Drug Developmental Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
J Toxicol Sci. 2012;37(4):723-37. doi: 10.2131/jts.37.723.
The present study aimed to establish candidate biomarker genes for the early detection of nephrotoxicity in mice, with a particular focus on nephrotoxicity caused by polyene macrolides. Comprehensive gene expression changes were evaluated using microarrays in a mouse model in which acute nephrotoxicity was induced by amphotericin B deoxycholate, trade name Fungizone. The upregulated genes identified through microarray analysis of kidney tissue of Fungizone-treated mice included several genes that have been reported as nephrotoxicity biomarkers in rats, and 14 genes were selected as candidate nephrotoxicity biomarkers. The usefulness of these genes as nephrotoxicity biomarkers in mice was evaluated further through expression profiling under several experimental conditions using real time RT-PCR. Expression of genes encoding kidney injury molecule 1, lipocalin 2, tissue inhibitor of metalloproteinase 1, and secreted phosphoprotein 1 was highly upregulated by Fungizone, nystatin, natamycin, amphotericin B methyl ester, and liposomal amphotericin B, and their area under the ROC curve values were more than 0.95. These genes were more sensitive at detecting nephrotoxicity than traditional clinical chemistry and histopathology parameters. This study provides novel evidence that these nephrotoxicity biomarker genes identified are translatable to mice, and that they are useful for early and sensitive detection of nephrotoxicity.
本研究旨在建立用于早期检测小鼠肾毒性的候选生物标志物基因，特别是针对多烯类大环内酯类抗生素引起的肾毒性。使用微阵列评估了氟康唑（两性霉素 B 去氧胆酸盐，商品名 Fungizone）诱导的急性肾毒性小鼠模型中的综合基因表达变化。通过对 Fungizone 处理的小鼠肾脏组织的微阵列分析，确定了上调的基因，其中包括一些已被报道为大鼠肾毒性生物标志物的基因，并且选择了 14 个基因作为候选肾毒性生物标志物。通过实时 RT-PCR 在几种实验条件下进行的表达谱分析，进一步评估了这些基因作为小鼠肾毒性生物标志物的有用性。编码肾损伤分子 1、脂联素 2、金属蛋白酶组织抑制剂 1 和分泌型磷蛋白 1 的基因的表达被 Fungizone、制霉菌素、纳他霉素、两性霉素 B 甲酯和脂质体两性霉素 B 高度上调，其 ROC 曲线下面积值均大于 0.95。这些基因比传统的临床化学和组织病理学参数更敏感地检测到肾毒性。这项研究提供了新的证据，表明这些鉴定出的肾毒性生物标志物基因可转化为小鼠，并且可用于早期和敏感地检测肾毒性。
