinase R-like ER kinase, PERK)/真核翻译起始因子eIF2的α亚基(phosphorylation of eukaryotic initiation factor-2α,eIF2α)/活化转录因子4(activated transcription factor 4,ATF4)/C/EBP同源蛋白(C/EBP-homologous protein, CHOP)通路介导的内质网应激对糖尿病大鼠肾组织损伤的改善作用及其机制。方法 通过高糖高脂饮食和腹腔注射低剂量链脲佐菌素(Streptozotocin, STZ)(30 mg/kg)诱导2型糖尿病大鼠模型。STZ注射后5周,糖尿病大鼠随机接受皮下注射或不皮下注射利拉鲁肽(0.2 mg/kg, 1次/12 h)治疗8周。将大鼠分为:NC组、DN组和DN+Lira组。测定糖尿病相关物理生化指标、肾脏组织病理学和超微结构变化。相应试剂盒分别检测超氧化物歧化酶(superoxide diamutase, SOD)、活性氧(reactive oxygen species, ROS)、丙二醛(malondialdehyde, MDA)和髓过氧化物酶(myeloperoxidase, MPO)水平。蛋白质免疫印迹分析内质网应激相关蛋白和PERK/eIF2α/ATF4/CHOP通路相关蛋白的表达。结果 STZ注射后5周后DN组的尾静脉空腹血糖(fasting blood glucos, FBG)始终高于NC组;STZ注射后13周(利拉鲁肽给药后8周),DN组和DN+Lira组FBG、血液糖化血红蛋白A_(1)c(hemoglobin A_(1)c, HbA_(1)c)、肾体重指数、血清肌酐(erum creatinine, SCr)和血尿素氮(blood urea nitrogen, BUN)显著高于NC组,体重显著低于NC组;DN+Lila组FBG、HbA_(1)c、肾体重指数、SCr和BUN显著低于DN组(P<0.05)。STZ注射后5周(利拉鲁肽给药后0周)时,DN组和DN+Lira组的尿白蛋白/尿肌酐比率显著高于NC组,差异有统计学意义(P<0.05)。研究结束(利拉鲁肽给药后8周)时,DN组和DN+Lira组的尿白蛋白/尿肌酐比率显著高于NC组,DN+Lila组的尿白蛋白/尿肌酐(urinary albumin/creatinine, ACR)显著低于DN组(P<0.05)。DN组和DN+Lira组系膜基质指数显著高于NC组,DN+Lira组系膜基质指数显著低于DN组,差异有统计学意义(P<0.05)。DN组葡Objective To investigate the effect of liraglutide on ameliorating renal tissue damage of diabetic rats by inhibiting kinase R-like ER kinase(PERK)/phosphorylation of eukaryotic initiation factor-2α(eIF2α)/activated transcription factor 4(ATF4)/C/EBP-homologous protein(CHOP)pathway mediated by endoplasmic reticulum stress and its mechanism.Methods A rat model of type 2 diabetes mellitus(T2DM)was induced by a high-carbohydrate,high-fat diet and intraperitoneal injection of low-dose Streptozotocin(STZ)(30 mg/kg).At 5 weeks after STZ injection,diabetic rats were randomly treated with subcutaneous injection or no subcutaneous injection of Liraglutide(0.2 mg/kg/12 h)for 8 weeks.The rats were divided into NC group,DN group and DN+Lira group.Diabetes-related physical and biochemical indexes,renal histopathology and ultrastructural changes were measured.The levels of superoxide diamutase(SOD),reactive oxygen species(ROS)level,malondialdehyde(MDA)and myeloperoxidase(MPO)were detected by corresponding kits,respectively.The expression of endoplasmic reticulum stress-related proteins and PERK/eIF2α/ATF4/CHOP pathway were analyzed by Western blotting.Results At 5 weeks after STZ injection,the fasting blood glucose(FBG)in the DN group was consistently higher than that in the NC group.At 13 weeks after STZ injection(8 weeks after Liraglutide administration),the DN group and DN+Lira group showed significantly higher FBG,hemoglobin A 1c(HbA 1c),renal body mass index,serum creatinine(SCr),and blood urea nitrogen(BUN)compared with the NC group,but significantly lower body weight compared with the NC group;The FBG,HbA 1c,renal body mass index,SCr,and BUN in the DN+Lila group were significantly lower than those in the DN group(P<0.05).At 5 weeks after STZ injection(0 week after Liraglutide administration),the urinary albumin/creatinine ratio(ACR)in the DN group and DN+Lira group was significantly higher than that in the NC group,and the difference was statistically significant(P<0.05).At the end of the study(8 weeks after administ

关 键 词：糖尿病肾病 利拉鲁肽 内质网应激 

分 类 号：R587.24[医药卫生—内分泌]