庆大霉素诱导的大鼠急性肾损伤模型中尿液生物标志物NGAL的研究  

Urinary biomarker NGAL in gentamicin-induced rat acute kidney injury model

作　　者：周晓冰[1] 朱聪[1] 屈哲[1] 林志[1] 王超[1] 霍艳[1] 汪巨峰[1] 李波[1] 

机构地区：[1]中国食品药品检定研究院国家药物安全评价监测中心药物非临床安全评价研究北京市重点实验室,北京100176

出　　处：《药物分析杂志》2016年第4期639-644,共6页Chinese Journal of Pharmaceutical Analysis

基　　金：十二五"重大新药创制"(2012ZX09302001);科技重大专项"关键技术研究"(2012ZX09505001-004)

摘　　要：目的:评价尿液中性粒细胞明胶酶相关载脂蛋白(NGAL)作为药物肾毒性生物标志物的实用性。方法:通过对Wistar大鼠腹腔注射60和120 mg·kg-1庆大霉素,每天给药1次,连续给药10 d,建立了大鼠急性肾损伤模型。应用ELISA和Luminex液相芯片方法检测分析各组动物尿液NGAL浓度,并与传统血清肾功能指标进行比较。结果:与对照组相比较,庆大霉素给药组动物肾脏重量的变化与给药时间及剂量具有一定相关性。组织病理学分析结果证实随着给药剂量及给药时间的增加,庆大霉素给药组动物出现肾小管细胞坏死损伤的动物数增加,且病变程度也随之加重。尿液生物标志物分析结果表明ELISA和Luminex液相芯片方法检测结果一致性较好,低、高剂量组动物给药后第4天,尿液中NGAL浓度开始大幅度升高,自第8天起,具有明显时间和剂量效应关系。受试者操作特性曲线(ROC)结果也表明NGAL的曲线下面积(AUC)明显高于肌酐(Cr),具有更高的灵敏度和特异性。结论:研究结果表明尿液NGAL可作为一种药物肾毒性的候选生物标志物,在药物的大鼠临床前安全性研究中将具有良好的应用前景。Objective：To evaluate the utility of neutrophil gelatinase-associated lipocalin（NGAL）as biomarker for detection of nephrotoxicity induced by drugs.Methods：A rat model of acute kidney injury was established by daily intraperitoneal injection of 60 or 120 mg·kg-1 gentamicin for consecutive 10 days.NGAL in urine from all groups were determined using ELISA and Luminex methods,and compared with traditional renal function markers.Results：Compared with the control group,the changes in kidney weight were found to be associated with the time and dosage of administration.Histopathological analysis demonstrated that the number of animals with tubular cell necrosis injury increased over time,and the severity of renal damage had been also aggravated,which were closely related to the treatment with gentamicin.Urinary biomarker analysis showed that the consistency of results was observed between ELISA and Luminex methods for detection of NGAL.On day 4,urine NGAL began to increase largely in animal from low- and high-dose groups.Obvious time-and dose-response were found since day 8.ROC analysis also proved that AUCs of NGAL were higher than that of Cr,suggesting that it was more sensitive and specific.Conclusion：NGAL could be applied as acandidate of nephrotoxicity biomarker for having showed good prospects in preclinical drug safety studies in rats.

关 键 词：庆大霉素 肾毒性 大鼠尿液 生物标记物 药物安全评价 中性粒细胞明胶酶相关载脂蛋白(NGAL) 药物毒性预测 ELISA法 Luminex液相芯片法 

分 类 号：R917[医药卫生—药物分析学]