Department of Chemistry, Tamkang University, Tamsui, New Taipei City, Taiwan.
Toxicol Appl Pharmacol. 2012 May 15;261(1):59-65. doi: 10.1016/j.taap.2012.03.011. Epub 2012 Mar 28.
Aristolochic acid (AA) is a component of Aristolochia plant extracts which is used as a treatment for different pathologies and their toxicological effects have not been sufficiently studied. The aim of this study was to evaluate AA-induced nephrotoxicity in zebrafish embryos. After soaking zebrafish embryos in AA, the embryos displayed malformed kidney phenotypes, such as curved, cystic pronephric tubes, pronephric ducts, and cases of atrophic glomeruli. The percentages of embryos with malformed kidney phenotypes increased as the exposure dosages of AA increased. Furthermore, AA-treated embryos exhibited significantly reduced glomerular filtration rates (GFRs) in comparison with mock-control littermates (mock-control: 100±2.24% vs. 10 ppm AA treatment for 3-5h: 71.48±18.84%~39.41±15.88%), indicating that AA treatment not only caused morphological kidney changes but also induced renal failure. In addition to kidney malformations, AA-treated zebrafish embryos also exhibited deformed hearts, swollen pericardiums, impaired blood circulation and the accumulation(s) of red blood cells. Whole-mount in situ hybridization studies using cmlc2 and wt1b as riboprobes indicated that the kidney is more sensitive than the heart to AA damage. Real-time PCR showed that AA can up-regulate the expression of proinflammatory genes like TNFα, cox2 and mpo. These results support the following conclusions: (1) AA-induced renal failure is mediated by inflammation, which causes circulation dysfunction followed by serious heart malformation; and (2) the kidney is more sensitive than the heart to AA injury.
马兜铃酸（AA）是马兜铃植物提取物的一种成分，被用于治疗多种疾病，但尚未充分研究其毒理学效应。本研究旨在评估 AA 诱导的斑马鱼胚胎肾毒性。将斑马鱼胚胎浸泡在 AA 中后，胚胎表现出畸形的肾脏表型，如弯曲的、囊性的前肾管、前肾导管和肾小球萎缩的情况。随着 AA 暴露剂量的增加，具有畸形肾脏表型的胚胎比例增加。此外，与mock 对照组相比，AA 处理的胚胎肾小球滤过率（GFR）显著降低（mock-control：100±2.24% vs. 10 ppm AA 处理 3-5h：71.48±18.84%~39.41±15.88%），表明 AA 处理不仅引起肾脏形态改变，还导致肾功能衰竭。除了肾脏畸形外，AA 处理的斑马鱼胚胎还表现出心脏畸形、心包肿胀、血液循环受损和红细胞堆积。使用 cmlc2 和 wt1b 作为探针的全胚胎原位杂交研究表明，肾脏比心脏对 AA 损伤更敏感。实时 PCR 显示，AA 可上调 TNFα、cox2 和 mpo 等促炎基因的表达。这些结果支持以下结论：（1）AA 诱导的肾功能衰竭是由炎症介导的，炎症导致循环功能障碍，随后出现严重的心脏畸形；（2）肾脏比心脏对 AA 损伤更敏感。
