Functional transepithelial transport measurements to detect nephrotoxicity in vitro using the RPTEC/TERT1 cell line

Lade...
Vorschaubild
Dateien
Secker_2-13bnedmpv0sag8.pdf
Secker_2-13bnedmpv0sag8.pdfGröße: 1.17 MBDownloads: 612
Datum
2019
Herausgeber:innen
Kontakt
ISSN der Zeitschrift
Electronic ISSN
ISBN
Bibliografische Daten
Verlag
Schriftenreihe
Auflagebezeichnung
ArXiv-ID
Internationale Patentnummer
EU-Projektnummer
DFG-Projektnummer
Projekt
Open Access-Veröffentlichung
Sammlungen
Gesperrt bis
Titel in einer weiteren Sprache
Forschungsvorhaben
Organisationseinheiten
Zeitschriftenheft
Publikationstyp
Zeitschriftenartikel
Publikationsstatus
Published
Erschienen in
Archives of Toxicology. 2019, 93(7), pp. 1965-1978. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-019-02469-8
Zusammenfassung

The kidney is a frequent target for organ-specific toxicity as a result of its primary function in controlling body fluids, for example, via resorption of amino acids, peptides, nutrients, ions, xenobiotics and water from the primary urine as well as excretion of metabolic waste products and hydrophilic and amphiphilic xenobiotics. Compounds exhibiting dose-limiting nephrotoxicity include drugs from highly diverse classes and chemical structures, e.g., antibiotics (gentamicin), chemotherapeutics (cisplatin), immunosuppressants (cyclosporine A and tacrolimus) or bisphosphonates (zoledronate). All of these compounds elicit nephrotoxicity primarily by injuring renal proximal tubule epithelial cells (RPTECs). However, prediction of a compound’s nephrotoxic potential in humans to support early unmasking of risk-bearing drug candidates remains an unmet challenge, mainly due to the complex kidney anatomy as well as pronounced inter- and intraspecies differences and lack of relevant and validated human in vitro models. Accordingly, we used the recently established human RPTEC/TERT1 cell line to carry out toxicity studies with a focus on impairment of functional characteristics, i.e., transepithelial electrical resistance (TEER), vectorial transport of water, cations, and anions. Results were compared to real-time cytotoxicity assessments using cellular impedance (xCELLigence assay) and the routine cell viability readout (MTT). As expected, most toxins caused exposure time- and concentration-dependent cytotoxicity. However, for some compounds (cyclosporine A and tacrolimus), transport processes were strongly impaired in absence of a concomitant decrease in cell viability. In conclusion, these data demonstrate that functional parameters are important, highly sensitive and meaningful additional readouts for nephrotoxicity assessment in human renal proximal tubule epithelial cells.

