Expression of xenobiotic transporters in the human renal proximal tubule cell line RPTEC/TERT1

Aschauer, Lydia; Carta, Giada; Vogelsang, Nadine; Schlatter, Eberhard; Jennings, Paul

doi:10.1016/j.tiv.2014.12.003

Cited by 68 publications

(65 citation statements)

References 67 publications

(81 reference statements)

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“…To overcome difficulties in expanding primary proximal tubule cells, lines of immortalized or conditionally immortalized proximal tubule cells have been developed, for example, using oncogenes (such as E6/E7 or SV40 large T antigen) or telomerase (for example TERT1) 66,111,112 . Although TERT1-immortalized renal proximal tubule cells can undergo at least 90 population doublings and possess several characteristics of proximal tubule cells, including microvilli, tight junctions, GGT activity, endocytic activity, and functional drug transporters, the functional characteristics of early and late passage cells have not been compared 66,113 . Conditionally immortalized proximal tubule cells exhibit tight junctions, endocytic activity, OCT2 and MDR1 function, and UGT activity, but like all renal proximal tubule cells in 2D culture, these conditionally immortalized proximal tubule cells lose OAT1 and OAT3 expression unless the proteins are transduced 34,112,114,115 .…”

Section: Preclinical Screens Of Nephrotoxicitymentioning

confidence: 99%

Advances in predictive in vitro models of drug-induced nephrotoxicity

et al. 2018

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In vitro screens for nephrotoxicity are currently poorly predictive of toxicity in humans. Although the functional proteins that are expressed by nephron tubules and mediate drug susceptibility are well known, current in vitro cellular models poorly replicate both the morphology and the function of kidney tubules and therefore fail to demonstrate injury responses to drugs that would be nephrotoxic in vivo. Advances in protocols to enable the directed differentiation of pluripotent stem cells into multiple renal cell types and the development of microfluidic and 3D culture systems have opened a range of potential new platforms for evaluating drug nephrotoxicity. Many of the new in vitro culture systems have been characterized by the expression and function of transporters, enzymes, and other functional proteins that are expressed by the kidney and have been implicated in drug-induced renal injury. In vitro platforms that express these proteins and exhibit molecular biomarkers that have been used as readouts of injury demonstrate improved functional maturity compared with static 2D cultures and represent an opportunity to model injury to renal cell types that have hitherto received little attention. As nephrotoxicity screening platforms become more physiologically relevant, they will facilitate the development of safer drugs and improved clinical management of nephrotoxicants.

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Section: Preclinical Screens Of Nephrotoxicitymentioning

confidence: 99%

Advances in predictive in vitro models of drug-induced nephrotoxicity

et al. 2018

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“…http:// www.lgcstandards-atcc.org/), and can be generally useful for investigating renal tubule function and toxicity in vitro (41)(42)(43)(44). For example ci-PTEC cells were used to investigate the impact of CYP3A5 and P-glycoprotein (P-gp/MDR1, ABCB1) genetic variation on tacrolimus metabolism, which could allow mechanistic insights into nephrotoxicity associated with this calcineurin inhibitor (44).…”

Section: Kidney Slicesmentioning

confidence: 99%

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

Scotcher

Jones²,

Posada

et al. 2016

AAPS J

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ABSTRACT.The programme for the 2015 AAPS Annual Meeting and Exhibition (Orlando, FL; 25-29 October 2015) included a sunrise session presenting an overview of the state-of-the-art tools for in vitro-in vivo extrapolation (IVIVE) and mechanistic prediction of renal drug disposition. These concepts are based on approaches developed for prediction of hepatic clearance, with consideration of scaling factors physiologically relevant to kidney and the unique and complex structural organisation of this organ. Physiologically relevant kidney models require a number of parameters for mechanistic description of processes, supported by quantitative information on renal physiology (system parameters) and in vitro/in silico drug-related data. This review expands upon the themes raised during the session and highlights the importance of high quality in vitro drug data generated in appropriate experimental setup and robust system-related information for successful IVIVE of renal drug disposition. The different in vitro systems available for studying renal drug metabolism and transport are summarised and recent developments involving state-of-the-art technologies highlighted. Current gaps and uncertainties associated with system parameters related to human kidney for the development of physiologically based pharmacokinetic (PBPK) model and quantitative prediction of renal drug disposition, excretion, and/or metabolism are identified.

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“…For example, in HK-2 cells, the expression of uptake transporters (OAT1, OAT3 and OCT2) was not detected and the expression of the apical efflux transporters (P-gp, MRPs) was low relative to human cortical tissue levels [21]. The RPTEC/TERT1 cell line expressed relevant transporters at both the mRNA and protein levels [22], but the establishment of functional transport assays was not successful with this cell line [16]. Immortalized cell lines are reported to be less sensitive than human primary renal proximal tubular cells and insensitive to well-known nephrotoxicants [23], which may be due in part to changes in drug transporter expression associated with immortalization [24].…”

Section: Introductionmentioning

confidence: 99%

Development and Application of Human Renal Proximal Tubule Epithelial Cells for Assessment of Compound Toxicity

Li¹,

Zhao²,

Huang³

et al. 2017

Curr. Chem. Genomics and Translat. Med.

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Kidney toxicity is a major problem both in drug development and clinical settings. It is difficult to predict nephrotoxicity in part because of the lack of appropriate in vitro cell models, limited endpoints, and the observation that the activity of membrane transporters which plays important roles in nephrotoxicity by affecting the pharmacokinetic profile of drugs is often not taken into account. We developed a new cell model using pseudo-immortalized human primary renal proximal tubule epithelial cells. This cell line (SA7K) was characterized by the presence of proximal tubule cell markers as well as several functional properties, including transporter activity and response to a few well-characterized nephrotoxicants. We subsequently evaluated a group of potential nephrotoxic compounds in SA7K cells and compared them to a commonly used human immortalized kidney cell line (HK-2). Cells were treated with test compounds and three endpoints were analyzed, including cell viability, apoptosis and mitochondrial membrane potential. The results showed that most of the known nephrotoxic compounds could be detected in one or more of these endpoints. There were sensitivity differences in response to several of the chemicals between HK-2 and SA7K cells, which may relate to differences in expressions of key transporters or other components of nephrotoxicity pathways. Our data suggest that SA7K cells appear as promising for the early detection of renal toxicants.

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Expression of xenobiotic transporters in the human renal proximal tubule cell line RPTEC/TERT1

Cited by 68 publications

References 67 publications

Advances in predictive in vitro models of drug-induced nephrotoxicity

Advances in predictive in vitro models of drug-induced nephrotoxicity

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

Development and Application of Human Renal Proximal Tubule Epithelial Cells for Assessment of Compound Toxicity

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