Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Nat Commun. 2019 May 3;10(1):2061. doi: 10.1038/s41467-019-09936-x.
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.
肾毒性是导致激酶抑制剂（KI）治疗中断的严重不良事件。在这里，我们通过 FDA 不良事件报告系统的荟萃分析表明，达沙替尼与肾小球毒性风险增加相关，而与高血压无关，这表明达沙替尼与足细胞之间存在直接联系。我们进一步研究了达沙替尼和其他具有不同肾毒性风险的可比 KI 的细胞效应。用达沙替尼处理的足细胞显示出焦点粘连、肌动蛋白细胞骨架和形态的显著变化，而其他 KI 则没有观察到这些变化。我们使用磷酸化蛋白质组学和激酶组谱分析来确定达沙替尼诱导肌动蛋白细胞骨架损伤的分子机制，并使用原子力显微镜来量化对细胞生物力学的损害。此外，达沙替尼在小鼠中的慢性给药导致可逆性肾小球功能障碍、应激纤维丧失和足突融合。我们的结论是，达沙替尼通过改变足细胞肌动蛋白细胞骨架引起肾毒性，导致细胞生物力学损伤。
