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Comparative Analysis of Proximal Tubule Cell Sources for in vitro Studies of Renal Toxicity

ABSTRACT: The kidneys are essential for eliminating drugs and chemicals from the human body, with renal epithelial cells being particularly vulnerable to damage caused by xenobiotics and their metabolites. Predicting renal toxicity before clinical trials remains a pressing challenge, necessitating more predictive in vitro models. However, the abundance of commercially available renal proximal tubule epithelial cell (RPTEC) sources complicates the selection of the most predictive cell types. This study compared RPTEC sources, including primary cells (Lonza) and various RPTEC lines, such as ciPTECs (Cell4Pharma), TERT1/RPTECs (ATCC), and HEK293 (GenoMembrane), alongside HepG2 cells for specificity comparison. We tested these cells' responses to 12 drugs to evaluate their predictive capabilities. Cells were cultured in 96-well or 384-well plates and exposed to drugs for 72 hours at concentrations ranging from 0.3 to 300 µM. The CellTiterGlo® assay measured cell viability, and transcriptome data from unexposed cells analyzed gene expression profiles using the TempO-seq® S1500+ panel. Cell viability data determined points of departure (PODs), compared to human serum Cmax,free values to assess safety margins. Gene expression showed primary kidney cells closely matched the human kidney medulla, followed by TERT1 and ciPTEC lines, with HEK lines showing the least correlation. This study highlights differences among RPTEC sources and their utility in drug safety studies for the renal proximal tubule, emphasizing unique gene expression patterns related to metabolism, ion transport, and cell development, which are vital for improving predictive models in renal toxicity assessment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268877 | GEO | 2025/04/02

REPOSITORIES: GEO

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Project description:Drugs and other xenobiotics are not only secreted/reabsorbed by the renal proximal tubule epithelial cells (RPTEC) but may also adversely impact kidney function. In vitro models that can afford prediction of toxic effects and model directional transport are in high demand in both drug and chemical safety; accordingly, active development of new models is underway. The objective of this study was to investigate physiological and transport function of various sources of human RPTECs under static and fluidic conditions. We tested TERT1-immortalized RPTECs, including OAT1-, OCT2- and OAT3-overexpressing variants) and two primary RPETC sources. Cells were cultured on transwell membranes in two conditions – static (24-well transwells) and fluidic (transwells placed into PhysioMimix TC12 organ-on-chip platform with 2 L/s flow). We evaluated barrier formation, transport, and gene expression. We show that primary RPTECs may not be suitable for studies of directional transport on transwell membranes because they form an inferior barrier even though they show generally more relevant expression of key transporters, especially when shear stress is present. Both TERT1 and -OAT1 and -OAT3 overexpressing cells formed robust barrier, but it was unaffected by shear stress. TERT1-OAT1 cells exhibited inhibitable pAH transport; shear stress increased pAH transport function of these cells. However, efficient tenofovir secretion and perfluorooctanoic acid (PFOA) reabsorption by TERT1-OAT1 cells were not modulated by shear stress. With respect to gene expression profiles, we found that both TERT1 and TERT1-OAT1 cells exhibited human kidney-like transcriptomes, but that shear stress did not result in an apparent enhancement of the kidney phenotype. Overall, our data show that addition of flow to in vitro studies of the renal proximal tubule may afford benefits in some aspects of kidney function, but that careful consideration of the impact such studies would have on the cost and throughput of the experiments is needed.

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Comparative Analysis of Proximal Tubule Cell Sources for in vitro Studies of Renal Toxicity

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