Pu Xue-Yan, Shen Jia-Ying, Deng Zhong-Ping, Zhang Ze-An
Center for Drug Safety Evaluation and Research, Shanghai University of Traditional Chinese Medicine, Room 1403, No. 1 Building, 1200 Cai Lun Road, Zhangjiang, Pudong, Shanghai, 201203, People's Republic of China.
Arch Toxicol. 2017 Mar;91(3):1473-1483. doi: 10.1007/s00204-016-1791-y. Epub 2016 Jul 15.
Aristolochic acid I (AAI) derived from a natural herbal alkaloid is a nephrotoxicant. AAI-induced acute kidney injury (AKI), a devastating clinical disease associated with high mortality rates, is difficult for early diagnosis. To address this issue, we identified and validated early-detection biomarkers for AAI-induced acute kidney injury via profiling microRNA expression in rats. Global miRNA expression profile analysis found that 21 miRNAs were significantly dysregulated in kidney of rats treated by 40 mg/kg AAI on day 2, day 4, or day 6, among which 5 miRNAs were upregulated at all three time points. Quantitative RT-PCR confirmed that miR-21-3p on day 4 and day 6 was obviously upregulated in kidney of rats treated by 40 mg/kg AAI. Further examination found that miR-21-3p was increased in plasma early on day 2 in 10 mg/kg AAI-treated rats, but not in non-target organs. Importantly, the elevation of plasma miR-21-3p preceded the increase in blood urea nitrogen and creatinine, and the presence of renal tubular injury, characterized by differential increase before and after the presence of renal tubular lesions. Our findings thus show that miRNA expression is upregulated in kidney and plasma of AKI rat induced by AAI, and plasma miR-21-3p may be served as a new potential biomarker for early diagnosing AAI-induced acute kidney injury in rats, and possibly in humans.
源自天然草药生物碱的马兜铃酸 I（AAI）是一种肾毒性物质。AAI 诱导的急性肾损伤（AKI）是一种死亡率高的严重临床疾病，早期诊断困难。为解决这一问题，我们通过分析大鼠体内微小 RNA（miRNA）的表达，鉴定并验证了 AAI 诱导急性肾损伤的早期检测生物标志物。全球 miRNA 表达谱分析发现，在第 2 天、第 4 天或第 6 天用 40 mg/kg AAI 处理的大鼠肾脏中，有 21 种 miRNA 显著失调，其中 5 种 miRNA 在所有三个时间点均上调。定量逆转录聚合酶链反应（qRT-PCR）证实，在第 4 天和第 6 天，40 mg/kg AAI 处理的大鼠肾脏中 miR-21-3p 明显上调。进一步检查发现，在第 2 天早期，10 mg/kg AAI 处理的大鼠血浆中 miR-21-3p 增加，但在非靶器官中未增加。重要的是，血浆 miR-21-3p 的升高先于血尿素氮和肌酐的增加以及肾小管损伤的出现，其特征是在肾小管病变出现前后有差异增加。因此，我们的研究结果表明，AAI 诱导的 AKI 大鼠肾脏和血浆中 miRNA 表达上调，血浆 miR-21-3p 可能作为一种新的潜在生物标志物，用于早期诊断大鼠以及可能在人类中由 AAI 诱导的急性肾损伤。
