ABSTRACT The hepcidin/ferroportin axis controls systemic iron homeostasis by regulating iron acquisition from the duodenum and the reticuloendothelial system, respective sites of iron absorption and recycling. Ferroportin is also abundant in the kidney, where it has been implicated in iron reabsorption. However, it remains unknown whether hepcidin regulates ferroportin-mediated iron reabsorption and whether such regulation is important for systemic iron homeostasis. To address these questions, we generated a novel mouse model with an inducible renal-tubule specific knock-in of fpnC326Y , which encodes a hepcidin-resistant FPNC326Y. Under iron-replete conditions, female mice harbouring this allele had lower renal iron content and higher serum and liver iron levels than controls. Under conditions of excess iron availability, male and female mice harbouring this allele had greater liver iron overload, but lower renal iron overload relative to controls. In addition, hemochromatosis mice harbouring a ubiquitous knock-in of fpnC326Y did not develop renal iron overload otherwise seen in the setting of excess iron availability. These findings are the first formal demonstration that hepcidin regulates ferroportin-mediated iron reabsorption. They also show that loss of this regulation contributes to liver iron overload while protecting the kidney in the setting of hemochromatosis. Our findings have important implications. First, they indicate that targeting the hepcidin/ferroportin axis for treating iron overload disorders will inhibit iron reabsorption and increase renal iron content. Second, they suggest that inhibition of iron reabsorption by raised hepcidin in chronic inflammatory conditions contributes to iron deficiency and that parenteral iron supplementation in this setting may cause renal iron overload.

The renal hepcidin/ferroportin axis controls iron reabsorption and determines renal and hepatic susceptibility to iron overload