3D Proximal Tubule Tissues Recapitulate Key Aspects of Renal Physiology to Enable Nephrotoxicity Testing

Area of Science:

• Biotechnology
• Renal Physiology
• Toxicology

Background:

• The kidney proximal tubule is susceptible to xenobiotic-induced toxicity, impacting drug development.
• Current preclinical models (2D cultures, animal studies) have limitations in predicting human clinical drug responses.
• Species-specific differences and limited in vitro functional lifespan hinder accurate nephrotoxicity assessment.

Purpose of the Study:

• To develop a fully cellular, 3D bioprinted human kidney proximal tubule model.
• To create a more predictive in vitro system for assessing tissue-level clinical outcomes and nephrotoxicity.
• To investigate epithelial-interstitial interactions in kidney pathophysiology.

Main Methods:

• Utilized Organovo's 3D bioprinting platform with renal fibroblasts, endothelial cells, and proximal tubule epithelial cells.
• Histological characterization to assess tissue structure, microvascularization, and extracellular matrix deposition.
• Functional assessment of epithelial cell polarity, transporter expression (P-gp, SGLT2), and response to nephrotoxins (cisplatin) and modulators (cimetidine, TGFβ).

Main Results:

• The 3D model exhibited microvascular network formation and extracellular matrix deposition.
• Epithelial cells displayed tight junction formation and functional renal transporters (P-gp, SGLT2).
• Cisplatin induced dose-dependent nephrotoxicity, rescued by cimetidine, confirming OCT2 transporter involvement.
• TGFβ treatment induced a fibrotic response, validated by gene expression and histology.

Conclusions:

• The 3D bioprinted proximal tubule model serves as a robust platform for mechanistic nephrotoxicity assessment.
• This model aids in understanding pathogenic states involving kidney epithelial-interstitial interactions.
• It represents a valuable adjunct to traditional animal studies for drug development and toxicology.