Mice with hepcidin-resistant ferroportin accumulate iron in the retina.
Because ferroportin (Fpn) is the only known mammalian cellular iron exporter, understanding its localization and regulation within the retina would shed light on the direction of retinal iron flux. The hormone hepcidin may regulate retinal Fpn, as it triggers Fpn degradation in the gut. Immunofluorescence was used to label Fpn in retinas of mice with 4 different genotypes (wild type; Fpn C326S, a hepcidin-resistant Fpn; hepcidin knockout; and ceruloplasmin/hephaestin double knockout). No significant difference in Fpn levels was observed in these retinas. Fpn localized to the abluminal side of the outer plexiform vascular endothelial cells, Müller glia cells, and the basolateral side of the retinal pigment epithelium. Adeno-associated virus (AAV)-hepcidin was injected into the eyes of hepcidin knockout mice, while AAV-lacZ was injected into the contralateral eyes as a control. AAV-hepcidin injected eyes had increased ferritin immunolabeling in retinal vascular endothelial cells. Fpn C326S mice had systemic iron overload compared to wild type and had the fastest retinal iron accumulation of any hereditary model studied to date. The results suggest that physiologic hepcidin levels are insufficient to alter Fpn levels within the retinal pigment epithelium and Müller cells, but may limit iron transport into the retina from vascular endothelial cells.
*F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Ophthalmology and Optometry, Innsbruck Medical University, Innsbruck, Austria; Department of Psychiatry and Behavioral Sciences, and Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA; Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, Heidelberg, Germany; and European Molecular Biology Laboratory, Heidelberg, Germany.
Milan
M
Theurl
*F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Ophthalmology and Optometry, Innsbruck Medical University, Innsbruck, Austria; Department of Psychiatry and Behavioral Sciences, and Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA; Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, Heidelberg, Germany; and European Molecular Biology Laboratory, Heidelberg, Germany.
Delu
D
Song
*F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Ophthalmology and Optometry, Innsbruck Medical University, Innsbruck, Austria; Department of Psychiatry and Behavioral Sciences, and Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA; Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, Heidelberg, Germany; and European Molecular Biology Laboratory, Heidelberg, Germany.
Esther
E
Clark
*F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Ophthalmology and Optometry, Innsbruck Medical University, Innsbruck, Austria; Department of Psychiatry and Behavioral Sciences, and Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA; Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, Heidelberg, Germany; and European Molecular Biology Laboratory, Heidelberg, Germany.
Jacob
J
Sterling
*F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Ophthalmology and Optometry, Innsbruck Medical University, Innsbruck, Austria; Department of Psychiatry and Behavioral Sciences, and Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA; Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, Heidelberg, Germany; and European Molecular Biology Laboratory, Heidelberg, Germany.
Steve
S
Grieco
*F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Ophthalmology and Optometry, Innsbruck Medical University, Innsbruck, Austria; Department of Psychiatry and Behavioral Sciences, and Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA; Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, Heidelberg, Germany; and European Molecular Biology Laboratory, Heidelberg, Germany.
Sandro
S
Altamura
*F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Ophthalmology and Optometry, Innsbruck Medical University, Innsbruck, Austria; Department of Psychiatry and Behavioral Sciences, and Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA; Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, Heidelberg, Germany; and European Molecular Biology Laboratory, Heidelberg, Germany.
Bruno
B
Galy
*F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Ophthalmology and Optometry, Innsbruck Medical University, Innsbruck, Austria; Department of Psychiatry and Behavioral Sciences, and Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA; Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, Heidelberg, Germany; and European Molecular Biology Laboratory, Heidelberg, Germany.
Matthias
M
Hentze
*F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Ophthalmology and Optometry, Innsbruck Medical University, Innsbruck, Austria; Department of Psychiatry and Behavioral Sciences, and Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA; Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, Heidelberg, Germany; and European Molecular Biology Laboratory, Heidelberg, Germany.
Martina U
MU
Muckenthaler
*F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Ophthalmology and Optometry, Innsbruck Medical University, Innsbruck, Austria; Department of Psychiatry and Behavioral Sciences, and Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA; Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, Heidelberg, Germany; and European Molecular Biology Laboratory, Heidelberg, Germany jdunaief@upenn.edu.
Joshua L
JL
Dunaief
D019943:Amino Acid Substitution; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D064451:Hepcidins / Q000235:genetics / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology; D000098742:Ferroportin
D027682:Cation Transport Proteins; C579599:Hamp protein, mouse; D064451:Hepcidins; D000098742:Ferroportin; D007501:Iron
blood–brain barrier; iron transport; retinal pigment epithelium; vascular endothelium