Disruption of podocyte cytoskeletal biomechanics by dasatinib leads to nephrotoxicity Journal Article

Authors: Calizo, R. C.; Bhattacharya, S.; van Hasselt, J. G. C.; Wei, C.; Wong, J. S.; Wiener, R. J.; Ge, X.; Wong, N. J.; Lee, J. J.; Cuttitta, C. M.; Jayaraman, G.; Au, V. H.; Janssen, W.; Liu, T.; Li, H.; Salem, F.; Jaimes, E. A.; Murphy, B.; Campbell, K. N.; Azeloglu, E. U.
Article Title: Disruption of podocyte cytoskeletal biomechanics by dasatinib leads to nephrotoxicity
Abstract: 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. © 2019, The Author(s).
Keywords: signal transduction; mitogen activated protein kinase; histopathology; sorafenib; erlotinib; sunitinib; hypertension; nonhuman; animal cell; phenotype; cell viability; mus; imatinib; apoptosis; nephrotoxicity; image analysis; inhibitor; dasatinib; morphology; genome analysis; drug mechanism; western blotting; gefitinib; pazopanib; vandetanib; immunoprecipitation; immunofluorescence test; axitinib; toxicity; nilotinib; cytoskeleton; proteinuria; lapatinib; transmission electron microscopy; actin filament; focal adhesion; stress fiber; atomic force microscopy; bosutinib; liquid chromatography-mass spectrometry; elasticity; elastography; crizotinib; cell disruption; biomechanics; podocyte; detection method; colorimetry; phosphoproteomics; nuclear size; kidney tubule cell; ruxolitinib; tofacitinib; focal adhesion kinase 2; cell component; article; glomerular dysfunction; mtt assay; morphometry; ec50; lim kinase; atomic force microscope elastography; high content image analysis; kinome
Journal Title: Nature Communications
Volume: 10
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2019-05-03
Start Page: 2061
Language: English
DOI: 10.1038/s41467-019-09936-x
PUBMED: 31053734
PROVIDER: scopus
PMCID: PMC6499885
Notes: Source: Scopus
Citation Impact
MSK Authors
  1. Edgar Alberto Jaimes
    33 Jaimes