Disruption of podocyte cytoskeletal biomechanics by dasatinib leads to nephrotoxicity
| Autor: | William J. Janssen, Hong Li, Tong Liu, J. G. Coen van Hasselt, Xuhua Ge, Gomathi Jayaraman, Jia-Jye Lee, Christina M. Cuttitta, Evren U. Azeloglu, Nicholas J. Wong, Robert J. Wiener, Fadi Salem, Edgar A. Jaimes, Rhodora Cristina Calizo, Smiti Bhattacharya, Chengguo Wei, Vivienne H. Au, Kirk N. Campbell, Jenny Wong, Barbara Murphy |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Science Dasatinib General Physics and Astronomy Antineoplastic Agents 02 engineering and technology Article General Biochemistry Genetics and Molecular Biology Cell Line Podocyte Nephrotoxicity Focal adhesion Mice 03 medical and health sciences Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases Adverse Drug Reaction Reporting Systems Animals Humans Medicine Kinome Renal Insufficiency Chronic lcsh:Science Drug safety Cytoskeleton Protein Kinase Inhibitors Actin Multidisciplinary Podocytes United States Food and Drug Administration business.industry Kinase urogenital system General Chemistry 021001 nanoscience & nanotechnology Actin cytoskeleton United States 3. Good health Actin Cytoskeleton Disease Models Animal 030104 developmental biology medicine.anatomical_structure Cancer research lcsh:Q 0210 nano-technology business medicine.drug |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-15 (2019) Nature Communications Nature Communications, 10, 2061 |
| ISSN: | 2041-1723 |
| Popis: | 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. Kinase inhibitors used in chemotherapy are known for their adverse effects on kidney physiology. Here, Calizo et al. show that dasatinib is associated with a higher risk of glomerular toxicity compared to other kinase inhibitors, due to deleterious effects on cytoskeletal biomechanics in podocytes. |
| Databáze: | OpenAIRE |
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