1. Disruption of podocyte cytoskeletal biomechanics by dasatinib leads to nephrotoxicity.
- Author
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Calizo RC, Bhattacharya S, van Hasselt JGC, Wei C, Wong JS, Wiener RJ, Ge X, Wong NJ, Lee JJ, Cuttitta CM, Jayaraman G, Au VH, Janssen W, Liu T, Li H, Salem F, Jaimes EA, Murphy B, Campbell KN, and Azeloglu EU
- Subjects
- Adverse Drug Reaction Reporting Systems statistics & numerical data, Animals, Cell Line, Disease Models, Animal, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Mice, Podocytes drug effects, Podocytes metabolism, Renal Insufficiency, Chronic chemically induced, United States, United States Food and Drug Administration, Actin Cytoskeleton drug effects, Antineoplastic Agents adverse effects, Dasatinib adverse effects, Podocytes pathology, Protein Kinase Inhibitors adverse effects, Renal Insufficiency, Chronic pathology
- 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.
- Published
- 2019
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