肾损伤分子-1、丛生蛋白和胱抑素C对庆大霉素诱导的大鼠肾损伤早期预测的研究

目的应用庆大霉素(GM)诱导的大鼠亚急性肾损伤模型,研究一组新的生物标志物肾损伤分子-1(kidneyinjury molecule-1,Kim-1)、丛生蛋白(clusterin)和胱抑素C(cystatinC)在尿液中的变化,并与传统生物标志物血肌酐(SCr)和尿素氮(BUN)进行比较,评价其对肾损伤的早期预测性。方法建立GM诱导的大鼠亚急性肾损伤动物模型,检测不同给药时间点模型组和对照组大鼠的SCr、BUN和尿Kim-1、clusterin与cystatinC水平,并进行肾组织病理学检查。结果在SCr、BUN和肾组织病理学未出现异常变化时,大鼠尿Kim-1、clusterin、cystatinC就表现出明显的升高,并随给药时间延长呈线性升高。在SCr、BUN和尿Kim-1、clusterin和cystatinC测定结果的ROC曲线中,尿Kim-1、clusterin和cystatinC的曲线下面积均大于0.9。结论尿Kim-1、clusterin和cystatinC在肾损伤中具有良好的敏感性和特异性,能够提高对药物诱导的肾损伤的早期预测能力。     

尿液新型生物标志物对顺铂诱导大鼠急性肾早期损伤的诊断效能研究

目的 在顺铂诱导的大鼠急性肾损伤模型中,系统评价短时间采尿下系列尿液肾毒性生物标志的诊断性能。方法 Wistar大鼠单次ip 6 mg·kg^-1顺铂构建急性肾损伤模型,在检疫期、给药后第3和6天分别收集给药后5 h对照组和顺铂组动物尿液和血样,使用日立7180全自动生化仪测定血清中丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、总胆红素(TBIL)、尿素氮(BUN)、肌酐(CRE)以及尿液样本中尿葡萄糖苷酶(NAG)、尿总蛋白(uTP)、尿肌酐(uCr)水平;使用Luminex仪器测定尿液中丛生蛋白(CLU)、谷胱甘肽S转移酶-α(GST-α)、干扰素诱导蛋白-10(IP-10)、肾损伤因子-1(KIM-1)、骨桥蛋白(OPN)、组织金属蛋白酶抑制剂-1(TIMP-1)、血管内皮生长因子-A(VEGF-A)、酸性糖蛋白(AGP)、白蛋白(Alb)、β₂微球蛋白(β₂M)、半胱氨酸蛋白酶抑制剂C(CysC)、表皮生长因子(EGF)、中性粒细胞明胶酶相关脂质运载蛋白(NGAL)水平。结合动物肾脏组织病理学检查,制作受试者操作特性曲线(ROC)进行肾毒性标志物的灵敏度和特异性分析。结果 顺铂组动物AST、ALT、TBIL值与各自对照组比较无统计学差异,且解剖大体检查并未发现除肾脏以外其他组织器官病变,排除其他组织器官病变对肾生物标志物变化的影响。组织病理学结果证实顺铂诱导动物模型均出现典型急性肾损伤:外髓质外带肾小管上皮细胞变性/坏死和髓质蛋白管型等。与对照组比较,传统标志物血清BUN和CRE在顺铂给药第6天、动物严重肾损伤时才出现显著升高(P<0.05);而IP-10、KIM-1、Alb、β2M和CLU生物标志物则在给药第3天已出现显著增加(P<0.05),且持续升高,增幅明显高于传统指标。ROC分析结果表明,IP-10、CysC、KIM-1和Alb的曲线下面积(AUC)明显优于BUN和CRE,具有更高的灵敏度和特异性。结论 尿液IP-10、CysC、KIM-1和Alb的肾毒性诊断性能优于传统生物标志物BUN和CRE,建议可作为药物致急性肾毒性早期诊断的生物标志物。     

