ATP/ADP biosensor organoids for drug nephrotoxicity assessment.
ATP/ADP biosensor organoids for drug nephrotoxicity assessment.
复制标题
用于药物肾毒性评估的ATP/ADP生物传感器类器官。
DOI：
10.3389/fcell.2023.1138504
复制
发表时间：
2023
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
药物肾毒性是住院患者常见的健康问题，也是药物开发的主要限制因素。来源于人多能干细胞的多节段肾类器官可以补充传统的细胞培养和动物实验，用于肾毒性评估。在这里，我们评估肾脏类器官在体外研究药物毒性的能力。肾类器官表达肾药物转运蛋白OAT 1、OAT 3和OCT 2，而人近端肾小管细胞系显示不存在OAT 1和OAT 3。替诺福韦和马兜铃酸（AA）诱导类器官中的近端肾小管损伤，OAT抑制剂丙磺舒可改善这种损伤，而不损伤足细胞。类似地，顺铂引起近端肾小管损伤，OCT抑制剂西咪替丁可缓解近端肾小管损伤，共同表明类器官近端小管中存在功能性OAT和OCT。在没有肾小管损伤的情况下，嘌呤霉素氨基糖苷（PAN）诱导肾类器官中肾小球足细胞的节段特异性损伤。用ATP/ADP生物传感器产生报告类器官，这可能适用于未来的高通量筛选。总之，肾类器官是多细胞环境中毒性评估的有用工具，可能有助于药物开发期间的肾毒性评估。
Drug nephrotoxicity is a common healthcare problem in hospitalized patients and a major limitation during drug development. Multi-segmented kidney organoids derived from human pluripotent stem cells may complement traditional cell culture and animal experiments for nephrotoxicity assessment. Here we evaluate the capability of kidney organoids to investigate drug toxicity in vitro. Kidney organoids express renal drug transporters, OAT1, OAT3, and OCT2, while a human proximal tubular cell line shows the absence of OAT1 and OAT3. Tenofovir and aristolochic acid (AA) induce proximal tubular injury in organoids which is ameliorated by an OAT inhibitor, probenecid, without damage to podocytes. Similarly, cisplatin causes proximal tubular damage that can be relieved by an OCT inhibitor, cimetidine, collectively suggesting the presence of functional OATs and OCTs in organoid proximal tubules. Puromycin aminonucleoside (PAN) induced segment-specific injury in glomerular podocytes in kidney organoids in the absence of tubular injury. Reporter organoids were generated with an ATP/ADP biosensor, which may be applicable to high-throughput screening in the future. In conclusion, the kidney organoid is a useful tool for toxicity assessment in the multicellular context and may contribute to nephrotoxicity assessment during drug development.
登录
查看更多内容
影响因子：
5.2
作者：
McSweeney KR;Gadanec LK;Qaradakhi T;Ali BA;Zulli A;Apostolopoulos V
通讯作者：
Apostolopoulos V
DOI：
10.1124/jpet.110.165779
发表时间：
2010-08-10
影响因子：
3.5
作者：
Camano, Sonia;Lazaro, Alberto;Tejedor, Alberto
通讯作者：
Tejedor, Alberto
影响因子：
13.6
作者：
Lemos, Dario R.;McMurdo, Michael;Duffield, Jeremy S.
通讯作者：
Duffield, Jeremy S.
影响因子：
6
作者：
Ciarimboli, Giuliano;Deuster, Dirk;Schlatter, Eberhard
通讯作者：
Schlatter, Eberhard
影响因子：
2.2
作者：
Guan, N;Ding, J;Yang, JY
通讯作者：
Yang, JY