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

Area of Science:

• Nephrology
• Toxicology
• Stem Cell Biology

Background:

• Kidneys are susceptible to drug and metabolite toxicity, particularly the proximal tubule (PT).
• Early detection of drug-induced nephrotoxicity requires relevant in vitro models.
• Current models may not fully replicate in vivo conditions for accurate toxicity prediction.

Purpose of the Study:

• To develop and validate a robust, versatile in vitro model of the human proximal tubule using induced pluripotent stem cells (iPSCs).
• To assess the model's capability in predicting drug-induced proximal tubule injury.
• To investigate the impact of perfusion on xenobiotic response and metallothionein upregulation.

Main Methods:

• Established a cell culture insert-based model using iPSC-derived proximal tubule cells.
• Maintained the model in a microphysiological system for up to ten days.
• Utilized perfusion to simulate dynamic physiological conditions and assessed responses to known nephrotoxicants (polymyxin B, cyclosporin A, cisplatin).

Main Results:

• The perfused iPSC-derived PT model successfully predicted drug-induced proximal tubule injury.
• Perfusion significantly influenced the model's response to xenobiotics.
• Upregulation of metallothioneins, a marker of in vivo nephrotoxicity, was detected in the dynamic, perfused model but not in static cultures.
• The model facilitated the investigation of nephrotoxicity prevention, demonstrating curcumin's potential to alleviate polymyxin-induced injury.

Conclusions:

• The perfused iPSC-derived proximal tubule model is a versatile and effective tool for in vitro nephrotoxicity studies.
• This model enables reliable early detection of nephrotoxic potential, supporting safer drug development.
• Dynamic, perfused in vitro systems are crucial for accurately mimicking in vivo responses to nephrotoxic agents and for evaluating protective strategies.