不同产地冬虫夏草对硫酸庆大霉素致急性肾损伤的保护作用

摘 要 目的： 考察西藏、青海两个不同产地冬虫夏草对硫酸庆大霉素所致大鼠急性肾损伤的保护作用。方法: 建立硫酸庆大霉素诱导的大鼠急性肾损伤模型,检测各组大鼠血清尿素氮（BUN）、肌酐(Cr)以及24 h尿液中N-乙酰-β-D-葡萄糖苷酶（NAG）、尿总蛋白等各项生化指标,HE染色观察各组大鼠肾脏组织病理学变化情况。结果: 与模型组相比,两个产地三个剂量组的血清Cr、BUN和尿液中NAG酶、总蛋白含量均显著下降（P ＜0.05）,肾组织细胞坏死情况也有所改善,但两个不同产地间的差异并不显著（P ＞0.05）。结论:青海和西藏两个产地冬虫夏草对硫酸庆大霉素引起的急性肾损伤都有一定的保护作用,但两者的作用效果相当,没有明显差异。     

预测庆大霉素、多柔比星和腺嘌呤致大鼠肾损伤的生物标志物

目的评价肾损伤尿液生物标志物对于不同药物诱导的大鼠肾损伤的早期诊断的应用价值。方法 1 SD大鼠分别ip给予硫酸庆大霉素30,100和200 mg·kg-1,每天1次,给药14 d,以给药当天为第1天(d 1),分别于d 4,d 7,d 10和d 15给药前采集动物尿液及全血;2 SD大鼠一次性分别iv给予多柔比星3,6和9 mg·kg-1,于药后d 4,d 7,d 10和d 15采集动物尿液及全血;3 SD大鼠分别ig给予腺嘌呤30和60 mg·kg-1,每天1次,给药10 d,于d 4,d 7和d 11给药前采集大鼠尿液及全血;检测动物尿液中肾损伤分子1(Kim-1)、丛生蛋白(Clu)、胱抑素C(Cys C)、β2微球蛋白(β2-MG)以及血清中肌酐(Cre)和尿素氮(BUN)的水平。HE染色观察各时间点肾组织病理变化。结果 1硫酸庆大霉素30 mg·kg-1组于d 10,100和200 mg·kg-1组于d 7可见肾间充质炎细胞浸润,肾小管扩张,近曲小管上皮细胞变性坏死,蛋白管型。30 mg·kg-1组Kim-1和Cys C于d 4,β2-MG于d 7开始升高(P<0.05),Cre和BUN无明显变化;100 mg·kg-1组Clu,Cys C和β2-MG于d 4开始升高(P<0.05),BUN于d 10开始升高(P<0.05),Cre无明显变化;200 mg·kg-1组Kim-1,Clu,Cys C和β2-MG于d 4开始升高(P<0.05),Cre于d 4、BUN于d 7开始升高(P<0.05)。2多柔比星6和9 mg·kg-1组d 15可见肾小管上皮细胞玻璃滴样变性,蛋白管型,肾小管扩张。6 mg·kg-1组Clu,Cys C,β2-MG于15 d开始升高(P<0.05),Cre和BUN无明显变化;9 mg·kg-1组β2-MG于d 10开始升高(P<0.05),Kim-1,Clu和Cys C于d 15开始升高(P<0.05),BUN于d 15开始升高(P<0.05),Cre无明显变化(P>0.05)。3腺嘌呤30 mg·kg-1组于d 11,60 mg·kg-1组d 4可见肾小管上皮细胞变性、肾小管扩张。30 mg·kg-1组Kim-1于d 4开始升高(P<0.05),Clu和Cys C于d 7,β2-MG于d 11开始降低(P<0.05),Cre和BUN无明显变化;60 mg·kg-1组Kim-1于d 4开始升高(P<0.05),Clu和Cys C于d 7,β2-MG于d 11开始降低(P<0.05),Cre和BUN于d 4开始升高(P<0.05)。各标志物ROC曲线下面积(AUC)两两比较结果显示,硫酸庆大霉素组Kim-1和Clu的AUC高于BUN;多柔比星组Cys C高于BUN,Clu的AUC高于Cre;腺嘌呤组Clu的AUC高于BUN,均具有统计学意义(P<0.05)。结论在硫酸庆大霉素及多柔比星损伤模型中,β2-MG出现变化较早,且在不同药物不同剂量下变化较为稳定,具有一定肾损伤早期预测的能力。Clu在3种肾损伤模型中均表现出了良好的预测能力,可作为肾损伤标志物应用于药物肾毒性的评价。     

