Fabrication of Nephrotoxic Model by Kidney-on-a-Chip Implementing Renal Proximal Tubular Function In Vitro

Abstract

Cisplatin, which is commonly used in tumor treatment, and gentamicin, which is widely used as an antibiotic, both induce nephrotoxicity as a side effect. In this study, a nephrotoxicity model for these two drugs was constructed using the organ-on-a-chip technology, which is an alternative to animal tests. Using injection-molded polycarbonate chips, human renal proximal tubular epithelial cells (HRPTECs) and human umbilical vein endothelial cells (HUVECs) were co-cultured to mimic the apical and basolateral sides. To induce nephrotoxicity, cisplatin and gentamicin were administered, and cell viability and toxicity markers were confirmed via cell viability, live/dead staining, and confocal fluorescence microscopy imaging of the samples. In addition, renal tubule function was quantitatively evaluated through transepithelial electrical resistance, glucose reabsorption, and permeability analyses, and the concentrations of the nephrotoxic biomarkers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were measured using enzyme-linked immunosorbent assay. An organ-on-a-chip model mimicking the apical and basolateral sides co-cultured with HRPTECs and HUVECs was developed, which served as a nephrotoxicity model with impaired renal function. This model is expected to resolve interspecies discrepancies in nephrotoxicity during drug development and significantly reduce the time and cost involved in preclinical and clinical trials.