A perfused iPSC-derived proximal tubule model for predicting drug-induced kidney injury

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro Pub Date : 2025-02-26 DOI:10.1016/j.tiv.2025.106038

Michelle Lechtenberg , Coraline Chéneau , Kevin Riquin , Leopold Koenig , Carlos Mota , Franck Halary , Eva-Maria Dehne

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引用次数: 0

Abstract

The kidney is frequently exposed to high levels of drugs and their metabolites, which can injure the kidney and the proximal tubule (PT) in particular. In order to detect nephrotoxicity early during drug development, relevant in vitro models are essential. Here, we introduce a robust and versatile cell culture insert-based iPSC-derived PT model, which can be maintained in a microphysiological system for at least ten days. We demonstrate the model's ability to predict drug-induced PT injury using polymyxin B, cyclosporin A, and cisplatin, and observe that perfusion distinctly impacts our model's response to xenobiotics. We observe that the upregulation of metallothioneins that is described in vivo after treatment with these drugs is reliably detected in dynamic, but not static in vitro PT models. Finally, we use our model to alleviate polymyxin-induced nephrotoxicity by supplementing the antioxidant curcumin. Together, these findings illustrate that our perfused iPSC-derived PT model is versatile and well-suited for in vitro studies investigating nephrotoxicity and its prevention. Reliable and user-friendly in vitro models like this enable the early detection of nephrotoxic potential, thereby minimizing adverse effects and reducing drug attrition.

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来源期刊

Toxicology in Vitro 医学-毒理学

CiteScore

6.50

自引率

3.10%

发文量

181

审稿时长

65 days

期刊介绍： Toxicology in Vitro publishes original research papers and reviews on the application and use of in vitro systems for assessing or predicting the toxic effects of chemicals and elucidating their mechanisms of action. These in vitro techniques include utilizing cell or tissue cultures, isolated cells, tissue slices, subcellular fractions, transgenic cell cultures, and cells from transgenic organisms, as well as in silico modelling. The Journal will focus on investigations that involve the development and validation of new in vitro methods, e.g. for prediction of toxic effects based on traditional and in silico modelling; on the use of methods in high-throughput toxicology and pharmacology; elucidation of mechanisms of toxic action; the application of genomics, transcriptomics and proteomics in toxicology, as well as on comparative studies that characterise the relationship between in vitro and in vivo findings. The Journal strongly encourages the submission of manuscripts that focus on the development of in vitro methods, their practical applications and regulatory use (e.g. in the areas of food components cosmetics, pharmaceuticals, pesticides, and industrial chemicals). Toxicology in Vitro discourages papers that record reporting on toxicological effects from materials, such as plant extracts or herbal medicines, that have not been chemically characterized.