转化生长因子-β1/Smad信号转导途径在大黄酸保护糖尿病大鼠肾脏中的机制探讨

目的 研究大黄酸对高脂饮食诱导的2型糖尿病大鼠肾脏的保护作用。方法 采用高脂饮食联合小剂量链脲佐菌素（STZ）35 mg/kg诱导2型糖尿病大鼠模型,分为模型组,大黄酸低、中、高剂量（50、100、150 mg/kg）组,二甲双胍（300 mg/kg）组,另设正常对照组。分别于0、2、4、8周测定大鼠血糖、尿微量白蛋白;8周末检测大鼠血清肌酐（Cr）、尿素氮（BUN）、总胆固醇（TC）与三酰甘油（TG）水平;HE染色观察肾脏组织病理;蛋白印记法检测大黄酸对糖尿病大鼠肾组织转化生长因子-β₁（TGF-β₁）与Smad3蛋白表达的影响。结果 模型组大鼠血糖及尿微量白蛋白较正常对照组均明显升高,大黄酸各剂量组均能降低糖尿病大鼠血糖及尿微量白蛋白水平,其中,大黄酸高剂量组能显著降低糖尿病大鼠血糖及尿微量白蛋白水平（P<0.05）;与模型组相比,大黄酸各剂量组可降低大鼠血清Cr、BUN、TC与TG值,但是大黄酸高剂量组能显著降低糖尿病大鼠血清Cr、BUN、TC与TG值（P<0.05）;病理学观察显示模型组大鼠肾组织病变较为明显,大黄酸高剂量组肾组织病变明显改善,且糖尿病大鼠肾组织TGF-β₁与Smad3蛋白表达显著下降（P<0.05）。结论 大黄酸对糖尿病肾病有预防作用,其机制可能与改善肾功能、调节血脂及下调肾组织TGF-β₁与Smad3蛋白的表达有关。     

肾毒性小分子代谢标志物在5种中药毒性评价的适用性研究

目的考察前期发现的肾毒性小分子代谢标志物在中药毒性评价中的适用性。方法以已知具有肾毒性的5种中药雷公藤、马钱子、广防己、大黄和苍耳子提取液ig给予大鼠建立肾脏损伤模型,收集给药1和7 d后的血样,应用超高效液相色谱-质谱联用（UPLC/Q-TOF-MS）检测5种肾毒性生物标志物胸苷、溶血磷脂酰胆碱LPC（16：1）、LPC（18：4）、LPC（20：5）和LPC（22：5）水平,建立支持向量机（SVM）预测模型对其毒性进行判断;全自动生化仪测定血清中Cr和BUN的水平;各组大鼠于取血后处死,迅速取肾脏进行HE染色,光学显微镜下观察病理表现。结果对照组没有表现出毒性。5种中药在给药1 d后,生化检测没有发现肾脏损伤,肾毒性支持向量机预测模型发现异常;在给药7天后,SVM的预测结果与生化和病理检测结果一致,均出现肾毒性。结论代谢组学技术结合支持向量机模型可将肾毒性小分子代谢物更加灵敏、快速、准确地用于中药肾脏毒性评价,对于临床药源性肾损伤的防治具有重要意义。     

