Disruption of podocyte cytoskeletal biomechanics by dasatinib leads to nephrotoxicity

Rhodora C. Calizo, Smiti Bhattacharya, J. G. Coen van Hasselt, Chengguo Wei, Jenny S. Wong, Robert J. Wiener, Xuhua Ge, Nicholas J. Wong, Jia-Jye Lee, Christina M. Cuttitta, Gomathi Jayaraman, Vivienne H. Au, William Janssen, Tong Liu, Hong Li, Fadi Salem, Edgar A. Jaimes, Barbara Murphy, Kirk N. Campbell and Evren U. Azeloglu ()
Additional contact information
Rhodora C. Calizo: Icahn School of Medicine at Mount Sinai
Smiti Bhattacharya: Icahn School of Medicine at Mount Sinai
J. G. Coen van Hasselt: Icahn School of Medicine at Mount Sinai
Chengguo Wei: Icahn School of Medicine at Mount Sinai
Jenny S. Wong: Icahn School of Medicine at Mount Sinai
Robert J. Wiener: Icahn School of Medicine at Mount Sinai
Xuhua Ge: Icahn School of Medicine at Mount Sinai
Nicholas J. Wong: Icahn School of Medicine at Mount Sinai
Jia-Jye Lee: Icahn School of Medicine at Mount Sinai
Christina M. Cuttitta: Icahn School of Medicine at Mount Sinai
Gomathi Jayaraman: Icahn School of Medicine at Mount Sinai
Vivienne H. Au: Icahn School of Medicine at Mount Sinai
William Janssen: Icahn School of Medicine at Mount Sinai
Tong Liu: Rutgers University–New Jersey Medical School
Hong Li: Rutgers University–New Jersey Medical School
Fadi Salem: Icahn School of Medicine at Mount Sinai
Edgar A. Jaimes: Renal Service, Memorial Sloan Kettering Cancer Center
Barbara Murphy: Icahn School of Medicine at Mount Sinai
Kirk N. Campbell: Icahn School of Medicine at Mount Sinai
Evren U. Azeloglu: Icahn School of Medicine at Mount Sinai

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09936-x

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