项目来源

台湾省政府科研基金(GRB)

项目主持人

庄乔琳

项目受资助机构

台湾省台北荣民总医院内科委员会一般内科

项目编号

V113C-072

立项年度

2024

立项时间

未公开

项目级别

省级

研究期限

未知 / 未知

受资助金额

827.00千元台币

学科

临床医学

学科代码

未公开

基金类别

基础研究/自行研究(机关预算)

类昇糖素胜肽-1受体促效剂Glucagon-like peptide 1 receptor agonists ; GLP-1 RAs ; 缺血—再灌注(ischemia reperfusion)损伤 ; 肝硬化 ; 肾脏血管反应性 ; Glucagon-like peptide 1 receptor agonists(GLP-1 RAs) ; ischemia-reperfusion injury ; liver cirrhosis ; renal vascular reactivity

参与者

未公开

参与机构

未公开

项目标书摘要：类昇糖素胜肽-1受体促效剂(Glucagon-like peptide 1 receptor agonists,GLP-1 RAs)是治疗糖尿病的新药，具有多重功能且很少有低血糖副作用。除了控制血糖、抑制食慾以达成体重减轻的效果，许多文献证实GLP-1 RAs具有抗发炎、抗氧化、抗纤维化、和血管扩张作用，可以降低血压、血脂，改善心血管功能，治疗非酒精性脂肪肝炎(Non-alcoholic steatohepatitis),也可以改善肾丝球超过滤与尿蛋白，减轻糖尿病肾病变的伤害，对於肾脏的缺血—再灌注(ischemia-reperfusion)损伤也具有保护效果。缺血—再灌注所导致的急性肾损伤是肝硬化患者并发感染或出血时常见的严重并发症，因此，我们计划探讨GLP-1 RAs在肝硬化合并急性肾损伤时的肾脏保护作用。本计划将以SD大鼠进行总胆管结紮诱发肝硬化进行研究。大鼠手术後，每周2次腹腔内注射vehicle或Dulaglutide(0.5 mg/kg),第28天随机接受肾脏缺血—再灌注後，置入代谢笼收集24小时尿液，第29天评估:(a)血流动力学参数：血压、心跳、门脉压力、上肠系膜动脉血流量及肾动脉血流量;(b)肝肾功能、血糖、血脂;(c)发炎因子:TNF-α、IL-1β、IL-6、ox-LDL、hs-CRP、SOD、MDA;(d)尿液分析:protein、NGAL、IL-18、L-FABP、[TIMP-2]×[IGFBP-7];(e)肾脏灌流：肾血管反应性;(f)肝脏eNOS/p-eNOS、iNOS、COX-1、COX-2、ERK/p-ERK、TGF-β、Smad、NF-kβ、MCP-1、AMPK;(g)肾脏eNOS/p-eNOS、iNOS、COX-1、COX-2、ETA、ETB、ERK/p-ERK、Akt/p-Akt、TGF-β、Smad、NF-kβ、MCP-1、AMPK;(h)肝脏与肾脏的氧化压力测试。

Application Abstract: Glucagon-like peptide 1 receptor agonists(GLP-1 RAs)are a class of anti-diabetic drugs with little adverse effect of hypoglycemia.The GLP-1 receptors are expressed in various organs,including the pancreas,liver,gut,kidneys,lungs,heart,and muscles.As a result,GLP-1-RAs demonstrated various pleiotropic properties and became a research hotspot.In addition to potent glucose-lowering activity,GLP-1RAs reduce appetite and body weight,lower blood pressure,decrease postprandial lipoprotein secretion,and attenuate systemic and tissue inflammation,actions that may contribute to a reduction of nonalcoholic fatty liver disease(NAFLD).Most importantly,some GLP-1 RAs have demonstrated cardiovascular and renal benefits through their protective properties against endothelial dysfunction,inflammation,oxidative stress,and fibrosis,leading to a reduction in atherosclerotic CVD,cardiovascular deaths,albuminuria progression,renal hyperfiltration,and ischemia-reperfusion injury.Acute kidney injury resulting from ischemia-reperfusion injury is a common and severe complication in cirrhosis patients complicated with infection or esophageal variceal bleeding.Therefore,the aim of this study is to evaluate the potential renoprotective effects of GLP-1 RAs in a rat model of biliary cirrhosis complicated with renal ischemia-reperfusion injury.Liver cirrhosis will be induced by common bile duct ligation(CBDL)in Sprague-Dawley rats.Rats will receive intraperitoneal injections of(i)vehicle(saline);or(ii)Dulaglutide(0.5 mg/kg)two times per week after operations.On the 28th day following surgery,rats will be randomized to sham operation or renal ischemia-reperfusion injury.Then,rats will be placed individually in the polycarbonate metabolic cages to collect 24-hour urine.On the 29th day,the following experiments will be performed:(a)Hemodynamic parameters measurements:mean arterial pressure,heart rate,portal pressure,superior mesenteric arterial blood flow,renal arterial blood flow;(b)Serum concentrations of biochemistry and inflammatory parameters:alanine aminotransferase,aspartate aminotransferase,total bilirubin,blood urea nitrogen,creatinine,sodium,glucose,lipid profiles,ox-LDL,hs-CRP,TNF-α,IL-1β,IL-6,SOD,MDA;(c)Urine biomarkers analyses:protein,NGAL,IL-18,L-FABP,[TIMP-2]×[IGFBP-7];(d)In situ kidney perfusion:the concentration-response curves to graded concentrations of endothelin-1;(e)Western analyses of livers:eNOS,p-eNOS,iNOS,COX-1,COX-2,ERK,p-ERK,TGF-β,Smad,MCP-1,NF-kβ,AMPK;(f)Western analyses of kidneys:eNOS,p-eNOS,iNOS,COX-1,COX-2,ETA,ETB,ERK,p-ERK,Akt,p-Akt,TGF-β,Smad,MCP-1,NF-kβ,AMPK;(f)oxidative stress analyses of livers and kidneys:MDA,GSH,the activity of GPx,SOD,and catalase.

项目受资助省

台湾省