罗沙司他抑制HIF-1α/Notch-1信号通路缓解单侧输尿管梗阻大鼠肾间质纤维化的研究

目的 研究罗沙司他(roxadustat,ROX)改善单侧输尿管梗阻(unilateral ureteral obstruction,UUO)大鼠肾间质纤维化(renal interstitial fibrosis,RIF)的机制。方法 48只♂SD大鼠随机分为假手术组、UUO组、UUO+ROX (25,50 mg·kg^-1)剂量组,每组12只。左侧输尿管结扎制备RIF大鼠模型,造模后第3天开始每天灌胃给药,连续给药21 d。测定大鼠血肌酐(Scr)、血尿素氮(BUN)水平;HE染色、Masson染色观察肾组织病理变化及胶原沉积情况;免疫组化法检测肾组织转化生长因子-β1(TGF-β1)表达情况。体外培养近曲小管上皮细胞,分为对照组、TGF-β1(5 ng·mL^-1)组、TGF-β1+二甲基亚砜(DMSO)组和TGF-β1+ROX (10,20,40 μmol·L^-1)组,细胞先用ROX或DMSO预处理2 h,再用TGF-β1(5 ng·mL-1)处理48 h。Western blotting检测肾组织和细胞内I型胶原(collagen Ⅰ)、Ⅲ型胶原(collagen Ⅲ)、E-钙黏蛋白(E-Cadherin)、纤维连接蛋白(Fibronectin)、α-平滑肌肌动蛋白(α-SMA)、波形蛋白(Vimentin)、低氧诱导因子1α(HIF-1α)、Notch-1、Notch-1胞内域(NICD)和Hes1的表达。结果 动物实验结果显示,与UUO组相比,ROX给药组大鼠Scr和BUN水平明显降低,肾组织胶原沉积明显减少,collagen Ⅰ和collagen Ⅲ的蛋白表达明显降低,RIF程度明显减轻;肾组织上皮细胞标志物E-Cadherin的表达明显升高而间质细胞标志物Fibronectin、α-SMA和Vimentin明显降低(P<0.05或P<0.01);同时肾组织HIF-1α、Notch-1、NICD和Hes1的表达明显下调(P<0.05或P<0.01)。细胞实验结果表明,与TGF-β1组相比,不同剂量ROX均能明显降低HIF-1α、Notch-1、NICD和Hes1的表达;显著上调E-Cadherin的表达,明显下调Fibronectin、α-SMA和Vimentin的表达(P<0.05或P<0.01)。结论 本研究结果提示ROX可减轻UUO大鼠RIF,其作用机制可能与抑制HIF-1α/Notch-1信号通路、逆转肾小管上皮细胞上皮-间质转分化有关。     

利用1H-NMR技术研究大黄素染毒后大鼠内源性代谢物的改变

目的 采用¹H NMR的代谢组学技术揭示大黄素的肾毒性机制,寻找肾脏损害的早期生物标志物.方法 雄性SD大鼠20只,随机分为溶剂对照,大黄素170、500、1 500 mg/(kg·d)3个剂量组,连续给药16 d,给药结束后收集24 h尿液,血浆及肾组织,测定¹H NMR谱,并进行血浆生化指标测定和肝脏组织病理学检查.结果 1 500 mg/(kg·d)大黄素服用16 d可引起大鼠血肌酐下降,大黄素可导致肾细胞胞浆中出现明显的空泡化改变.代谢成分的改变主要表现为血液中乳酸、糖、氨基酸和脂肪酸成分下降;尿液中乳酸、糖和氨基酸成分增加;肾脏组织中醋酸盐和肌酐/肌酸明显升高,乳酸和胆碱/磷酸卵磷脂水平下降,饱和与不饱和脂肪酸及磷脂的成分比例明显改变.结论 代谢组学分析在识别药物诱导代谢成分改变方面较传统技术更灵敏;脂肪和能量代谢紊乱参与了大黄素的肾毒性,尿液中氨基酸、葡萄糖氧化三甲胺(TMAO)及肌酐可作为大黄素诱导肾组织损害的潜在生物标志物.     

化学药物诱导的大鼠急性肾损伤模型中肾损伤分子-1表达的研究

目的：观察肾损伤分子-1(kidney injury molecule-1,Kim-l)在由顺铂、庆大霉素、环孢素诱导大鼠急性肾损伤(acute kidneyinjury,AKI)模型肾组织内的变化,探讨其与AKI之间的相关性。 方法：建立庆大霉素、顺铂、环孢素诱导大鼠AKI模型,运用实时荧光定量PCR法检测肾Kim-1基因表达水平,Western blot法检测肾脏Kim-1蛋白表达水平,分析肾Kim-1表达水平与急性肾损伤的相关性。结果：病理学检查发现顺铂、庆大和环孢素对大鼠肾脏造成不同程度的肾小管损伤,所建AKI模型成功。各模型组与对应对照组比较,肾Kim-l mRNA水平均高于阴性对照组,差异具有统计学意义（P 均＜0.05）;肾Kim-l蛋白在各阴性对照组内呈阴性结果,而在顺铂、庆大和环孢素AKI模型组内均呈阳性表达。结论：化学药物诱导AKI发生时,肾Kim-1基因转录和蛋白表达水平与肾损伤直接相关,为以尿Kim-1作为预测早期肾损伤的生物标志物提供可靠依据。     

