Human kidney organoids model the tacrolimus nephrotoxicity and elucidate the role of autophagy
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 tacr...
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The Korean Association of Internal Medicine
2021
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oai:doaj.org-article:1cdcf2c8f8544d2a884a0e270371f0bb2021-11-08T00:59:06ZHuman kidney organoids model the tacrolimus nephrotoxicity and elucidate the role of autophagy1226-33032005-664810.3904/kjim.2020.323https://doaj.org/article/1cdcf2c8f8544d2a884a0e270371f0bb2021-11-01T00:00:00Zhttp://www.kjim.org/upload/pdf/kjim-2020-323.pdfhttps://doaj.org/toc/1226-3303https://doaj.org/toc/2005-6648Background/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.Jin Won KimSun Ah NamEunjeong SeoJong Young LeeDohui KimJi Hyeon JuSun Woo LimHong Lim KimHyung Wook KimChul Woo YangJin KimDong Sung KimYong Kyun KimThe Korean Association of Internal MedicinearticleautophagykidneyorganoidstacrolimusMedicineRENThe Korean Journal of Internal Medicine, Vol 36, Iss 6, Pp 1420-1436 (2021) |
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autophagy kidney organoids tacrolimus Medicine R |
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autophagy kidney organoids tacrolimus Medicine R Jin Won Kim Sun Ah Nam Eunjeong Seo Jong Young Lee Dohui Kim Ji Hyeon Ju Sun Woo Lim Hong Lim Kim Hyung Wook Kim Chul Woo Yang Jin Kim Dong Sung Kim Yong Kyun Kim Human kidney organoids model the tacrolimus nephrotoxicity and elucidate the role of autophagy |
| description |
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. |
| format |
article |
| author |
Jin Won Kim Sun Ah Nam Eunjeong Seo Jong Young Lee Dohui Kim Ji Hyeon Ju Sun Woo Lim Hong Lim Kim Hyung Wook Kim Chul Woo Yang Jin Kim Dong Sung Kim Yong Kyun Kim |
| author_facet |
Jin Won Kim Sun Ah Nam Eunjeong Seo Jong Young Lee Dohui Kim Ji Hyeon Ju Sun Woo Lim Hong Lim Kim Hyung Wook Kim Chul Woo Yang Jin Kim Dong Sung Kim Yong Kyun Kim |
| author_sort |
Jin Won Kim |
| title |
Human kidney organoids model the tacrolimus nephrotoxicity and elucidate the role of autophagy |
| title_short |
Human kidney organoids model the tacrolimus nephrotoxicity and elucidate the role of autophagy |
| title_full |
Human kidney organoids model the tacrolimus nephrotoxicity and elucidate the role of autophagy |
| title_fullStr |
Human kidney organoids model the tacrolimus nephrotoxicity and elucidate the role of autophagy |
| title_full_unstemmed |
Human kidney organoids model the tacrolimus nephrotoxicity and elucidate the role of autophagy |
| title_sort |
human kidney organoids model the tacrolimus nephrotoxicity and elucidate the role of autophagy |
| publisher |
The Korean Association of Internal Medicine |
| publishDate |
2021 |
| url |
https://doaj.org/article/1cdcf2c8f8544d2a884a0e270371f0bb |
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