Abstract
The hepcidin/ferroportin axis controls systemic iron homeostasis by regulating iron acquisition from the duodenum and reticuloendothelial system, respective sites of iron absorption and recycling. Ferroportin is also abundant in the kidney, where it has been implicated in tubular iron reabsorption. However, it remains unknown whether endogenous hepcidin regulates ferroportin-mediated iron reabsorption under physiological conditions, and whether such regulation is important for kidney and/or systemic iron homeostasis. To address these questions, we generated a novel mouse model with an inducible kidney-tubule specific knock-in of fpnC326Y, which encodes a hepcidin-resistant ferroportin termed FPNC326Y. Under conditions of normal iron availability, female mice harboring this allele had consistently decreased kidney iron but only transiently increased systemic iron indices. Under conditions of excess iron availability, male and female mice harboring this allele had milder kidney iron overload, but greater systemic iron overload relative to controls. Additionally, despite comparable systemic iron overload, kidney iron overload occurred in wild type mice fed an iron-loaded diet but not in hemochromatosis mice harboring a ubiquitous knock-in of fpnC326Y. Thus, our study demonstrates that endogenous hepcidin controls ferroportin-mediated tubular iron reabsorption under physiological conditions. It also shows that such control is important for both kidney and systemic iron homeostasis in the context of iron overload.
Highlights
The findings of the present study have implications that must be considered in the management of iron disorders and in the development of new iron therapies
Our results demonstrate that endogenous hepcidin antimicrobial peptide (HAMP) directly regulates FPN-mediated iron absorption and that this regulation is important for both renal and systemic iron homeostasis, in the setting of excess iron availability
We compared the pattern of tissue iron overload in these mice with that seen in wild-type mice fed an iron-loaded diet from weaning for 3 months. Both Fpnwt/ C326Ymice and wild-type mice fed an iron-loaded diet had DISCUSSION The most important finding of the present study is that endogenous HAMP controls FPN-mediated iron reabsorption
Summary
The findings of the present study have implications that must be considered in the management of iron disorders and in the development of new iron therapies. FPN is abundant in the kidney and has been implicated in iron reabsorption.[11,12,13,14] it remains unknown if renal FPN is subject to regulation by endogenous HAMP under normal physiological conditions, and if so, whether such regulation is important for systemic and/or renal 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 HAMP-resistant FPNC326Y protein. Our results demonstrate that endogenous HAMP directly regulates FPN-mediated iron absorption and that this regulation is important for both renal and systemic iron homeostasis, in the setting of excess iron availability
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