title: Iron importers Zip8 and Zip14 are expressed in retina and regulated by retinal iron levels.
abstract: Intracellular retinal iron accumulation has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of irreversible blindness among individuals over the age of 50. Ceruloplasmin/hephaestin double knockout mice (Cp/Heph DKO) and hepcidin knockout mice (Hepc KO) accumulate retinal iron and model some features of AMD. Two canonical pathways govern cellular iron import - transferrin-bound iron import and non-transferrin bound iron import. In Cp/Heph DKO and Hepc KO iron-loaded retinas, transferrin-bound iron import is downregulated. Despite this effort to reduce cellular iron burden, iron continues to accumulate in these retinas in an age-dependent manner. Quantitative RT-PCR and Western analysis were used to quantify the expression of three ferrous iron importers, Dmt1, Zip8, and Zip14, in wild-type (Wt), Cp/Heph DKO, and Hepc KO retinas. Zip8 and Zip14 protein levels were analyzed using Western analysis in mice injected intravitreally with either apo- or holo-transferrin to elucidate one possible mechanism of Zip14 regulation in the retina. Both zip8 and zip14 were expressed in the mouse retina. Paradoxically, protein levels of non-transferrin bound iron importers were upregulated in both Cp/Heph DKO and Hepc KO retinas. Intravitreal holo-transferrin injection decreased Zip 14 protein levels. These data indicate that Zip8 and Zip14 may take up increasing amounts of non-transferrin bound iron in these two mouse models of retinal iron accumulation. Their upregulation in these already iron-loaded retinas suggests a vicious cycle leading to toxicity.
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, 305 Stellar-Chance Laboratory, 422 Curie Blvd, Philadelphia, PA 19104, USA. Electronic address: jacobst@sas.upenn.edu.
authors.forename: Jacob
authors.initials: J
authors.lastname: Sterling
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, 305 Stellar-Chance Laboratory, 422 Curie Blvd, Philadelphia, PA 19104, USA. Electronic address: spg65@drexel.edu.
authors.forename: Samyuktha
authors.initials: S
authors.lastname: Guttha
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, 305 Stellar-Chance Laboratory, 422 Curie Blvd, Philadelphia, PA 19104, USA. Electronic address: yingsong@mail.med.upenn.edu.
authors.forename: Ying
authors.initials: Y
authors.lastname: Song
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, 305 Stellar-Chance Laboratory, 422 Curie Blvd, Philadelphia, PA 19104, USA. Electronic address: delusong@mail.med.upenn.edu.
authors.forename: Delu
authors.initials: D
authors.lastname: Song
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, 305 Stellar-Chance Laboratory, 422 Curie Blvd, Philadelphia, PA 19104, USA. Electronic address: majdahadziahmetovic@gmail.com.
authors.forename: Majda
authors.initials: M
authors.lastname: Hadziahmetovic
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, 305 Stellar-Chance Laboratory, 422 Curie Blvd, Philadelphia, PA 19104, USA. Electronic address: jdunaief@upenn.edu.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Dunaief
mesh_terms: D000818:Animals; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D058449:Intravitreal Injections; D007501:Iron / Q000378:metabolism*; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012160:Retina / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014168:Transferrin / Q000008:administration & dosage
chemical_list: D027682:Cation Transport Proteins; C500556:SLC39A14 protein, mouse; C499256:Slc39a8 protein, mouse; D014168:Transferrin; D012313:RNA; D007501:Iron
keywords: Age-related macular degeneration (AMD); Ceruloplasmin; Hepcidin; Hephaestin; Iron; Retina; Zip14; Zip8