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Canagliflozin mediated dual inhibition of mitochondrial glutamate dehydrogenase and complex I : an off-target adverse effect

Canagliflozin mediated dual inhibition of mitochondrial glutamate dehydrogenase and complex I : an off-target adverse effect

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SECKER, Philipp F., Sascha BENEKE, Nadja SCHLICHENMAIER, Johannes DELP, Simon GUTBIER, Marcel LEIST, Daniel R. DIETRICH, 2018. Canagliflozin mediated dual inhibition of mitochondrial glutamate dehydrogenase and complex I : an off-target adverse effect. In: Cell death & disease. 9(2), 226. eISSN 2041-4889. Available under: doi: 10.1038/s41419-018-0273-y

@article{Secker2018-02-14Canag-41619, title={Canagliflozin mediated dual inhibition of mitochondrial glutamate dehydrogenase and complex I : an off-target adverse effect}, year={2018}, doi={10.1038/s41419-018-0273-y}, number={2}, volume={9}, journal={Cell death & disease}, author={Secker, Philipp F. and Beneke, Sascha and Schlichenmaier, Nadja and Delp, Johannes and Gutbier, Simon and Leist, Marcel and Dietrich, Daniel R.}, note={Article Number: 226} }

<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/rdf/resource/123456789/41619"> <dc:contributor>Schlichenmaier, Nadja</dc:contributor> <dc:contributor>Secker, Philipp F.</dc:contributor> <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/41619/1/Secker_2-1qyoy8xzc1rka6.pdf"/> <dc:creator>Leist, Marcel</dc:creator> <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2018-02-27T14:42:49Z</dc:date> <dc:language>eng</dc:language> <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <dc:contributor>Dietrich, Daniel R.</dc:contributor> <dc:creator>Gutbier, Simon</dc:creator> <dc:creator>Secker, Philipp F.</dc:creator> <dc:creator>Beneke, Sascha</dc:creator> <dcterms:issued>2018-02-14</dcterms:issued> <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/> <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2018-02-27T14:42:49Z</dcterms:available> <foaf:homepage rdf:resource="http://localhost:8080/jspui"/> <dcterms:title>Canagliflozin mediated dual inhibition of mitochondrial glutamate dehydrogenase and complex I : an off-target adverse effect</dcterms:title> <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/41619/1/Secker_2-1qyoy8xzc1rka6.pdf"/> <dc:contributor>Beneke, Sascha</dc:contributor> <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <dc:contributor>Delp, Johannes</dc:contributor> <dcterms:abstract xml:lang="eng">Recent FDA Drug Safety Communications report an increased risk for acute kidney injury in patients treated with the gliflozin class of sodium/glucose co-transport inhibitors indicated for treatment of type 2 diabetes mellitus. To identify a potential rationale for the latter, we used an in vitro human renal proximal tubule epithelial cell model system (RPTEC/TERT1), physiologically representing human renal proximal tubule function. A targeted metabolomics approach, contrasting gliflozins to inhibitors of central carbon metabolism and mitochondrial function, revealed a double mode of action for canagliflozin, but not for its analogs dapagliflozin and empagliflozin. Canagliflozin inhibited the glutamate dehydrogenase (GDH) and mitochondrial electron transport chain (ETC) complex I at clinically relevant concentrations. This dual inhibition specifically prevented replenishment of tricarboxylic acid cycle metabolites by glutamine (anaplerosis) and thus altered amino acid pools by increasing compensatory transamination reactions. Consequently, canagliflozin caused a characteristic intracellular accumulation of glutamine, glutamate and alanine in confluent, quiescent RPTEC/TERT1. Canagliflozin, but none of the classical ETC inhibitors, induced cytotoxicity at particularly low concentrations in proliferating RPTEC/TERT1, serving as model for proximal tubule regeneration in situ. This finding is testimony of the strong dependence of proliferating cells on glutamine anaplerosis via GDH. Our discovery of canagliflozin-mediated simultaneous inhibition of GDH and ETC complex I in renal cells at clinically relevant concentrations, and their particular susceptibility to necrotic cell death during proliferation, provides a mechanistic rationale for the adverse effects observed especially in patients with preexisting chronic kidney disease or previous kidney injury characterized by sustained regenerative tubular epithelial cell proliferation.</dcterms:abstract> <dc:contributor>Leist, Marcel</dc:contributor> <dc:creator>Delp, Johannes</dc:creator> <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/41619"/> <dc:contributor>Gutbier, Simon</dc:contributor> <dc:creator>Schlichenmaier, Nadja</dc:creator> <dc:creator>Dietrich, Daniel R.</dc:creator> </rdf:Description> </rdf:RDF>

Dateiabrufe seit 27.02.2018 (Informationen über die Zugriffsstatistik)

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