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Analysis of Chemical Transport by IPSC-Derived Proximal Tubular Cell (PTC)-Like Cells and Other Emerging Human Kidney Cell Models for Drug Toxicity Screening

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IRC-SET 2022

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Abstract

The kidney is a main target for drug-and chemical-induced toxicity, and the renal proximal tubule is frequently affected. Many widely-prescribed drugs are nephrotoxic. Reliable renal proximal tubular cell (PTC) models are needed for developing improved in vitro assays for nephrotoxicity prediction. PTC in the human kidney express various transporters for drugs and chemicals, which are often down-regulated in vitro. This renders the cells inactive to nephrotoxicants, which is a main problem in nephrotoxicity testing. Here, I addressed organic anion uptake by three different PTC models: conditionally immortalised proximal tubular epithelial cells (ciPTEC) stably transfected with OAT1 and OAT3 expression constructs (ciPTEC-OAT1 and ciPTEC-OAT3) and human-induced pluripotent stem cell (iPSC)-derived PTC-like cells. In addition, the activity of the renal organic anion transporters OAT1 and OAT3 was assessed. These transporters are important for the cellular uptake of a wide range of nephrotoxicants. The results showed that the cell culture medium has a major impact on organic anion uptake. A proprietary novel medium for PTC-like cells was formulated (Renal Tox Medium) that sustained high organic anion uptake in vitro. Furthermore, the results showed that OAT1 and/or OAT3 activity in PTC-like cells was superior compared to ciPTEC-OAT1 and ciPTEC-OAT3 cells, which are currently the PTC models favoured by the pharmaceutical industry. The results also showed that ciPTEC cell lines consisted of inhomogeneous cell populations. Together, the results suggest that PTC-like cells, in combination with the here developed proprietary Renal Tox Medium, could provide a more suitable solution for industry and academia.

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Acknowledgements

I’d like to thank my two mentors, Dr. Riga Tawo (NBL-SIFBI, A*STAR) and Team Leader and Principal Research Scientist Dr. Daniele Zink (NBL-SIFBI, A*STAR) for their unwavering support, invaluable guidance and utmost dedication. I also express my deepest gratitude to A*STAR Senior Fellow Professor Jackie Y. Ying, and NBL Director and YRP Chair Ms Noreena AbuBakar for this incredible experience. They have all inspired me in immeasurable ways. This work was supported by the NanoBioLab (NBL), Biomedical Research Council, A*STAR and the Singapore Institute of Food and Biotechnology Innovation (SIFBI), Biomedical Research Council, A*STAR.

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Authors and Affiliations

  1. Raffles Institution, Singapore, Singapore

    Treruangrachada Anantaya Kylin

  2. Singapore Institute of Food and Biotechnology Innovation, A*STAR, Singapore, Singapore

    Riga Tawo & Daniele Zink

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  1. Treruangrachada Anantaya Kylin
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  2. Riga Tawo
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  3. Daniele Zink
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Corresponding author

Correspondence to Treruangrachada Anantaya Kylin .

Editor information

Editors and Affiliations

  1. Singapore Institute of Technology, Singapore, Singapore

    Huaqun Guo

  2. Singapore Institute of Technology, Singapore, Singapore

    Ian McLoughlin

  3. Department of Information Systems Technology and Design, Singapore University of Technology and Design, Singapore, Singapore

    Eyasu Getahun Chekole

  4. Agency for Science Technology and Research, Experimental Drug Development Centre, Singapore, Singapore

    Umayal Lakshmanan

  5. Department of Applied Mathematics and Computer Science, Technical University of Denmark, Kongens Lyngby, Denmark

    Weizhi Meng

  6. Singapore Institute of Technology, Singapore, Singapore

    Peng Cheng Wang

  7. School of Cyber Science and Technology, Beihang University, Beijing, China

    Jiqiang Lu

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© 2023 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

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Kylin, T.A., Tawo, R., Zink, D. (2023). Analysis of Chemical Transport by IPSC-Derived Proximal Tubular Cell (PTC)-Like Cells and Other Emerging Human Kidney Cell Models for Drug Toxicity Screening. In: Guo, H., et al. IRC-SET 2022. Springer, Singapore. https://doi.org/10.1007/978-981-19-7222-5_26

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