Korean J Intern Med.
2021 Nov;36(6):1420-1436. 10.3904/kjim.2020.323.
Human kidney organoids model the tacrolimus nephrotoxicity and elucidate the role of autophagy
- Affiliations
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- 1Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- 2Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
- 3Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang, Korea
- 4Catholic iPSC Research Center, and Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- 5Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- 6Integrative Research Support Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- KMID: 2521738
- DOI: http://doi.org/10.3904/kjim.2020.323
Abstract
- Background/Aims
Tacrolimus has been used as an immunosuppressive agent in organ transplantation. Despite the therapeutic benefits, tacrolimus’s use is limited due to its nephrotoxicity. To reduce tacrolimus nephrotoxicity, effective humanized experimental models may be helpful. Here, we modeled tacrolimus nephrotoxicity using kidney organoids derived from human inducible pluripotent stem cells (iPSCs) in vitro.
Methods
Kidney organoids were differentiated from the CMC11 iPSC cell line, re-seeded in 96-well plates, and treated with tacrolimus at doses of 0, 30, or 60 μM for 24 hours. This in vitro model was compared to a mouse model of tacrolimus nephrotoxicity and the associated mechanisms were investigated.
Results
The size of the kidney organoids and cell viability decreased in dose-dependent manners after treatment with tacrolimus. The number of tubular cells decreased with a loss of polarity, similar to the effects seen in mouse tacrolimus nephrotoxicity. Ultrastructural analysis showed numerous vacuoles in the proximal tubular cells of the kidney organoids treated with tacrolimus. Tacrolimus treatment induced oxidative stress and mitochondrial dysfunction, and autophagic activity was enhanced in the kidney organoids. Rapamycin, an autophagy inducer, accelerated cell death in the kidney organoid model of tacrolimus nephrotoxicity, which was attenuated by treatment with 3-methyladenine, an autophagy inhibitor. These findings indicate that the augmentation of autophagy by rapamycin treatment accelerated tacrolimus nephrotoxicity.
Conclusions
Our data suggest that human kidney organoids are an effective in vitro model of tacrolimus nephrotoxicity and that autophagy plays a critical role in tacrolimus nephrotoxicity.
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