庆大霉素致大鼠急性肾损伤的尿液生物标志物  

Urine biomarkers after acute kidney injury in rats induced by gentamycin

作　　者：邱云良 洪敏 富欣 黄欢夏 马璟 

机构地区：[1]国家上海新药安全评价研究中心,上海201203

出　　处：《中国药理学与毒理学杂志》2014年第2期248-254,共7页Chinese Journal of Pharmacology and Toxicology

基　　金：国家科技重大专项(2012ZX09302002);国家科技重大专项(2012ZX09505-001-003)~~

摘　　要：目的探讨大鼠急性肾损伤后尿液新生物标志物时间和剂量依懒性,以寻找敏感和特异的新生物标志物。方法 SD大鼠分别im给予硫酸庆大霉素注射液0,5,20和80 mg·kg-1,每天1次,按照给药次数又分为给药1,3,7,14 d和给药14 d恢复期28 d亚组,共计20组,给药后24 h,取血检测尿素氮(BUN)和肌酐(CRE),取尿用干化学法检测尿蛋白,用酶联免疫法(ELISA)检测肾损伤分子-1(KIM-1)、用电化学发光免疫法检测β2微球蛋白(β2-MG);HE染色观察肾组织病理改变。结果尿蛋白结果显示,给予庆大霉素80 mg·kg-17和14 d,个别雌性大鼠可见尿蛋白明显阳性(3+),恢复期末有明显恢复趋势。给药80 mg·kg-17 d组雌性大鼠BUN和CRE明显升高(P<0.05),雄性大鼠CRE升高(P<0.05),BUN有升高趋势;给药80 mg·kg-114 d组雌雄大鼠BUN和CRE均明显升高(P<0.05),20 mg·kg-1组雌性大鼠CRE升高(P<0.05),恢复期末,雌雄大鼠BUN和CRE恢复正常。肾组织病理学结果显示,给药20和80 mg·kg-13 d组肾见局灶性肾小管扩张,给药20 mg·kg-17和14 d组肾见炎细胞浸润和局灶性肾小管扩张,给药80 mg·kg-17和14 d组肾见局灶性肾小管上皮细胞变性坏死、炎细胞浸润、局灶性管型(轻度),给药80 mg·kg-1恢复期28 d组肾见嗜碱性小管、肾小管管型。给药20和80 mg·kg-13,7和14 d组雌雄大鼠KIM-1明显升高(P<0.05),给药80 mg·kg-1恢复期28 d组雌雄大鼠和给药20 mg·kg-1的雄性大鼠KIM-1明显升高(P<0.05),但有恢复趋势;给药80 mg·kg-13 d组雌雄大鼠β2-MG明显升高(P<0.05),给药20和80 mg·kg-17和14 d组雌雄大鼠β2-MG明显升高(P<0.05或P<0.01),给药80 mg·kg-1雌雄大鼠和给药20 mg·kg-1的雌性大鼠恢复期28 d组β2-MG明显升高(P<0.05),但也有恢复趋势。结论与传统的各项检测指标相比,KIM-1和β2-MG在庆大霉素诱导的急性肾损伤模型中具有较好的敏感性和特异性。OBJECTIVE To investigate the time and dose relation of new urine bio markers in rat model of acute kidney injury induced by genta mycin （GM）to search for more sensitive,noninvasive and specific markers than traditional approaches to monitor nephrotoxicity.METHODS SD Rats were im treated with GM5,20,80 mg·kg -1 or saline once daily.Rats were randomly divided into 20 subgroups：treated for 1 ,3,7,14 d and 14 d followed with 28 d recovery period.Ten rats per group （5 rats per sex）were scarified at 24 h after the last dosing or the end of recovery period.Blood sa mples were col-lected for blood urea nitrogen （BUN）and creatinine（CRE）analysis.Urine was collected at each nec-ropsy for urine protein by dry che mistry method,for kidney injury molecule-1 （KIM-1 ）analysis by ELISA, and for β2-microglobulin （β2-MG）analysis by ELISA.Kidneys were obtained for histological exa mination after HE stains.RESULTS Positive protein（3 ＋）was noted for several fe male animals treated for 7 or 14 d at 80 mg·kg -1 and the tendency of recovery were noted at the end of recovery period.Co mpared with those in saline control group treated for 7 d,the seru m BUN and CRE levels for fe males and the CRE level for males were significantly increased at 80 mg·kg -1 （P 〈0.05）,and the BUN level showed the tendency of increase for males at 80 mg·kg -1 （P ＆gt;0.05）.When treated for 14 d,the seru m BUN and CRE levels for fe males and males at 80 mg·kg -1 and the seru m CRE level for fe males at 20 mg·kg -1 were significantly increased when compared with those in saline control group（P 〈0.05）. The seru m BUN and CRE recovered to base line for all animals treated for 14 d followed by a 28 d recov-ery period.Histopathological observation of kidney tissues indicated that focal tubule dilatation was noted for animals treated for 3 d at 20 and 80 mg·kg -1 ,infla mmatory cell infiltration and focal tubule dilatation were noted at 20 mg·kg -1 and focal renal tubular epithelial cell degeneration,infla mm

关 键 词：肾毒性 肾损伤分子-1 Β2微球蛋白 

分 类 号：R595.3[医药卫生—内科学]