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血管紧张素Ⅱ1型受体及其拮抗剂对肾脏损伤和高糖诱导巨噬细胞的影响 预览

Effects of Losartan on high glucose-induced bone marrow sources of macrophages and the relationship of angiotensin Ⅱ type 1 receptor with renal pathological damage
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摘要 目的探究糖尿病肾病(DN)患者肾脏损伤与血管紧张素Ⅱ1型受体(AT1R)的表达及巨噬细胞浸润之间的关系,以及AT1R拮抗剂氯沙坦对巨噬细胞的调控作用。方法收集不同病理分期的DN患者肾穿刺样本,并收集肾癌患者的癌旁组织作为癌旁对照组,免疫组化法检测不同病理分期患者肾组织中AT1R的表达以及CD68阳性巨噬细胞的浸润;从医院HIS系统调取患者信息,比较肾穿刺前服用过血管紧张素Ⅱ1型受体拮抗剂(ARB)类药物的患者与未服用过ARB类药物的患者之间巨噬细胞浸润的改变。细胞实验以骨髓来源的巨噬细胞作为研究对象,高糖作为刺激因素,不同浓度的氯沙坦作为干预因素;采用流式细胞术测定巨噬细胞的纯度、共刺激分子的表达以及吞噬能力;采用实时荧光定量PCR法以及Elisa法测定各组细胞中炎症因子、巨噬细胞分型标记物的mRNA及蛋白表达;应用一氧化氮(NO)试剂盒检测各组细胞培养上清液中NO的表达。结果与癌旁对照组相比,DNⅢ型和Ⅳ型患者的肾脏中AT1R的表达有明显上升趋势,差异具有统计学意义(P<0.05)。随着DNⅢ型和Ⅳ型患者的肾脏中AT1R的表达上升,巨噬细胞浸润明显增加(P<0.05)。此外,在相同病理分期的患者中,服用过ARB类药物的患者较未服用的患者其肾组织中的巨噬细胞浸润明显减少(P<0.05)。细胞实验结果进一步证实使用氯沙坦干预后能显著减少巨噬细胞活化,抑制高糖诱导的巨噬细胞M1型分化。结论 AT1R在肾脏中的表达水平及巨噬细胞浸润程度与DN患者肾脏损伤程度成正相关,ARB类药物能减轻DN患者肾脏组织中巨噬细胞浸润及活化。 Objective To explore the relationship between renal injury and angiotensinⅡtype 1 receptor(AT1R)expression and macrophage infiltration in patients with diabetic nephropathy(DN)and to investigate the regulatory effect of ATIR inhibitor losartan on macrophages.Methods The renopuncture samples of DN patients with different pathological stages were collected and the expression of AT1R and infiltration of CD68~+macrophages were detected in the renal tissues by immunohistochemistry(IHC).The macrophage infiltration in renal tissues was also compared between AT1R blocking drug-treated patients and control patients.In addition,high glucose-treated bone marrow-derived macrophages were used as an in vitro model.The AT1R blocker losartan was given to inhibit AT1R in macrophage in vitro.The purity and the expression of co-stimulatory molecules and cell phagocytic ability of macrophages were detected by flow cytometry.The mRNA and protein expression of inflammatory cytokines and subtyping markers of macrophage was determined by qRT-PCR and ELISA assays.NO production in cell culture supernatant was also measured by NO detection kit.Results The AT1R expression was significantly up-regulated in the renal tissue of patients with type III and IV DN as compared with the peritumorial control group(P<0.05).The macrophage infiltration in renal tissues from those patients was also greatly increased accordingly.In addition,the macrophage infiltration was repressed in ARB drugs-treated patients when compared with control group(P<0.05).The results of cell experiments further validated that the losartan intervention ameliorated high glucose-induced macrophages activation.Conclusions The AT1R expression and macrophage infiltration in renal tissues are positively correlated with the degree of renal injury of DN patients.The macrophage infiltration in renal tissues from DN patients could be repressed by ARB drugs.
作者 江肖 吴永贵 JIANG Xiao;WU Yong-gui(Department of Nephrology,the First Affiliated Hospital of Anhui Medical University,Hefei 230022,China)
出处 《临床肾脏病杂志》 2019年第2期126-133,140共9页 Journal Of Clinical Nephrology
基金 国家自然科学基金(No.81770722).
关键词 血管紧张素Ⅱ1型受体 巨噬细胞 糖尿病肾病 Angiotensin Ⅱ type 1 receptor Macrophage Diabetic nephropathy
作者简介 江肖,女,硕士,住院医师,研究方向:肾脏病理诊断,电话:0551-62922111,E-mail:jiangxiaochina@qq.com;通信作者:吴永贵,男,教授、主任医师、博士生导师,研究方向:糖尿病肾病发病机理,电话:0551-62922111,E-mail:wuyonggui@medmail.com.cn.
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