GLP-1受体通过SIRT3减轻脓毒症急性肾损伤炎症反应及细胞凋亡  

Glucagon like peptide-1 receptor alleviates inflammation and apoptosis in sepsis-induced acute kidney injury via SIRT3

作　　者：艾晨牧 雷小保[1] 李桂成[1] 段智[1] 王香 AI Chen-mu;LEI Xiao-bao;LI Gui-cheng;DUAN Zhi;WANG Xiang(Department of Critical Care Medicine,the First People's Hospital of Chenzhou,Chenzhou,Hunan 423000,China)

机构地区：[1]郴州市第一人民医院重症医学科,湖南郴州423000

出　　处：《热带医学杂志》2020年第7期870-874,F0004,共6页Journal of Tropical Medicine

基　　金：湖南省自然科学基金(2018JJ3015,2018JJ6004);郴州市科技发展计划项目(zdyf201924);郴州市第一人民医院院内项目(N2019-057);湘南学院院内课题(2019XJ80)。

摘　　要：目的探讨Glucagon like peptide-1 receptor(GLP-1R)对脓毒症急性肾损伤(AKI)炎症反应及细胞凋亡的影响及其可能机制。方法通过盲肠结扎穿孔(CLP)法建立AKI模型。30只小鼠随机分为五组:对照组:小鼠建立假模型后接受溶剂处理;药物对照组:小鼠建立假模型接受GLP-1R激动剂利拉鲁肽(2 mg/kg)处理;模型组:小鼠建立AKI模型接受溶剂处理;治疗组:小鼠建立AKI模型后利拉鲁肽(2 mg/kg)处理;抑制剂组:小鼠建立AKI模型后接受利拉鲁肽(2 mg/kg)及silent mating type information regulation2 homolog-3(SIRT3)抑制剂3-TYP(5 mg/kg)处理。Western blot法检测SIRT3蛋白表达。酶联免疫法检测血清肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、IL-6水平。自动生化分析仪检测血清肌酐及尿素氮水平。TUNEL染色法检测肾组织细胞凋亡。结果与对照组比较,模型组SIRT3表达及活性分别显著下降为(70.1±4.5)%及(73.7±5.3)%,血清TNF-α、IL-1β、IL-6、肌酐、尿素氮及肾细胞凋亡分别显著增加为(359.8±36.5)pg/mL、(290.0±26.7)pg/mL、(852.3±41.0)ng/mL、(59.0±8.7)μmol/L、(25.2±7.0)mmol/L、(49.0±9.3)个/视野,差异均有统计学意义(P<0.05)。与模型组比较,治疗组SIRT3表达及活性显著增加为(87.0±6.4)%及(85.4±7.3)%,血清TNF-α、IL-1β、IL-6、肌酐、尿素氮及肾细胞凋亡分别显著下降为(282.7±16.9)pg/mL、(189.0±14.2)pg/mL、(461.2±34.0)ng/mL、(38.7±5.9)μmol/L、(17.7±2.9)mmol/L、(21.0±5.2)个/视野,差异均有统计学意义(P<0.05)。与治疗组比较,抑制剂组血清TNF-α、IL-1β、IL-6、肌酐、尿素氮及肾细胞凋亡分别显著增加为(347.8±30.6)pg/mL、(265.9±28.5)pg/mL、(838.7±34.9)ng/mL、(57.5±7.2)μmol/L、(26.8±4.7)mmol/L、(47.0±12.0)个/视野,差异均有统计学意义(P<0.05)。结论激活GLP-1R可以显著抑制脓毒症AKI中炎症反应及细胞凋亡,改善肾功能,其机制与上调SIRT3表达有关。Objective To investigate the effects and mechanism of glucagon like peptide-1 receptor(GLP-1 R)on the inflammation and apoptosis in the sepsis-induced acute kidney injury.Methods Mice underwent cecal ligation and puncture(CLP)to mimic sepsis-induced acute kidney injury.A total of 30 mice were randomly divided into five groups:mice in control group received a sham AKI model and treatment with vehicle;mice in drug-control group received a sham AKI model and treatment with liraglutide(2 mg/kg);mice in model group received a AKI model and treatment with vehicle;mice in treatment group received a AKI model and treatment with liraglutide(2 mg/kg);mice in inhibitor group received a AKI model and treatment with liraglutide(2 mg/kg)and 3-TYP(5 mg/kg),the inhibitor of silent mating type information regulation 2 homolog-3(SIRT3).The expression of SIRT3 was detected by Western blot.The serum concentrations of TNF-α,IL-1αand IL-6 were determined by ELISA kits.The concentrations of creatinine and urea nitrogen in serum were measured by an automatic biochemical analyzer.The cell apoptosis was determined by the terminal deoxyribonucleotidyl transferase-mediated deoxyuridine 5-Triphosphate-Digoxigenin nick end labeling(TUNEL)assay.Results Compared with the control group,the expression and activity of SIRT3 in model group were respectively decreased to(70.1±4.5)%and(73.7±5.3)%;the serum concentration of TNF-α,IL-1α,IL-6,creatinine,urea nitrogen and apoptotic cell in model group were respectively increased to(359.8±36.5)pg/mL,(290.0±26.7)pg/mL,(852.3±41.0)ng/mL,(59.0±8.7)μmol/L,(25.2±7.0)mmol/L and(49.0±9.3)/visual field.Compared with the model group,the expression and activity of SIRT3 in treatment group were respectively increased to(87.0±6.4)%and(85.4±7.3)%;the serum concentration of TNF-α,IL-1α,IL-6,creatinine,urea nitrogen and apoptotic cell in treatment group were respectively decreased to(282.7±16.9)pg/mL,(189.0±14.2)pg/mL,(461.2±34.0)ng/mL,(38.7±5.9)μmol/L,(17.7±2.9)mmol/L and(21.0±5.2)/visual field.

关 键 词：急性肾损伤 G蛋白偶联受体 炎症 凋亡 

分 类 号：R692[医药卫生—泌尿科学]