Nature communications, 2019-05, Vol.10 (1), p.2061-15, Article 2061
2019
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- Autor(en) / Beteiligte
- Titel
- Disruption of podocyte cytoskeletal biomechanics by dasatinib leads to nephrotoxicity
- Ist Teil von
- Nature communications, 2019-05, Vol.10 (1), p.2061-15, Article 2061
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Nephrotoxicity is a critical adverse event that leads to discontinuation of kinase inhibitor (KI) treatment. Here we show, through meta-analyses of FDA Adverse Event Reporting System, that dasatinib is associated with high risk for glomerular toxicity that is uncoupled from hypertension, suggesting a direct link between dasatinib and podocytes. We further investigate the cellular effects of dasatinib and other comparable KIs with varying risks of nephrotoxicity. Dasatinib treated podocytes show significant changes in focal adhesions, actin cytoskeleton, and morphology that are not observed with other KIs. We use phosphoproteomics and kinome profiling to identify the molecular mechanisms of dasatinib-induced injury to the actin cytoskeleton, and atomic force microscopy to quantify impairment to cellular biomechanics. Furthermore, chronic administration of dasatinib in mice causes reversible glomerular dysfunction, loss of stress fibers, and foot process effacement. We conclude that dasatinib induces nephrotoxicity through altered podocyte actin cytoskeleton, leading to injurious cellular biomechanics.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-019-09936-xTitel-ID: cdi_doaj_primary_oai_doaj_org_article_8269d038cbb047b6863d44efd06fc28f
- Format
- –
- Schlagworte
- Actin, Actin Cytoskeleton - drug effects, Adverse Drug Reaction Reporting Systems - statistics & numerical data, Animals, Antineoplastic Agents - adverse effects, Atomic force microscopy, Biomechanics, Cell Line, Cytoskeleton, Dasatinib - adverse effects, Disease Models, Animal, Disruption, Enzyme inhibitors, Fibers, Humans, Hypertension, Kinases, Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy, Mice, Microscopy, Molecular modelling, Morphology, Podocytes - drug effects, Podocytes - metabolism, Podocytes - pathology, Protein Kinase Inhibitors - adverse effects, Renal Insufficiency, Chronic - chemically induced, Renal Insufficiency, Chronic - pathology, Toxicity, United States, United States Food and Drug Administration