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Development of a Highly Differentiated Human Primary Proximal Tubule MPS Model (aProximate MPS Flow)

Lookup NU author(s): Elena Tasinato, Dr Kathryn GarnerORCiD, Dr Colin Brown

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2023 by the authors.The kidney proximal tubule (PT) mediates renal drug elimination in vivo and is a major site of drug-induced toxicity. To reliably assess drug efficacy, it is crucial to construct a model in which PT functions are replicated. Current animal studies have proven poorly predictive of human outcome. To address this, we developed a physiologically relevant micro-physiological system (MPS) model of the human PT, the aProximate MPS Flow platform (Patent No: G001336.GB). In this model, primary human PT cells (hPTCs) are subjected to fluidic media flow and a shear stress of 0.01–0.2 Pa. We observe that these cells replicate the polarity of hPTCs and exhibit a higher expression of all the key transporters of SLC22A6 (OAT1), SLC22A8 (OAT3), SLC22A2 (OCT2), SLC47A1 (MATE1), SLC22A12 (URAT1), SLC2A9 (GLUT9), ABCB1 (MDR1), ABCC2 (MRP2), LRP2 (megalin), CUBN (cubilin), compared with cells grown under static conditions. Immunofluorescence microscopy confirmed an increase in OAT1, OAT3, and cilia protein expression. Increased sensitivity to nephrotoxic protein cisplatin was observed; creatinine and FITC-albumin uptake was significantly increased under fluidic shear stress conditions. Taken together, these data suggest that growing human PT cells under media flow significantly improves the phenotype and function of hPTC monolayers and has benefits to the utility and near-physiology of the model.

Publication metadata

Author(s): Pisapia F, O'Brien D, Tasinato E, Garner KL, Brown CDA

Publication type: Article

Publication status: Published

Journal: Bioengineering

Year: 2024

Volume: 11

Issue: 1

Print publication date: 01/01/2024

Online publication date: 21/12/2023

Acceptance date: 19/12/2023

Date deposited: 05/02/2024

ISSN (electronic): 2306-5354

Publisher: MDPI

URL: https://doi.org/10.3390/bioengineering11010007

DOI: 10.3390/bioengineering11010007

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