ATP/ADP biosensor organoids for drug nephrotoxicity assessment

Koichiro Susa; Kenichi Kobayashi; Pierre Galichon; Takuya Matsumoto; Akitoshi Tamura; Ken Hiratsuka; Navin R Gupta; Iman K Yazdi; Joseph V Bonventre; Ryuji Morizane

doi:10.3389/fcell.2023.1138504

ATP/ADP biosensor organoids for drug nephrotoxicity assessment

Front Cell Dev Biol. 2023 Mar 2:11:1138504. doi: 10.3389/fcell.2023.1138504. eCollection 2023.

Authors

Koichiro Susa^{1

2

3}, Kenichi Kobayashi^{2

4}, Pierre Galichon^{1

2}, Takuya Matsumoto^{1

2

5}, Akitoshi Tamura¹, Ken Hiratsuka^{1

2

4

5}, Navin R Gupta^{1

2

4}, Iman K Yazdi^{1

5

6

7}, Joseph V Bonventre^{1

2

6

7}, Ryuji Morizane^{1

2

4

5

8}

Affiliations

¹ Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.
² Harvard Medical School, Boston, MA, United States.
³ Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan.
⁴ Massachusetts General Hospital, Boston, MA, United States.
⁵ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States.
⁶ Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.
⁷ Harvard-MIT Division of Health Sciences &Technology, Massachusetts Institute of Technology, Cambridge, MA, United States.
⁸ Harvard Stem Cell Institute, Cambridge, MA, United States.

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

Abstract

Grants and funding