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A Paper-Based Human Kidney Proximal Tubule-on-a-Chip for Efficacy of SGLT2 Inhibitors and Methotrexate-Induced
Hui Liu1, Gui-Mu Guo2, Zi-Wei Yu2
1Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
Abstract:
The human kidney proximal tubule is responsible for glucose reabsorption and serves as a primary target for exogenous toxins. While conventional in vitro cell-based models offer cost-effective alternatives to animal testing, they often fail to replicate the structural and functional complexity of the native proximal tubule. Here, we developed a paper-based human kidney proximal tubule-on-a-chip that mimicked key physiological functions, bridging between traditional cell cultures and animal models. Utilizing porous paper, the chip recreated an in vivo-like three-dimensional microenvironment that supported proximal tubule-specific functions and reproduced essential physiological processes including dynamic glycogen metabolism, glucose reabsorption, and drug transport. The model enabled precise pharmacodynamics evaluation of sodium-glucose co-transporter 2 (SGLT2) inhibitors, yielding median effect concentrations of 0.954 ng/mL for dapagliflozin and 2.685 ng/mL for canagliflozin. The platform maintained consistently high glucose reabsorption inhibition rates (94.59%-95.03%) under different conditions following SGLT2 inhibitors treatment. Furthermore, the methotrexate (MTX)-induced nephrotoxicity evaluation was performed by MTT assay, LDH assay, and glucose reabsorption measurements. The chip accurately reproduced MTX transport dynamics, demonstrating its potential for pharmacokinetic studies. Thus, the paper-based model serves as a reliable platform for pharmacokinetic and nephrotoxicity assessments, offering a valuable tool to replace animal testing and support Reduce, Refine, and Replace experimentation.
Insights
A novel paper-based kidney-on-a-chip accurately models human proximal tubule functions, including glucose reabsorption and drug transport. This platform enables reliable nephrotoxicity and pharmacokinetic assessments, supporting the replacement of animal testing.
Area of Science:
- Biomedical Engineering
- Renal Physiology
- Toxicology
Background:
- The human kidney proximal tubule is crucial for glucose reabsorption and susceptible to toxins.
- Traditional cell cultures lack the complexity of native kidney tubules.
- A need exists for advanced in vitro models to bridge the gap between cell cultures and animal studies.
Purpose of the Study:
- To develop a paper-based kidney proximal tubule-on-a-chip model.
- To mimic in vivo-like microenvironment and physiological functions.
- To evaluate its utility for pharmacodynamics, pharmacokinetics, and nephrotoxicity studies.
Main Methods:
- Fabrication of a paper-based chip utilizing porous paper.
- Incorporation of human kidney proximal tubule cells to create a 3D microenvironment.
- Assessment of glucose reabsorption, glycogen metabolism, drug transport, and methotrexate-induced nephrotoxicity.
Main Results:
- The chip successfully replicated proximal tubule functions like glucose reabsorption and drug transport.
- Accurate pharmacodynamics of SGLT2 inhibitors (dapagliflozin, canagliflozin) were determined.
- Methotrexate transport dynamics and nephrotoxicity were reliably reproduced, correlating with in vivo observations.
Conclusions:
- The paper-based kidney-on-a-chip is a robust platform for physiological and toxicological studies.
- It offers a valuable alternative to animal testing for drug development and safety assessment.
- This model supports the principles of Reduce, Refine, and Replace in animal experimentation.
