Elnaz Gozalpour* and Katherine S. Fenner Pages 310 - 326 ( 17 )
Background: Renal proximal tubule (PT) epithelial cells, expressing uptake and efflux transporters at basolateral and apical membranes, are the location of active renal drug secretion and reabsorption. In addition to singly transfected cells, an in vitro renal cell-based model is a requirement to study the active renal secretion of drugs, drug-drug interactions (DDIs), drug-induced kidney injury, nephrotoxicity holistically and potentially renal replacement therapies.
Objectives: So far, two-dimensional (2D) cell culture of primary and immortalized PT cells has been the only tool to study drugs active secretion, interactions and nephrotoxicity, however a number of in vivo characteristics of cells such as drug transporter expression and function, along with morphological features are lost during in vitro cell culture. Cellular microenvironment, extracellular matrix, cell-cell interactions, microfluidic environment and tubular architecture are the factors lacking in 2D cell culture. Currently, there are a few 3D cell culture platforms mimicking the in vivo conditions of PT cells and thus potentially enabling the necessary factors for the full functional PT cells.
Conclusion: In this review, we address in vivo physiological and morphological characteristics of PT cells, comparing their available sources and remaining in vivo features. In addition, 2D and 3D cell culture platforms and the influence of cell culture architecture on the physiological characteristics of cells are reviewed. Finally, future perspective of 3D models, kidney and multi organs on a chip, generation of kidney organoids, other ex vivo renal models and their capabilities to study drug disposition and in vitro-in vivo extrapolation are described.
Active renal secretion, drug-drug interactions, drug transporters, kidney, nephrotoxicity, organ on chip, renal model, renal proximal tubule cells.
Safety and ADME Translational Sciences Department, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca R&D, Cambridge CB4 0FZ, Safety and ADME Translational Sciences Department, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca R&D, Cambridge CB4 0FZ