Disruption of podocyte cytoskeletal biomechanics by dasatinib leads to nephrotoxicity

Area of Science:

• Nephrology
• Molecular Biology
• Pharmacology

Background:

• Nephrotoxicity is a significant side effect of kinase inhibitor (KI) therapy, often necessitating treatment cessation.
• Glomerular toxicity associated with KIs can be severe and requires further mechanistic understanding.

Purpose of the Study:

• To investigate the direct link between dasatinib and podocyte injury.
• To elucidate the molecular mechanisms underlying dasatinib-induced nephrotoxicity.
• To evaluate the impact of dasatinib on podocyte cellular biomechanics.

Main Methods:

• Meta-analyses of FDA Adverse Event Reporting System data.
• In vitro studies using dasatinib-treated podocytes.
• Phosphoproteomics and kinome profiling.
• Atomic force microscopy.
• In vivo studies with chronic dasatinib administration in mice.

Main Results:

• Dasatinib treatment is linked to high risk for glomerular toxicity, independent of hypertension.
• Dasatinib alters podocyte focal adhesions, actin cytoskeleton, and morphology.
• Molecular profiling identified dasatinib-induced injury to the actin cytoskeleton.
• Atomic force microscopy revealed impaired cellular biomechanics in dasatinib-treated podocytes.
• Mice treated with dasatinib exhibited reversible glomerular dysfunction and podocyte structural changes.

Conclusions:

• Dasatinib induces nephrotoxicity by directly targeting podocytes.
• Alterations in the podocyte actin cytoskeleton and cellular biomechanics are key mechanisms of dasatinib-induced kidney injury.
• These findings highlight a specific mechanism of KI-related nephrotoxicity.