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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.
Highlights
Iron deficiency has been associated with kidney injury
We used 10 and 100 μMdeferasirox to explore the molecular mechanisms of deferasirox nephrotoxicity
Deferasirox-induced cell death increased in a time-dependent manner (Fig. 1D).The percentage of hypodiploid cells, typical of apoptosis, was higher at 10 μM than at 50–100 μM deferasirox (Fig. 1E), suggesting a dose-dependent shift in the mode of cell death
Summary
Iron deficiency has been associated with kidney injury. Deferasirox is an oral iron chelator used to treat blood transfusion-related iron overload. We explored the therapeutic modulation of deferasirox-induced proximal tubular cell death in culture. 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. Scarce data are available on the molecular mechanisms of nephrotoxicity and the reasons for the specific proximal tubular sensitivity to the drug. We have explored the molecular mechanisms of deferasirox nephrotoxicity in cultured proximal tubular cells as well as the opportunities for therapeutic manipulation. Deferasirox-induced proximal tubular cell death had features of both apoptosis and necrosis and was dependent on iron availability. Other commonly used inhibitors of apoptotic or necroptotic cell death were unable to prevent cell death
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