Format

Send to

Choose Destination
Nat Commun. 2019 May 3;10(1):2061. doi: 10.1038/s41467-019-09936-x.

Disruption of podocyte cytoskeletal biomechanics by dasatinib leads to nephrotoxicity.

Author information

1
Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
2
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
3
Department of Mechanical Engineering, Columbia University, New York, NY, 10027, USA.
4
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
5
Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University-New Jersey Medical School, Newark, NJ, 07103, USA.
6
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
7
Renal Service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
8
Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. evren.azeloglu@mssm.edu.
9
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. evren.azeloglu@mssm.edu.

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.

PMID:
31053734
PMCID:
PMC6499885
DOI:
10.1038/s41467-019-09936-x
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center