Current State of In vitro Cell-Based Renal Models

Gozalpour, Elnaz; Fenner, Katherine

doi:10.2174/1389200219666180119115133

Cited by 20 publications

(15 citation statements)

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“…Cryopreserved and freshly isolated RPTECs each come with their own challenges. The availability of primary tissue is limited, and many protocols exist for purifying proximal tubules from other renal cells (Gozalpour and Fenner, 2018). Cryopreservation can assist with availability issues, and cryopreserved RPTECs have been shown to express kidney tubule specific markers (Adler et al, 2016) and are more differentiated than cell lines like HK-2 (David et al, 2004); however, cryopreserved RPTECs lack strong transporter mRNA expression compared with freshly isolated renal tissue (Van der Hauwaert et al, 2014).…”

Section: Common Sources Of Kidney Cellsmentioning

confidence: 99%

“…Cryopreservation can assist with availability issues, and cryopreserved RPTECs have been shown to express kidney tubule specific markers (Adler et al, 2016) and are more differentiated than cell lines like HK-2 (David et al, 2004); however, cryopreserved RPTECs lack strong transporter mRNA expression compared with freshly isolated renal tissue (Van der Hauwaert et al, 2014). RPTECs have been used extensively in nephrotoxicity investigations and were reviewed recently (Gozalpour and Fenner, 2018). RPTECs were used to describe biotransformationrelated nephrotoxicity of cisplatin (Wainford et al, 2008) and TCA (Racine et al, 2014).…”

Section: Common Sources Of Kidney Cellsmentioning

confidence: 99%

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Emerging Kidney Models to Investigate Metabolism, Transport, and Toxicity of Drugs and Xenobiotics

Bajaj¹,

Chowdhury²,

Yucha³

et al. 2018

Drug Metab Dispos

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The kidney is a major clearance organ of the body and is responsible for the elimination of many xenobiotics and prescription drugs. With its multitude of uptake and efflux transporters and metabolizing enzymes, the proximal tubule cell (PTC) in the nephron plays a key role in the disposition of xenobiotics and is also a primary site for toxicity. In this minireview, we first provide an overview of the major transporters and metabolizing enzymes in the PTCs responsible for biotransformation and disposition of drugs. Next, we discuss different cell sources that have been used to model PTCs in vitro, their pros and cons, and their characterization. As current technology is inadequate to evaluate reliably drug disposition and toxicity in the kidney, we then discuss recent advancements in kidney microphysiological systems (MPS) and the need to develop robust in vitro platforms that could be routinely used by pharmaceutical companies to screen compounds. Finally, we discuss the new and exciting field of stem cell-derived kidney models as potential cell sources for future kidney MPS. Given the push from both regulatory agencies and pharmaceutical companies to use more predictive "human-like" in vitro systems in the early stages of drug development to reduce attrition, these emerging models have the potential to be a game changer and may revolutionize how renal disposition and kidney toxicity in drug discovery are evaluated in the future.

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Section: Common Sources Of Kidney Cellsmentioning

confidence: 99%

Section: Common Sources Of Kidney Cellsmentioning

confidence: 99%

Emerging Kidney Models to Investigate Metabolism, Transport, and Toxicity of Drugs and Xenobiotics

Bajaj¹,

Chowdhury²,

Yucha³

et al. 2018

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…Renal tubular epithelial cells are prone to lose their characteristics when cultured under standard in vitro conditions . One of the reasons might be that while the ECM and BM promote many cell functions, including proliferation and differentiation via their mechanical and physical properties and stimuli, an ECM or BM‐like structure is often absent in vitro.…”

Section: The Role Of the Bm In Kidney Tubulesmentioning

confidence: 99%

Renal Tubular‐ and Vascular Basement Membranes and their Mimicry in Engineering Vascularized Kidney Tubules

Genderen

Jansen

Cheng

et al. 2018

Adv Healthcare Materials

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The high prevalence of chronic kidney disease leads to an increased need for renal replacement therapies. While there are simply not enough donor organs available for transplantation, there is a need to seek other therapeutic avenues as current dialysis modalities are insufficient. The field of regenerative medicine and whole organ engineering is emerging, and researchers are looking for innovative ways to create (part of) a functional new organ. To biofabricate a kidney or its functional units, it is necessary to understand and learn from physiology to be able to mimic the specific tissue properties. Herein is provided an overview of the knowledge on tubular and vascular basement membranes' biochemical components and biophysical properties, and the major differences between the two basement membranes are highlighted. Furthermore, an overview of current trends in membrane technology for developing renal replacement therapies and to stimulate kidney regeneration is provided.

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“…In cryopreserved human renal proximal tubule epithelial cells (hRPTECs), fluidic culture conditions promoted a 12-fold increase in MATE2-K gene expression (mediated by nuclear factor erythroidderived 2), which also translated into enhanced functional transport activity, shown by the reduced accumulation of the fluorescent substrate 49,6-diamidino-2-phenylindole (Fukuda et al, 2017). The lack of OATs in renal in vitro models has long been a bottleneck in DMPK studies (Gozalpour and Fenner, 2018); to date, the actual mechanism by which cells lose these transporters is not fully understood. Human proximal tubule cells grown in an MPS model with continuous flow showed glucose reuptake as well as uptake of the prototypical OAT substrate para-aminohippuric acid, a functionality that was absent when the same cells were grown on transwell filters.…”

Section: Drug Transporter Characterization In Mps Modelsmentioning

confidence: 99%

Perspective on the Application of Microphysiological Systems to Drug Transporter Studies

Caetano-Pinto

Stahl

2018

Drug Metab Dispos

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Transmembrane flux of a drug within a tissue or organ frequently involves a complex system of transporters from multiple families that have redundant and overlapping specificities. Current in vitro systems poorly represent physiology, with reduced expression and activity of drug transporter proteins; therefore, novel models that recapitulate the complexity and interplay among various transporters are needed. The development of microphysiological systems that bring simulated physiologic conditions to in vitro cell culture models has enormous potential to better reproduce the morphology and transport activity across several organ models, especially in tissues such as the liver, kidney, intestine, or the blood-brain barrier, in which drug transporters play a key role. The prospect of improving the in vitro function of organ models highly prolific in drug transporters holds the promise of implementing novel tools to study these mechanisms with far more representative biology than before. In this short review, we exemplify recent developments in the characterization of perfused microphysiological systems involving the activity of drug transporters. Furthermore, we analyze the challenges and opportunities for the implementation of such systems in the study of transporter-mediated drug disposition and the generation of clinically relevant physiology-based in silico models incorporating relevant drug transport activity.

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Current State of In vitro Cell-Based Renal Models

Cited by 20 publications

References 0 publications

Emerging Kidney Models to Investigate Metabolism, Transport, and Toxicity of Drugs and Xenobiotics

Emerging Kidney Models to Investigate Metabolism, Transport, and Toxicity of Drugs and Xenobiotics

Renal Tubular‐ and Vascular Basement Membranes and their Mimicry in Engineering Vascularized Kidney Tubules

Perspective on the Application of Microphysiological Systems to Drug Transporter Studies

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