ATP/ADP biosensor organoids for drug nephrotoxicity assessment

Frontiers in Cell and Developmental Biology

Cell and Developmental Biology

Kenichi Kobayashi¹  Akitoshi Tamura²  Pierre Galichon³  Koichiro Susa⁴  Joseph V. Bonventre⁵  Navin R. Gupta⁶  Ken Hiratsuka⁷  Ryuji Morizane⁸  Takuya Matsumoto⁹  Iman K. Yazdi^1,10 

[1] Harvard Medical School, Boston, MA, United States;Massachusetts General Hospital, Boston, MA, United States;Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States;Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States;Harvard Medical School, Boston, MA, United States;Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States;Harvard Medical School, Boston, MA, United States;Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan;Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States;Harvard Medical School, Boston, MA, United States;Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States;Harvard-MIT Division of Health Sciences &Technology, Massachusetts Institute of Technology, Cambridge, MA, United States;Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States;Harvard Medical School, Boston, MA, United States;Massachusetts General Hospital, Boston, MA, United States;Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States;Harvard Medical School, Boston, MA, United States;Massachusetts General Hospital, Boston, MA, United States;Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States;Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States;Harvard Medical School, Boston, MA, United States;Massachusetts General Hospital, Boston, MA, United States;Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States;Harvard Stem Cell Institute, Cambridge, MA, United States;Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States;Harvard Medical School, Boston, MA, United States;Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States;Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States;Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States;Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States;Harvard-MIT Division of Health Sciences &Technology, Massachusetts Institute of Technology, Cambridge, MA, United States;

关键词: nephron;    organoid;    ATP;    drug development;    transporter;    kidney;    KIM-1;   

DOI  :  10.3389/fcell.2023.1138504

 received in 2023-01-06, accepted in 2023-02-15,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

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