Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics

Wilmes, Anja; Bielow, Chris; Ranninger, Christina; Bellwon, Patricia; Aschauer, Lydia; Limonciel, Alice; Chassaigne, Hubert; Kristl, Theresa; Aiche, Stephan; Huber, Christian G.; Guillou, Claude; Hewitt, Philipp; Leonard, Martin O.; Dekant, W.; Bois, Frédéric; Jennings, Paul

doi:10.1016/j.tiv.2014.10.006

Cited by 106 publications

(100 citation statements)

References 67 publications

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“…RPTEC/TERT1 cells took up the dye preferentially from the basolateral side and we could also demonstrate a net transport across the cells to the luminal compartment. We have previously shown that RPTEC/TERT1 take up cisplatin preferentially from the basolateral compartment and transport it to the apical compartment leading to cellular accumulation and activation of the p53 and Nrf2 pathways (Wilmes et al, 2014b). Organic anion transporters mediate the uptake of several xenobiotics including penicillin, beta-lactam antibiotics, several antivirals such as adefovir and cidofovir, methotrexate and the mycotoxin ochratoxin A (Cihlar et al, 1999;De Broe and RochRamel, 2008;Ho et al, 2000;Limonciel and Jennings, 2014;Mandikova et al, 2013;Mulato et al, 2000;Uwai et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…In fact the inclusion of biokinetics was a major aim in the Predict-IV project, where cisplatin (Wilmes et al, 2014b), adefovir dipivoxil (Crean et al 2014) and cyclosporine A (CsA) were studied in detail in the human renal proximal tubule cell line RPTEC/TERT1. The RPTEC/TERT1 cell line was chosen as they exhibit several characteristics of their in vivo counterparts such as well-developed polarisation, responsiveness to parathyroid hormone, pH-dependent ammoniagenesis, c-glutamyl transferase activity, functional protein uptake and a transepithelial electrical resistance (TEER) similar to primary proximal tubule cells (Wieser et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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

Aschauer

Carta

Vogelsang

et al. 2015

Toxicology in Vitro

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Aschauer

Carta

Vogelsang

et al. 2015

Toxicology in Vitro

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“…Traditionally, the techniques used to detect cellular damage in nephrotoxic events involve imaging approaches for visualizing expression of cell markers, cell viability, apoptosis assays, quantitative reverse transcription-PCR, and omics approaches. 12,29 Although these methods provide information about the mechanisms of toxicity of the drugs, they are time-consuming, require the use of chromophores or fluorophores, and, most importantly, are usually limited to providing ''end-point'' data rather than real-time monitoring. An emerging trend in the field of in vitro toxicology is to use electronic impedance spectroscopy (EIS) for monitoring cells.…”

Section: Introductionmentioning

confidence: 99%

Early Detection of NephrotoxicityIn VitroUsing a Transparent Conducting Polymer Device

Huerta

Rivnay

RamuzMarc

et al. 2016

Applied In Vitro Toxicology

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Electrical methods for monitoring cell toxicity are becoming increasingly popular because of their amenability for longer-term, continuous, and label-free monitoring. Microfabrication techniques are also opening the way for miniaturization of devices and integration with microphysiometer or lab-on-chip-type devices. In the present work, we demonstrate the use of a transparent conducting polymer device, termed the ''organic electrochemical transistor'' (OECT), which we have used to monitor the effects of a subset of known nephrotoxicants (cisplatin, tobramycin, and gentamycin) on cell integrity in vitro. Based on a similar principle to traditional electronic impedance spectroscopy, the OECT provides an even more sensitive way to detect small changes in ionic currents in an electrolyte, as a result of inherent amplification of signal provided thanks to the transistor format. The device monitored the ability of the human renal proximal tubular epithelial cells, a human primary cell culture model of the kidney proximal tubule, to act as a barrier to ion flow (analogous to transepithelial resistance), even though this was not possible with a commercially available instrument (cellZscope). Further, the device demonstrated extremely rapid nephrotoxicity even at low concentrations, the transparency of the device allowed in situ monitoring of cells on the device, as well as immunofluorescence staining of key biomarkers of kidney tubule function: KIM-1 and ZO-1. Correlation of electrical and optical data was demonstrated as a powerful tool for validation of the method. In summary, the OECT is presented as an extremely versatile tool for highly sensitive nephrotoxicity monitoring, amenable for future integration into microfabricated lab-on-chip platforms.

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“…The study showed the usefulness of metabolomics (MTX) 3 for discrimination of toxins. A more complex experimental design was utilized for toxicity profiling of long term cyclosporine A exposures (2,13). Cells were cultured on microporous filters and treated with two concentrations of compounds for 14 days.…”

mentioning

confidence: 99%

Nephron Toxicity Profiling via Untargeted Metabolome Analysis Employing a High Performance Liquid Chromatography-Mass Spectrometry-based Experimental and Computational Pipeline

Ranninger

Rurik

Limonciel

et al. 2015

Journal of Biological Chemistry

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Background: Drug toxicity testing calls for in vitro assays as alternatives to animal models. Results: OpenMS and KNIME are applicable for processing of HPLC-MS data sets to reveal metabolic changes upon chloroacetaldehyde treatment of kidney cells. Conclusion: Most significant changes are related to oxidative stress. Significance: Comprehensive multiomics studies support the risk assessment at an early stage of drug development.

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Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics

Cited by 106 publications

References 67 publications

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

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

Early Detection of NephrotoxicityIn VitroUsing a Transparent Conducting Polymer Device

Nephron Toxicity Profiling via Untargeted Metabolome Analysis Employing a High Performance Liquid Chromatography-Mass Spectrometry-based Experimental and Computational Pipeline

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