The suppression of hepcidin by anemia and erythropoietin (EPO) is mediated by a fall in serum iron

Abstract

Hepcidin (the principal negative iron regulatory hormone) decreases after blood loss or exogenous EPO, allowing increased iron absorption or release from stores (Nicolas et al, JCI 2002; Nicolas et al, Blood Cells Mol. Dis. 2002) and facilitating the (re)expansion of the red blood cell (RBC) pool. However, it is not clear whether the immediate signal for hepcidin suppression is increased erythropoietin, decreased iron, or anemia-associated tissue hypoxia. We postulated that anemia and EPO regulate hepcidin by a fall in serum iron due to iron utilization for hemoglobin synthesis. We used carboplatin and adriamycin, two antineoplastic agents that inhibit RBC production by different mechanisms, to arrest RBC production and hemoglobin synthesis, and so dissociate the direct effects of anemia and EPO on hepcidin from their indirect effects via increased iron utilization for hemoglobin synthesis. As expected, mice with severe anemia due to phlebotomy or mice given exogenous EPO both increased RBC production accompanied by a fall in serum iron and in hepatic hepcidin mRNA concentration. When mice were given carboplatin before phlebotomy or EPO, RBC production was inhibited, serum iron rose significantly, and hepatic hepcidin mRNA rose in parallel despite anemia or EPO. Adriamycin or neutralizing EPO antibody given before phlebotomy produced the same effect, suggesting that carboplatin did not directly upregulate hepcidin. Serum-amyloid-A-1 and fibrinogen-γ (acute phase reactants) expression did not increase in response to carboplatin or adriamycin, indicating that the increase in hepcidin was not regulated by inflammation. Conclusion Hepcidin suppression by anemia or EPO is mediated by increased iron utilization and a fall in serum iron, and not by the direct effects of anemia or EPO.