title: Deferasirox-induced iron depletion promotes BclxL downregulation and death of proximal tubular cells.
abstract: Iron deficiency has been associated with kidney injury. Deferasirox is an oral iron chelator used to treat blood transfusion-related iron overload. Nephrotoxicity is the most serious and common adverse effect of deferasirox and may present as an acute or chronic kidney disease. However, scarce data are available on the molecular mechanisms of nephrotoxicity. We explored the therapeutic modulation of deferasirox-induced proximal tubular cell death in culture. Deferasirox induced dose-dependent tubular cell death and AnexxinV/7AAD staining showed features of apoptosis and necrosis. However, despite inhibiting caspase-3 activation, the pan-caspase inhibitor zVAD-fmk failed to prevent deferasirox-induced cell death. Moreover, zVAD increased deferasirox-induced cell death, a feature sometimes found in necroptosis. Electron microscopy identified mitochondrial injury and features of necrosis. However, neither necrostatin-1 nor RIP3 knockdown prevented deferasirox-induced cell death. Deferasirox caused BclxL depletion and BclxL overexpression was protective. Preventing iron depletion protected from BclxL downregulation and deferasirox cytotoxicity. In conclusion, deferasirox promoted iron depletion-dependent cell death characterized by BclxL downregulation. BclxL overexpression was protective, suggesting a role for BclxL downregulation in iron depletion-induced cell death. This information may be used to develop novel nephroprotective strategies. Furthermore, it supports the concept that monitoring kidney tissue iron depletion may decrease the risk of deferasirox nephrotoxicity.
authors.affiliation: Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.|IRSIN, Madrid, Spain.|REDINREN, Madrid, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Martin-Sanchez
authors.affiliation: Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.|IRSIN, Madrid, Spain.|REDINREN, Madrid, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Gallegos-Villalobos
authors.affiliation: Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.|IRSIN, Madrid, Spain.|REDINREN, Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Fontecha-Barriuso
authors.affiliation: Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.|IRSIN, Madrid, Spain.|REDINREN, Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Carrasco
authors.affiliation: Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.|IRSIN, Madrid, Spain.|REDINREN, Madrid, Spain.
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Sanchez-Niño
authors.affiliation: IRSIN, Madrid, Spain.|REDINREN, Madrid, Spain.|Biomedical Research Institute of Salamanca, University of Salamanca, Salamanca, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Lopez-Hernandez
authors.affiliation: Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.|IRSIN, Madrid, Spain.|REDINREN, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.affiliation: Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.|IRSIN, Madrid, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.affiliation: Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.|IRSIN, Madrid, Spain.|REDINREN, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.|IRSIN, Madrid, Spain.|REDINREN, Madrid, Spain.
authors.forename: Ana Belén
authors.initials: AB
authors.lastname: Sanz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001565:Benzoates / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D000077588:Deferasirox; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D007501:Iron / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008954:Models, Biological; D009336:Necrosis; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: D001565:Benzoates; D014230:Triazoles; D051020:bcl-X Protein; D007501:Iron; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053148:Caspase 3; D000077588:Deferasirox