Quantitative gene expression analysis in a nonhuman primate model of antibiotic-induced nephrotoxicity
Quantitative gene expression analysis in a nonhuman primate model of antibiotic-induced nephrotoxicity
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DOI：
10.1016/j.taap.2004.02.001
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发表时间：
2004-10-01
影响因子：
3.8
通讯作者：
Rosenblum, IY
中科院分区：
文献类型：
--
作者：
Davis, JW;Goodsaid, FM;Rosenblum, IY
已经描述了使用微阵列的啮齿动物模型的肾毒性的基因表达模式。为了确定先前确定的显著基因表达变化是否适用于多个物种，我们研究了暴露于两种肾毒物后雌性食蟹猴肾脏中的定量基因表达变化。动物接受氨基糖苷类庆大霉素（10 mg/kg）、实验寡糖抗生素依维诺霉素（30或60 mg/kg）或庆大霉素（10 mg/kg）和依维诺霉素（30 mg/kg）联合给药7天。接受这些药物联合给药的猴早在第1天就出现肾脏病变。到第7天，仅给予60 mg/kg依维诺霉素的猴也出现了肾脏病变，而暴露于两种化合物的组出现了更广泛的肾脏损伤。使用定量实时PCR证实了先前报道的与啮齿动物模型中的肾毒性相关的几个基因的调节。其中，waf-1，基质金属蛋白酶9和波形蛋白的变化与毒性的基因组指标的定义一致。此外，我们确定了三个早期基因生物标志物，可能是预测药物诱导的肾毒性：丛生蛋白，骨桥蛋白，甲型肝炎病毒细胞受体-L逻辑回归表明基因表达的变化和组织病理学病变的发展的概率之间的高度相关性。这些结果首次证实了非人灵长类动物模型中与肾毒性相关的啮齿类动物基因表达变化，并为识别预测食蟹猴中药物诱导的肾小管损伤发作的早期基因表达变化提供了初步证据。(C)2004年由Elsevier Inc.出版
Gene expression patterns using microarrays have been described for rodent models of nephrotoxicity. To determine if significant gene expression changes previously identified have application across multiple species, we studied quantitative gene expression changes in the kidneys of female cynomolgus monkeys after exposure to two nephrotoxicants. Animals were dosed with the aminoglycoside gentamicin (10 mg/kg), the experimental oligosaccharide antibiotic everninomicin (30 or 60 mg/kg), or a combination of gentamicin (10 mg/kg) and everninomicin (30 mg/kg) for 7 days. Monkeys receiving these drugs in combination developed renal lesions as early as Day 1. By Day 7, monkeys dosed with 60 mg/kg everninomicin alone also developed renal lesions, while the group exposed to both compounds had more extensive renal damage. The modulation of several genes previously reported to be associated with nephrotoxicity in rodent models was confirmed using quantitative real-time PCR. Among these, waf-1, matrix metalloproteinase-9, and vimentin exhibited changes consistent with the definition of a genomic indicator of toxicity. In addition, we identified three early gene biomarkers that may be predictive of drug-induced nephrotoxicity: clusterin, osteopontin, and hepatitis A virus cellular receptor-L Logistic regression demonstrated a high degree of correlation between changes in gene expression and the probability of the development of histopathologic lesions. These results are the first confirming rodent gene expression changes associated with nephrotoxicity in a nonhuman primate model and provide preliminary evidence for identifying early gene expression changes predicting the onset of drug-induced renal tubular damage in cynomolgus monkeys. (C) 2004 Published by Elsevier Inc.