药物肾毒性是住院患者常见的医疗问题，也是药物开发中的主要限制因素。从人类多能干细胞衍生的多段肾器官样，可以补充传统细胞培养和动物实验进行肾毒性评估。在这里，我们评估了肾器官的能力，以研究体外药物毒性。肾器官表达肾脏药物转运体OAT1，OAT3和OCT2，而人类近端小管细胞系显示缺乏OAT1和OAT3。Tenofovir和马兜铃酸（AA）诱导器型小管损伤在器官样中，这是通过OAT抑制剂probenecid改善的，而没有摧毁足细胞。同样，顺铂引起近端小管损伤，可以通过OCT抑制剂西咪替丁缓解，共同暗示器官样近端小管中存在功能性OAT和OCT。在肾器官样中，PAN诱导了固有小球足细胞的分段特异性损伤，在缺乏小管损伤的情况下。生成了一个ATP / ADP生物传感器的报告工具，该工具在未来可以应用于高通量筛选。总之，肾器官样是用于多细胞情境的毒性评估的有用工具，并可促进药物开发过程中的肾毒性评估。Copyright © 2023 Susa，Kobayashi，Galichon，Matsumoto，Tamura，Hiratsuka，Gupta，Yazdi，Bonventre和Morizane.

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.Copyright © 2023 Susa, Kobayashi, Galichon, Matsumoto, Tamura, Hiratsuka, Gupta, Yazdi, Bonventre and Morizane.