尿中肾损伤分子1水平升高对大鼠早期肾损伤的预测作用

目的评价尿中肾损伤分子1(KIM-1)对大鼠早期肾损伤的预测作用。方法制备顺铂、庆大霉素和环孢素诱导的大鼠肾损伤模型。顺铂模型大鼠于单次ip给药后第3,5,6和7天,庆大霉素模型于首次ip给药后第3,7,10和13天,环孢素模型于首次ig给药后第8,15,36和53天通过腹主动脉取血,分离血清。各组大鼠于处死前24 h收集尿液。用自动生化仪检测血清肌酐(SCr)和血尿素氮(BUN)及尿肌酐(UCr)水平,采用ELISA法检测尿KIM-1水平,HE染色进行肾脏组织病理学检查。结果与正常对照组相比,顺铂模型大鼠单次给药后第3天肾组织病理改变不明显,而尿KIM-1升高了4.7倍,SCr和BUN升高了0.3和0.7倍;第5和6天,KIM-1升高了10.0和8.7倍,SCr升高了1.9和3.3倍,BUN升高了3.0和5.1倍,第5天肾组织出现明显的病理改变;第7天,KIM-1水平升高了16.5倍,SCr和BUN水平略降,为正常对照组的1.2和3.0倍。庆大霉素模型大鼠,与正常对照组比较,于首次给药后第7天,SCr和BUN水平和肾组织未见明显改变,KIM-1水平升高了2.6倍;第10和13天,SCr水平升高了1.7和1.6倍,BUN升高了2.0和1.9倍,KIM-1升高了12.5和33.9倍,第10天肾组织出现明显的病理改变。环孢素模型大鼠,与正常对照组比较,在第8天,SCr和BUN水平和肾组织未见异常,KIM-1升高了正常对照组的0.6倍;第15,36和53天,KIM-1分别升高了1.7,4.3和9.3倍,SCr分别为1.0,1.0和1.2倍,BUN分别升高了0.4,0.6和1.2倍,肾组织在第53天时出现明显的病理改变。顺铂模型组SCr,BUN和KIM-1的受试者操作特性曲线的曲线下面积(AUC)分别为0.934,0.953和0.979,庆大霉素模型组SCr,BUN和KIM-1的AUC分别为0.877,0.713和0.932,环孢素模型组SCr,BUN和KIM-1的AUC分别为0.668,0.766和0.976。结论在顺铂、庆大霉素和环孢素诱导的肾损伤模型中,尿KIM-1可用于早期肾损伤的预测。     

Comparison of kidney injury molecule-1 and other nephrotoxicity biomarkers in urine and kidney following acute exposure to gentamicin, mercury, and chromium.

Sensitive biomarkers are needed to detect kidney injury at the earliest stages. The objective of this study was to determine whether the appearance of kidney injury molecule-1 (Kim-1) protein ectodomain in urine and kidney injury molecule-1/hepatitis A viral cellular receptor-1 (Kim-1/Havcr1) gene expression in kidney tissue may be more predictive of renal injury after exposure to nephrotoxicants when compared to traditionally used biomarkers. Male Sprague-Dawley rats were injected with a range of doses of gentamicin, mercury (Hg; HgCl2), or chromium (Cr; K2Cr2O7). The results showed that increases in urinary Kim-1 and kidney Kim-1/Havcr1 gene expression paralleled the degree of severity of renal histopathology and were detected at lower doses of nephrotoxicants when compared to blood urea nitrogen (BUN), serum creatinine, and urinary N-acetyl-beta-D-glucosaminidase (NAG). In a time course study, urinary Kim-1 was elevated within 24 h after exposure to gentamicin (100 mg/kg), Hg (0.25 mg/kg), or Cr (5 mg/kg) and remained elevated through 72 h. NAG responses were nephrotoxicant dependent with elevations occurring early (gentamicin), late (Cr), or no change (Hg). At 72 h, after treatment with any of the three nephrotoxicants, there was increased Kim-1 immunoreactivity and necrosis involving approximately 50% of the proximal tubules; however, only urinary Kim-1 was significantly increased, while BUN, serum creatinine, and NAG were not different from controls. In rats treated with the hepatotoxicant galactosamine (1.1 mg/kg), serum alanine aminotransferase was increased, but no increase in urinary Kim-1 was observed. Urinary Kim-1 and kidney Kim-1/Havcr1 expression appear to be sensitive and tissue-specific biomarkers that will improve detection of early acute kidney injury following exposure to nephrotoxic chemicals and drugs.     

