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首页> 外文期刊>Journal of applied toxicology >In vitro gene expression analysis of nephrotoxic drugs in rat primary renal cortical tubular cells.
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In vitro gene expression analysis of nephrotoxic drugs in rat primary renal cortical tubular cells.

机译：肾毒性药物在大鼠原代肾皮质肾小管细胞中的体外基因表达分析。

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Rat primary renal cortical tubular cells were exposed to seven test substances, some with, and some without, known direct renal tubular cell toxicity. Cells were exposed to the substances at either one-third or one-tenth of the TC50 for cytotoxicity for 6 h or 24 h, so as not to induce cytotoxicity but to cause some transcriptional changes. Transcriptional profiles were investigated by using the Affymetrix Rat Toxicology U34 arrays, containing probes for more than 850 genes and ESTs. Four direct toxicants, cisplatin (CDDP), its less nephrotoxic analogue carboplatin (CBDCA), cephaloridine and gentamicin, were grouped together in a hierarchical clustering. In addition, the four direct toxicants affected more than 32 transcripts at their subcytotoxic concentrations at either 6 h or 24 h exposure. On the other hand, diclofenac, cyclosporine A and zinc, which are not considered to be directly toxic to tubules, affected less than 12 transcripts. Decreased Map3k12 and increased Hmox1 were commonly observed among the four direct toxicants, which appeared to be responses to cellular damage. Two platinum complexes, CDDP and CBDCA, induced similar changes, regardless of exposure duration or concentration. The types of transcriptional changes observed in this study were consistent with previously reported in vivo data, although there were some differences. These observations suggest that an in vitro gene expression analysis approach using GeneChip is feasible for screening for direct tubular toxicity of drugs and may help to clarify the underlying mechanisms of tubular toxicity.
机译：将大鼠原代肾皮质肾小管细胞暴露于7种受试物质，有些具有和不具有已知的直接肾小管直接毒性。将细胞暴露在TC50的三分之一或十分之一处的物质下，使其细胞毒性持续6 h或24 h，以便不诱导细胞毒性而是引起某些转录变化。通过使用Affymetrix大鼠毒理学U34阵列研究转录概况，该阵列包含超过850个基因和EST的探针。四种直接有毒物质顺铂（CDDP），其肾毒性较小的类似物卡铂（CBDCA），头孢啶和庆大霉素归类在一起。此外，在暴露6h或24h时，四种直接毒物的亚细胞毒性浓度会影响32种以上的转录本。另一方面，双氯芬酸，环孢素A和锌（被认为对肾小管无直接毒性）影响的转录物少于12个。通常在四种直接有毒物质中观察到Map3k12减少和Hmox1增加，这似乎是对细胞损伤的反应。无论暴露持续时间或浓度如何，两种铂络合物CDDP和CBDCA都会引起类似的变化。在这项研究中观察到的转录变化的类型与先前报道的体内数据一致，尽管存在一些差异。这些观察结果表明，使用GeneChip进行体外基因表达分析的方法可用于筛选药物的直接肾小管毒性，并且可能有助于阐明肾小管毒性的潜在机制。

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