Zusammenfassung in einer weiteren Sprache
Fachgebiet (DDC)
570 Biowissenschaften, Biologie
Schlagwörter
Kidney, Nephrotoxicity, Proximal tubule, In vitro, Epithelial transport
Konferenz
Rezension
undefined / . - undefined, undefined
Zitieren
ISO 690SECKER, Philipp Fabian, Nadja SCHLICHENMAIER, Mario BEILMANN, Ulrich DESCHL, Daniel R. DIETRICH, 2019. Functional transepithelial transport measurements to detect nephrotoxicity in vitro using the RPTEC/TERT1 cell line. In: Archives of Toxicology. 2019, 93(7), pp. 1965-1978. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-019-02469-8
BibTex
@article{Secker2019-07Funct-45951,
  year={2019},
  doi={10.1007/s00204-019-02469-8},
  title={Functional transepithelial transport measurements to detect nephrotoxicity in vitro using the RPTEC/TERT1 cell line},
  number={7},
  volume={93},
  issn={0340-5761},
  journal={Archives of Toxicology},
  pages={1965--1978},
  author={Secker, Philipp Fabian and Schlichenmaier, Nadja and Beilmann, Mario and Deschl, Ulrich and Dietrich, Daniel R.}
}
RDF
<rdf:RDF
    xmlns:dcterms="http://purl.org/dc/terms/"
    xmlns:dc="http://purl.org/dc/elements/1.1/"
    xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#"
    xmlns:bibo="http://purl.org/ontology/bibo/"
    xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#"
    xmlns:foaf="http://xmlns.com/foaf/0.1/"
    xmlns:void="http://rdfs.org/ns/void#"
    xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > 
  <rdf:Description rdf:about="https://kops.uni-konstanz.de/server/rdf/resource/123456789/45951">
    <dc:contributor>Schlichenmaier, Nadja</dc:contributor>
    <dc:creator>Dietrich, Daniel R.</dc:creator>
    <dcterms:abstract xml:lang="eng">The kidney is a frequent target for organ-specific toxicity as a result of its primary function in controlling body fluids, for example, via resorption of amino acids, peptides, nutrients, ions, xenobiotics and water from the primary urine as well as excretion of metabolic waste products and hydrophilic and amphiphilic xenobiotics. Compounds exhibiting dose-limiting nephrotoxicity include drugs from highly diverse classes and chemical structures, e.g., antibiotics (gentamicin), chemotherapeutics (cisplatin), immunosuppressants (cyclosporine A and tacrolimus) or bisphosphonates (zoledronate). All of these compounds elicit nephrotoxicity primarily by injuring renal proximal tubule epithelial cells (RPTECs). However, prediction of a compound’s nephrotoxic potential in humans to support early unmasking of risk-bearing drug candidates remains an unmet challenge, mainly due to the complex kidney anatomy as well as pronounced inter- and intraspecies differences and lack of relevant and validated human in vitro models. Accordingly, we used the recently established human RPTEC/TERT1 cell line to carry out toxicity studies with a focus on impairment of functional characteristics, i.e., transepithelial electrical resistance (TEER), vectorial transport of water, cations, and anions. Results were compared to real-time cytotoxicity assessments using cellular impedance (xCELLigence assay) and the routine cell viability readout (MTT). As expected, most toxins caused exposure time- and concentration-dependent cytotoxicity. However, for some compounds (cyclosporine A and tacrolimus), transport processes were strongly impaired in absence of a concomitant decrease in cell viability. In conclusion, these data demonstrate that functional parameters are important, highly sensitive and meaningful additional readouts for nephrotoxicity assessment in human renal proximal tubule epithelial cells.</dcterms:abstract>
    <dc:language>eng</dc:language>
    <dc:creator>Deschl, Ulrich</dc:creator>
    <dcterms:title>Functional transepithelial transport measurements to detect nephrotoxicity in vitro using the RPTEC/TERT1 cell line</dcterms:title>
    <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/45951"/>
    <dc:contributor>Dietrich, Daniel R.</dc:contributor>
    <dc:creator>Beilmann, Mario</dc:creator>
    <dcterms:rights rdf:resource="https://rightsstatements.org/page/InC/1.0/"/>
    <dc:contributor>Deschl, Ulrich</dc:contributor>
    <dc:creator>Schlichenmaier, Nadja</dc:creator>
    <dcterms:issued>2019-07</dcterms:issued>
    <foaf:homepage rdf:resource="http://localhost:8080/"/>
    <dc:rights>terms-of-use</dc:rights>
    <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2019-06-06T09:19:54Z</dcterms:available>
    <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2019-06-06T09:19:54Z</dc:date>
    <dc:creator>Secker, Philipp Fabian</dc:creator>
    <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/45951/1/Secker_2-13bnedmpv0sag8.pdf"/>
    <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/>
    <dc:contributor>Secker, Philipp Fabian</dc:contributor>
    <dc:contributor>Beilmann, Mario</dc:contributor>
    <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/45951/1/Secker_2-13bnedmpv0sag8.pdf"/>
  </rdf:Description>
</rdf:RDF>
Interner Vermerk
xmlui.Submission.submit.DescribeStep.inputForms.label.kops_note_fromSubmitter
Kontakt
URL der Originalveröffentl.
Prüfdatum der URL
Prüfungsdatum der Dissertation
Finanzierungsart
Kommentar zur Publikation
Allianzlizenz
Corresponding Authors der Uni Konstanz vorhanden
Internationale Co-Autor:innen
Universitätsbibliographie
Ja
Begutachtet
Ja