浅谈中药的临床合理应用

目前全球范围内不合理用药现象都很严重.我国的药品不良反应中有10％～30％是源于不合理用药引起的,可见合理用药以保证患者用药安全是医药工作者的职责,也是亟待解决的问题.从中药的临床应用各环节入手,涉及辨明品种、选择适当的炮制品、严格遵循用药剂量、煎煮方法和服用方法要适宜、中西药配伍要得当以及中药师调配和发药要细心等方面...     

The utility of a rodent model in detecting pediatric drug-induced nephrotoxicity.

A multi-age rat model was used to identify potential age-related differences in renal injury following exposure to gentamicin (GM). In this study, 10-, 25-, 40-, and 80-day-old Sprague-Dawley rats were dosed with GM at 0, 50, or 100 mg kg(-1) body weight per day (mkd) sc for 6 or 14 days. Urine samples were collected up to 72 h after initial dosing. The maximum tolerated dose was lower in 10-day-old rats than for other ages (none survived 11 days of treatment). Eighty-day-old rats given the highest dose showed a diminished rate of growth and an increase in serum creatinine, blood urea nitrogen (BUN), urinary kidney injury molecule-1 (Kim-1), and renal pathology. Ten- and 40-day-old rats given 100 mkd of GM for 6- or 14 days also had increased levels of serum BUN and Cr and renal pathology, whereas only mild renal alterations were found in 25-day-old rats. After 6 days of treatment with 100 mkd GM, significant increases in Havcr-1 (Kim-1) gene expression were detected only in 10- and 80-day-old rats. In urine samples, nuclear magnetic resonance and ultra performance liquid chromatography/mass spectrometry analysis detected changes related to GM efficacy (e.g., hippurate) and increases in metabolites related to antioxidant activity, which was greatest in the 80-day-old rats. The magnitude of the genomic, metabonomic, and serum chemistry changes appeared to correlate with the degree of nephropathy. These findings indicate that an experimental animal model that includes several developmental stages can detect age-related differences in drug-induced organ toxicities and may be a useful predictor of pediatric drug safety in preclinical studies.     

六味地黄丸对顺铂诱导大鼠急性肾损伤的保护作用

目的评价六味地黄丸对顺铂诱导的大鼠肾脏损伤模型的保护作用及其作用机制。方法雄性Wistar大鼠随机分为对照组、模型组、六味地黄丸(0.54、1.08 g/kg)组。注射用顺铂7.5 mg/kg单次腹腔注射建立模型,六味地黄丸ig 10 d。采用肌氨酸氧化酶法检测各组血清中肌酐(Cr)、尿素氮(BUN)含量,采用WST-1法检测肾组织中超氧化物歧化酶(SOD),采用化学比色法检丙二醛(MDA)、谷胱甘肽过氧化物酶(GSH-Px)水平,采用ELISA方法检测肾损伤因子-1(Kim-1)浓度。检测肾组织中核转录因子E2相关因子2(Nrf2)、醌氧化还原酶1(NQO1)、血氧合酶1(HO-1)、Kelch样环氧氯丙烷相关蛋白1(Keap1)的m RNA相对表达量。结果六味地黄丸可减轻顺铂诱导的急性肾损伤大鼠肾小管损伤。六味地黄丸(0.54、1.08 g/kg)组肾脏系数显著低于模型组(P0.05)。予六味地黄丸后,Cr、BUN明显低于模型组(P0.05)。Kim-1值明显降低(P0.05);SOD、GSH-Px活力显著升高,MDA含量明显下降(P0.05);Nrf2、NQO1、HO-1的m RNA相对表达量高于模型组,Keap-1的m RNA表达受到抑制,表达量低于模型组(P0.05),且1.08 g/kg较0.54 g/kg差异更明显(P0.05)。结论六味地黄丸对顺铂诱导的大鼠急性肾损伤有显著的保护作用,其机制与激活Nrf2通路有关。     

Evaluation of Cadmium-Induced Nephrotoxicity Using Urinary Metabolomic Profiles in Sprague-Dawley Male Rats

