High hepcidin level accounts for the nigral iron accumulation in acute peripheral iron intoxication rats

Hepcidin is considered to be a circulatory hormone and a major mechanism regulating iron homeostasis. Our previous publication revealed that acute iron intoxication induced iron deposit and dopaminergic neuron degeneration in the substantia nigra (SN) of a rat model. However, whether and how hepcidin functions in this nigral iron accumulation has not been elucidated. In the present study, we observed a decreased of FPN1 protein level in the SN triggered by peripheral iron overload within 4. h, which correlated with a high hepcidin level. To further investigate the role of intracellular hepcidin under iron overload circumstances, we assessed the expression of hepcidin mRNA and FPN1 protein in vitro. We observed that hepcidin mRNA level was up-regulated and FPN1 protein level was down-regulated in MES23.5 dopaminergic cells in a period of 4. h incubation with iron. Both in pCMV-XL4-hepcidin transfected and hepcidin-treated cells, decreased FPN1 protein levels were observed. Our data provide direct evidence that the role for intracellular hepcidin generated in the SN is particularly relevant to restrict iron release by down-regulation FPN1 expression in this region, thus an important contributor to the abnormal iron deposit occurred at an early stage in conditions of peripheral iron intoxication.