兰索拉唑通过增强肾小管上皮细胞焦亡促进顺铂诱导的急性肾损伤  

Lansoprazole promotes cisplatin-induced acute kidney injury by enhancing pyroptosis of renal tubular epithelial cells

作　　者：徐起 吴永贵[1] Xu Qi;Wu Yonggui(Dept of Nephropathy,The First Affiliated Hospital of Anhui Medical University,Hefei230022)

机构地区：[1]安徽医科大学第一附属医院肾脏内科,合肥230022

出　　处：《安徽医科大学学报》2024年第11期1911-1919,共9页Acta Universitatis Medicinalis Anhui

基　　金：国家自然科学基金项目(编号:81770722);2023年度安徽医科大学基础与临床提升计划项目(编号:2023xkjT034)。

摘　　要：目的探讨兰索拉唑(LPZ)对顺铂(CIS)诱导的小鼠急性肾损伤与肾小管上皮细胞损伤的影响。方法将C57BL/6J小鼠与肾小管上皮细胞分为以下4组:正常对照(NC)组、兰索拉唑(LPZ)组、顺铂(CIS)组和顺铂+兰索拉唑(CIS+LPZ)组。动物实验采用生理盐水溶解LPZ(25 mg/kg),连续3 d腹腔注射小鼠LPZ后,腹腔注射顺铂(20 mg/kg)一次。继续喂养小鼠3 d,收集小鼠血清检测血肌酐(CRE)和尿素氮(BUN)水平。采用HE染色、PAS染色观察肾脏病理,透射电镜观察肾脏超微结构改变。Western blot、免疫组化检测肾损伤因子-1(KIM-1)、中性粒细胞明胶酶相关脂质运载蛋白(NGAL)与焦亡相关蛋白表达水平的改变。细胞实验选用顺铂(20μmol/L)与LPZ(5μmol/L)刺激细胞24 h后,采用Western blot、Real-time PCR检测KIM-1、NGAL以及焦亡相关因子的表达。结果与NC组相比,CIS组CRE和BUN水平升高,LPZ处理后加重了小鼠的血清学指标(P<0.001)。肾脏组织病理学检查显示,与CIS组相比,LPZ+CIS组小鼠肾组织肾小管扩张明显、炎症细胞浸润和糖原沉积增加(P<0.001)。电镜结果表明CIS组小鼠线粒体肿胀,膜密度增加,线粒体嵴减少或缺失,LPZ+CIS组加重了这些变化。体内、体外实验均证实LPZ处理后促进了CIS诱导的小鼠急性肾损伤与肾小管上皮细胞中肾脏损伤因子KIM-1、NGAL与肾脏焦亡关键因子(Caspase 1、GSDMD、NLRP3和IL-18)的表达水平的升高(P<0.001)。结论LPZ通过增强肾小管上皮细胞焦亡促进顺铂诱导的肾脏损伤。Objective To investigate the effect of lansoprazole(LPZ)on cisplatin-induced acute kidney injury in mice and renal tubular epithelial cell injury.Methods C57BL/6J mice and renal tubular epithelial cells were divided into normal control(NC)group,lansoprazole(LPZ)group,cisplatin(CIS)group and cisplatin+lansoprazole(CIS+LPZ)group.In animal experiments,LPZ(25 mg/kg)was dissolved in normal saline,and the mice were intraperitoneally injected with LPZ for three consecutive days followed by cisplatin(20 mg/kg).Mice were fed normally for 3 days,and serum samples were collected to detect serum creatinine(CRE)and blood urea nitrogen(BUN)levels.HE staining and PAS staining were used to observe renal pathology,and transmission electron microscopy was used to observe renal ultrastructure.Western blot and immunohistochemistry were used to detect the changes in the expression levels of KIM-1,NGAL and pyroptosis-related proteins.In the cell experiment,the cells were treated with cisplatin(20μmol/L)and LPZ(5μmol/L)for 24 hours,and the expressions of KIM-1,NGAL and pyroptosis-related factors were detected by Western blot and Real-time PCR.Results Compared with the NC group,CRE and BUN levels increased in the CIS group,and LPZ treatment aggravated the serological indicators of the mice(P<0.001).Histopathological examination showed that compared with the CIS group,the LPZ+CIS group had obvious renal tubular dilatation,inflammatory cell infiltration and glycogen deposition in the renal tissue(P<0.001).Electron microscopy showed swelling of mitochondria,increased membrane density and decreased or absent mitochondrial crista in CIS group,which were aggravated by LPZ+CIS group.In vivo and in vitro experiments confirmed that LPZ treatment promoted CIS-induced acute kidney injury in mice and increased the expression levels of kidney injury factors KIM-1,NGAL and key factors of renal pyroptosis(Caspase 1,GSDMD,NLRP3 and IL-18)in renal tubular epithelial cells(P<0.001).Conclusion Lansoprazole promotes cisplatin-induced acute kidney injury

关 键 词：急性肾损伤 兰索拉唑 焦亡 顺铂 炎症 

分 类 号：R285.5[医药卫生—中药学]