The aim of this study was to investigate urinary metabolomic profiles associated with cadmium (Cd)-induced nephrotoxicity and their potential mechanisms. Metabolomic profiles were measured by high-resolution ¹H-nuclear magnetic resonance (NMR) spectroscopy in the urine of rats after oral exposure to CdCl₂ (1, 5, or 25 mg/kg) for 6 wk. The spectral data were further analyzed by a multivariate analysis to identify specific urinary metabolites. Urinary excretion levels of protein biomarkers were also measured and CdCl₂ accumulated dose-dependently in the kidney. High-dose (25 mg/kg) CdCl₂ exposure significantly increased serum blood urea nitrogen (BUN), but serum creatinine (sCr) levels were unchanged. High-dose CdCl₂ (25 mg/kg) exposure also significantly elevated protein-based urinary biomarkers including osteopontin, monocyte chemoattractant protein-1 (MCP-1), kidney injury molecules-1 (Kim-1), and selenium-binding protein 1 (SBP1) in rat urine. Under these conditions, six urinary metabolites (citrate, serine, 3-hydroxyisovalerate, 4-hydroxyphenyllactate, dimethylamine, and betaine) were involved in mitochondrial energy metabolism. In addition, a few number of amino acids such as glycine, glutamate, tyrosine, proline, or phenylalanine and carbohydrate (glucose) were altered in urine after CdCl₂ exposure. In particular, the metabolites involved in the glutathione biosynthesis pathway, including cysteine, serine, methionine, and glutamate, were markedly decreased compared to the control. Thus, these metabolites are potential biomarkers for detection of Cd-induced nephrotoxicity. Our results further indicate that redox metabolomics pathways may be associated with Cd-mediated chronic kidney injury. These findings provide a biochemical pathway for better understanding of cellular mechanism underlying Cd-induced renal injury in humans.     

补肾化浊胶囊对庆大霉素诱发大鼠急性肾损害作用的实验观察

目的 探讨补肾化浊胶囊对庆大霉素（GM）致大鼠肾脏损伤时肾功能变化以及血、尿中相关指标的影响.方法 给药21d后,采用大剂量注射GM致大鼠急性肾损伤模型,同时给予补肾化浊胶囊高、低剂量混悬液灌胃.治疗7 d,观察4组血肌酐（Cr）,尿素氮（BUN、总蛋白（TP）和白蛋白（ALB）的变化;另观察4组尿蛋白、葡萄糖、酮体的变化及肾组织的病理改变.结果 补肾化浊胶囊高、低剂量组血清中Cr、BUN、TP和ALB含量较模型组同指标比较差异有统计学意义（P〈0.05）;尿中尿蛋白、葡萄糖、酮体含量较模型组同指标比较差异有统计学意义（P〈0.05）.补肾化浊胶囊高、低剂量组的相同指标与对照组比较差异无统计学意义（P〉0.05）.结论 补肾化浊胶囊对GM诱发大鼠急性肾损伤有显著保护作用.     

Preclinical evaluation of novel urinary biomarkers of cadmium nephrotoxicity

As a result of the widespread use of Cd in industry and its extensive dissemination in the environment, there has been considerable interest in the identification of early biomarkers of Cd-induced kidney injury. Kim-1 is a transmembrane glycoprotein that is not detectable in normal kidney, but is up-regulated and shed into the urine following ischemic or nephrotoxic injury. Recent studies utilizing a sub-chronic model of Cd exposure in the rat have shown that Kim-1 is an early urinary marker of Cd-induced kidney injury. Kim-1 was detected in the urine 4-5 weeks before the onset of proteinuria and 1-3 weeks before the appearance of urinary metallothionein and Clara cell protein 16, which are standard markers of Cd nephrotoxicity. In the present study, we have compared the time course for the appearance of Kim-1 in the urine with the time course for the appearance of alpha glutathione-S-transferase (α-GST), N-acetyl-β-d-glucose amidase (NAG) and Cd, each of which have been used or proposed as urinary markers of Cd nephrotoxicity. Adult male Sprague-Dawley rats were given daily subcutaneous injections of 0.6 mg (5.36 μmoles)/kg Cd, 5 days per week for up to 12 weeks. One day each week, 24 h urine samples were collected and analyzed for protein, creatinine and the various markers. The results showed that significant levels of Kim-1 appeared in the urine as early as 6 weeks into the treatment protocol and then continued to rise for the remainder of the 12 week treatment period. By contrast, significant levels of α-GST and NAG did not appear in the urine until 8 and 12 weeks, respectively, while proteinuria was not evident until 10 weeks. The urinary excretion of Cd was below the level of detection until week 4 and then showed a slow, linear increase over the next 6 weeks before increasing markedly between weeks 10 and 12. These results provide additional evidence that Kim-1 is a sensitive biomarker of the early stages of Cd-induced proximal tubule injury.