Hepcidin mitigates renal ischemia-reperfusion injury by modulating systemic iron homeostasis

Abstract

Iron-mediated oxidative stress is implicatedin thepathogenesisof renal ischemia-reperfusion injury.Hepcidin is an endogenous acute phase hepatic hormone that prevents iron export fromcells by inducing degradation of the only known iron export protein, ferroportin. In this study, we used a mouse model to investigate the effect of renal ischemia-reperfusion injury on systemic iron homeostasis and determine if dynamicmodulation of iron homeostasiswith hepcidin has therapeutic benefit in the treatment ofAKI. Renal ischemia-reperfusion injury induced hepatosplenic iron export through increased ferroportin expression, which resulted in hepatosplenic iron depletion and an increase in serum and kidney nonheme iron levels. Exogenous hepcidin treatment prevented renal ischemia-reperfusion-induced changes in iron homeostasis. Hepcidin also decreased kidney ferroportin expression and increased the expression of cytoprotective H-ferritin. Hepcidininduced restoration of iron homeostasis was accompanied by a significant reduction in ischemia-reperfusion- induced tubular injury, apoptosis, renal oxidative stress, and inflammatory cell infiltration. Hepcidin-deficient mice demonstrated increased susceptibility to ischemia-reperfusion injury compared with wild-type mice. Reconstituting hepcidin-deficient mice with exogenous hepcidin induced hepatic iron sequestration, attenuated the reduction in renal H-ferritin and reduced renal oxidative stress, apoptosis, inflammation, and tubular injury.Hepcidin-mediated protection was associatedwith reduced serumIL-6 levels. In summary, renal ischemia- reperfusion injury results in profound alterations in systemic iron homeostasis. Hepcidin treatment restores iron homeostasis and reduces inflammation to mediate protection in renal ischemia-reperfusion injury, suggesting that hepcidin-ferroportin pathway holds promise as a novel therapeutic target in the treatment of AKI.