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镉暴露致大鼠肾损伤的量效关系及其机制 被引量:16

Dose-dependent induction ofrenal injury by cadmium in rats
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摘要 目的:探讨不同剂量氯化镉(CdCl2)染毒对大鼠肾损伤的量效关系及其机制。方法:雄性SD大鼠40只,随机分为0、1、3和5 mg/kg CdCl2染毒组,每天灌胃1次。连续染毒4周后检测血清尿素氮(BUN)和肌酐(SCr)水平评价肾功能;HE染色观察肾脏病理损伤;透射电镜观察肾组织超微结构变化;DHE及MitoSOX荧光探针检测肾组织中活性氧(ROS)含量变化;免疫印迹检测SOD1、SOD2、GPx-1、CAT、Bax、Bcl-2以及GRP78蛋白的表达。结果:与对照组比较,镉暴露后大鼠体质量及肾体比差异无统计学意义(P〉0.05);随CdCl2剂量增加,血清BUN含量逐渐增加(r=0.463,P〈0.05);肾脏病理损伤进行性加重,出现肾小球肾小管肿胀,肾小管管2腔狭窄、上皮细胞坏死脱落堆积于管腔、管腔内可见管型,肾间质充血,炎细胞浸润;超微结构观察显示,肾小管上皮细胞线粒体损伤,肿胀、变形、空泡样变程度逐渐加重;肾组织中ROS含量逐渐增加;抗氧化酶SOD2、GPx-1和CAT表达逐渐增加(r依次为0.854、0.975、0.918,P均〈0.05),SOD1表达逐渐减少(r=-0.987,P〈0.05);肾脏组织促凋亡蛋白Bax表达在0-3 mg/kg CdCl2处理组逐渐增加(r=0.226,P〈0.05),抑凋亡蛋白Bcl-2表达逐渐减少(r=-0.85,P〈0.05),Bax/Bcl-2呈剂量依赖性升高(r=0.83,P〈0.05);同时,内质网应激标志蛋白GRP78的表达也随CdCl2剂量增加而升高(r=0.913,P〈0.05)。结论:不同剂量镉暴露致雄性SD大鼠肾脏损伤存在剂量效应关系,其作用机制可能是镉暴露导致氧化还原稳态失衡,从而引起氧化应激,进一步引起凋亡和组织损伤。 OBJECTIVE:This study was designed to investigate the dose-dependent relationship and the possible mechanisms of renal injury by cadmium in rats.METHODS:Forty male rats were randomly divided into four groups(0,1,3 and 5 mg/kg CdCl2) groups.The rats were intra-gastrically administrated CdCl2 daily to investigate the induction of renal injury.Blood urea nitrogen(BUN) and serum creatinine(SCr) were measured to evaluate renal function.Kidney tissues were stained with hematoxylin-eosin(HE) and observed for histopathological changes.Transmission electron microscopye was used to detect ultrastructural abnormalities.Levels of ROS in kidney was detected by DHE and MitoSOX staining.The levels of SOD1,SOD2,GPx-1,CAT,Bax,Bcl-2,GRP78 were measured by Western blotting.RESULTS:After exposure to CdCl2 for 4 weeks,the relative kidney weights showed no significant difference among the4 groups.As the dose of CdCl2 increased,the levels of BUN elevated gradually(r=0.463,P〈0.05).Pathological damages to kidneys were progressively aggravated.Swelling of glomerulus and renal tubule,and necrosis of tubular epithelial cells were observed under light microscopy.And it was also observed that the lumina of renal tubules contained necrotic epithelial cellular debris and casts.Interstitial hyperemia and inflammatory infiltration were found as well.The ultrastructure of mitochondria in the epithelium of proximal convoluted tubule showed swelling,deformation and vacuolation in a dose-dependent manner.The level of kidney ROS elevated gradually.Levels of SOD2,GPx-1 and CAT wereupregulated(r=0.854,0.975,0.918,P all0.05) while SOD1 were downregulated(r=-0.987,P〈0.05) as the dose of CdCl2 increased.Meanwhile,levels of the apoptosis-promoting Bax increased(r=0.226,P〈0.05) while the antiapoptotic Bcl-2 decreased(r=-0.85,P〈0.05) and the ratio of Bax/Bcl-2 increased(r=0.83,P〈0.05).The levels of GRP78 also increased when the dose of CdCl2 increased(r=0.913,P〈0.05).CONCLUSION:The results demonstrate that there was a dose-dependent toxic effect of CdCl2 on renal structure and function.Moreover,oxidative stress might be the key mechanism involved in the toxicity of cadmium because of increased antioxidase expression and levels of ROS.
出处 《癌变.畸变.突变》 CAS CSCD 2016年第6期446-452,共7页 Carcinogenesis,Teratogenesis & Mutagenesis
基金 国家自然科学基金(81473010) 陕西省自然科学基金(2016JM8024)
关键词 镉暴露 肾损伤 剂量效应关系 氧化应激 活性氧 cadmium exposure renal injury dose-dependent oxidative stress reactive oxygen species
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