Wang Er-Jia, Snyder Ronald D, Fielden Mark R, Smith Roger J, Gu Yi-Zhong
Department of Genetic and Molecular Toxicology, Drug Safety and Metabolism Division, Schering-Plough Corporation, Summit, NJ 07901, USA.
Toxicology. 2008 Apr 18;246(2-3):91-100. doi: 10.1016/j.tox.2007.12.031. Epub 2008 Jan 16.
Drug-induced renal injury is a common finding in the early preclinical phase of drug development. But the specific genes responding to renal injury remain poorly defined. Identification of drug-induced gene changes is critical to provide insights into molecular mechanisms and detection of renal damage. To identify genes associated with the development of drug-induced nephrotoxicity, a literature survey was conducted and a panel of 48 genes was selected based on gene expression changes in multiple published studies. Male Sprague-Dawley rats were dosed daily for 1, 3 or 5 days to the known nephrotoxicants gentamicin, bacitracin, vancomycin and cisplatin, or the known hepatotoxicants ketoconazole, 1-naphthyl isothiocyanate and 4,4-diaminodiphenylmethane. Histopathological evaluation and clinical chemistry revealed renal proximal tubular necrosis in rats treated with the nephrotoxicants, but not from those treated with the hepatotoxicants. RNA was extracted from the kidney, and RT-PCR was performed to evaluate expression profiles of the selected genes. Among the genes examined, 24 genes are confirmed to be highly induced or repressed in rats treated with nephrotoxicants; further investigation identified that 5 of the 24 genes were also altered by hepatotoxicants. These data led to the identification of a set of genomic biomarker candidates whose expression in kidney is selectively regulated only by nephrotoxicants. Among those genes displaying the highest expression changes specifically in nephrotoxicant-treated rats were kidney injury molecule 1 (Kim1), lipocalin 2 (Lcn2), and osteopontin (Spp1). The establishment of such a genomic marker set offers a new tool in our ongoing quest to monitor nephrotoxicity.
药物性肾损伤是药物研发临床前早期阶段的常见现象。但对肾损伤产生反应的具体基因仍不清楚。识别药物诱导的基因变化对于深入了解分子机制和检测肾损伤至关重要。为了识别与药物性肾毒性发展相关的基因，我们进行了文献调研，并根据多项已发表研究中的基因表达变化，挑选出了一个包含48个基因的基因组合。对雄性斯普拉格-道利大鼠每日给药1天、3天或5天，分别给予已知的肾毒性药物庆大霉素、杆菌肽、万古霉素和顺铂，或已知的肝毒性药物酮康唑、1-萘基异硫氰酸酯和4,4'-二氨基二苯甲烷。组织病理学评估和临床化学检测显示，接受肾毒性药物治疗的大鼠出现肾近端小管坏死，而接受肝毒性药物治疗的大鼠未出现。从肾脏提取RNA，并进行逆转录聚合酶链反应（RT-PCR）以评估所选基因的表达谱。在所检测的基因中，有24个基因在接受肾毒性药物治疗的大鼠中被证实受到高度诱导或抑制；进一步研究发现，这24个基因中有5个也受到肝毒性药物的影响。这些数据促成了一组基因组生物标志物候选物的识别，其在肾脏中的表达仅受肾毒性药物的选择性调控。在肾毒性药物治疗的大鼠中表达变化最大的基因包括肾损伤分子1（Kim1）、脂质运载蛋白2（Lcn2）和骨桥蛋白（Spp1）。建立这样一组基因组标志物为我们持续监测肾毒性提供了一种新工具。
