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Updated: May 3, 2026
Isolation of Primary Human Proximal Tubule Epithelial Cells and Their Use in Creating a Microphysiological Model of the Renal Proximal Tubule
Published on: May 9, 2025
Identification of nephrotoxic compounds with embryonic stem-cell-derived human renal proximal tubular-like cells
Yao Li1, Karthikeyan Kandasamy, Jacqueline Kai Chin Chuah
1Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore.
Abstract:
The kidney is a major target for drug-induced toxicity, and the renal proximal tubule is frequently affected. Nephrotoxicity is typically detected only late during drug development, and the nephrotoxic potential of newly approved drugs is often underestimated. A central problem is the lack of preclinical models with high predictivity. Validated in vitro models for the prediction of nephrotoxicity are not available. Major problems are related to the identification of appropriate cell models and end points. As drug-induced kidney injury is associated with inflammatory reactions, we explored the expression of inflammatory markers as end point for renal in vitro models. In parallel, we developed a new cell model. Here, we combined these approaches and developed an in vitro model with embryonic stem-cell-derived human renal proximal tubular-like cells that uses the expression of interleukin (IL)-6 and IL-8 as end points. The predictivity of the model was evaluated with 41 well-characterized compounds. The results revealed that the model predicts proximal tubular toxicity in humans with high accuracy. In contrast, the predictivity was low when well-established standard in vitro assays were used. Together, the results show that high predictivity can be obtained with in vitro models employing pluripotent stem cell-derived human renal proximal tubular-like cells.
Insights
Developing new preclinical models is crucial for predicting drug-induced kidney injury. This study introduces a highly accurate in vitro model using human renal proximal tubular cells to detect nephrotoxicity early.
Area of Science:
- Nephrology
- Toxicology
- Stem Cell Biology
Background:
- Kidney toxicity is a significant concern in drug development, often detected late.
- Current preclinical models lack the predictive power to identify nephrotoxic drugs effectively.
- Validated in vitro models for predicting drug-induced kidney injury are urgently needed.
Purpose of the Study:
- To develop a novel, highly predictive in vitro model for assessing drug-induced nephrotoxicity.
- To identify reliable endpoints for early detection of renal proximal tubule damage.
- To improve the accuracy of preclinical nephrotoxicity screening.
Main Methods:
- Developed an in vitro model using human embryonic stem cell-derived renal proximal tubular-like cells.
- Utilized the expression of inflammatory markers, specifically interleukin (IL)-6 and IL-8, as predictive endpoints.
- Validated the model's predictivity using 41 well-characterized compounds.
Main Results:
- The novel in vitro model demonstrated high accuracy in predicting human proximal tubular toxicity.
- The model's performance significantly outperformed established standard in vitro assays.
- Interleukin (IL)-6 and IL-8 expression proved to be reliable indicators of drug-induced kidney injury.
Conclusions:
- Pluripotent stem cell-derived renal proximal tubular-like cells offer a promising platform for predictive nephrotoxicity testing.
- This advanced in vitro model enables earlier and more accurate detection of drug-induced kidney injury.
- The findings highlight the potential to reduce late-stage drug development failures due to unforeseen renal toxicity.
