Developmental nephrotoxicity of aristolochic acid in a zebrafish model
Developmental nephrotoxicity of aristolochic acid in a zebrafish model
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DOI：
10.1016/j.taap.2012.03.011
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发表时间：
2012-05-15
影响因子：
3.8
通讯作者：
Chen, Yau-Hung
中科院分区：
文献类型：
--
作者：
Ding, Yu-Ju;Chen, Yau-Hung
马兜铃酸（AA）是马兜铃属植物提取物的一种成分，用于治疗不同的病理学，其毒理学作用尚未得到充分研究。本研究的目的是评估AA诱导的斑马鱼胚胎肾毒性。斑马鱼胚胎在AA中浸泡后，胚胎表现出畸形的肾脏表型，如弯曲的囊状前肾管、前肾管和萎缩的肾小球。随着AA暴露剂量的增加，肾畸形胚胎的比例增加。此外，与模拟对照同窝仔相比，AA处理的胚胎表现出显著降低的肾小球滤过率（GFR（模拟对照：100 +/- 224% vs. 10 ppm AA处理3-5 h：71.48 +/-18.84%与39.41 +/- 15.88%相似），表明M处理不仅引起肾脏形态学改变，而且还引起肾功能衰竭。除肾脏畸形外，M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蓄积。使用cmlc 2和wt 1b作为核糖核酸探针的整体原位杂交研究表明，肾脏比心脏对AA损伤更敏感。Real-time PCR显示AA可上调TNF α、cox 2和MPO等促炎基因的表达。这些结果支持以下结论：（1）AA诱导的肾衰竭是由炎症介导的，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。(C)2012 Elsevier Inc. All rights reserved.
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 +/- 224% vs. 10 ppm AA treatment for 3-5 h: 71.48 +/- 18.84%similar to 39.41 +/- 15.88%), indicating that M treatment not only caused morphological kidney changes but also induced renal failure. In addition to kidney malformations, M-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 TNF alpha, 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. (C) 2012 Elsevier Inc. All rights reserved.