Frontiers in Cell and Developmental Biology (Mar 2023)
ATP/ADP biosensor organoids for drug nephrotoxicity assessment
- Koichiro Susa,
- Koichiro Susa,
- Koichiro Susa,
- Kenichi Kobayashi,
- Kenichi Kobayashi,
- Pierre Galichon,
- Pierre Galichon,
- Takuya Matsumoto,
- Takuya Matsumoto,
- Takuya Matsumoto,
- Akitoshi Tamura,
- Ken Hiratsuka,
- Ken Hiratsuka,
- Ken Hiratsuka,
- Ken Hiratsuka,
- Navin R. Gupta,
- Navin R. Gupta,
- Navin R. Gupta,
- Iman K. Yazdi,
- Iman K. Yazdi,
- Iman K. Yazdi,
- Iman K. Yazdi,
- Joseph V. Bonventre,
- Joseph V. Bonventre,
- Joseph V. Bonventre,
- Joseph V. Bonventre,
- Ryuji Morizane,
- Ryuji Morizane,
- Ryuji Morizane,
- Ryuji Morizane,
- Ryuji Morizane
Affiliations
- Koichiro Susa
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Koichiro Susa
- Harvard Medical School, Boston, MA, United States
- Koichiro Susa
- Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
- Kenichi Kobayashi
- Harvard Medical School, Boston, MA, United States
- Kenichi Kobayashi
- Massachusetts General Hospital, Boston, MA, United States
- Pierre Galichon
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Pierre Galichon
- Harvard Medical School, Boston, MA, United States
- Takuya Matsumoto
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Takuya Matsumoto
- Harvard Medical School, Boston, MA, United States
- Takuya Matsumoto
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Akitoshi Tamura
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Ken Hiratsuka
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Ken Hiratsuka
- Harvard Medical School, Boston, MA, United States
- Ken Hiratsuka
- Massachusetts General Hospital, Boston, MA, United States
- Ken Hiratsuka
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Navin R. Gupta
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Navin R. Gupta
- Harvard Medical School, Boston, MA, United States
- Navin R. Gupta
- Massachusetts General Hospital, Boston, MA, United States
- Iman K. Yazdi
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Iman K. Yazdi
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Iman K. Yazdi
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Iman K. Yazdi
- Harvard-MIT Division of Health Sciences &Technology, Massachusetts Institute of Technology, Cambridge, MA, United States
- Joseph V. Bonventre
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Joseph V. Bonventre
- Harvard Medical School, Boston, MA, United States
- Joseph V. Bonventre
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Joseph V. Bonventre
- Harvard-MIT Division of Health Sciences &Technology, Massachusetts Institute of Technology, Cambridge, MA, United States
- Ryuji Morizane
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Ryuji Morizane
- Harvard Medical School, Boston, MA, United States
- Ryuji Morizane
- Massachusetts General Hospital, Boston, MA, United States
- Ryuji Morizane
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Ryuji Morizane
- Harvard Stem Cell Institute, Cambridge, MA, United States
- DOI
- https://doi.org/10.3389/fcell.2023.1138504
- Journal volume & issue
-
Vol. 11
Abstract
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.
Keywords
