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, Evren U. Azeloglu

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


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.

Original languageEnglish
Article number2061
JournalNature Communications
Issue number1
StatePublished - 1 Dec 2019


Dive into the research topics of 'Disruption of podocyte cytoskeletal biomechanics by dasatinib leads to nephrotoxicity'. Together they form a unique fingerprint.

Cite this