Iron importers Zip8 and Zip14 are expressed in retina and regulated by retinal iron levels. (February 2017)

• Record Type: Journal Article
• Authors: Sterling, Jacob; Guttha, Samyuktha; Song, Ying; Song, Delu; Hadziahmetovic, Majda; Dunaief, Joshua L.
• Is Part Of: Experimental eye research. Volume 155(2017)
• Page Start: 15
• Page End: 23
• Publication Date: 2017-02
• Subjects: Zip8 -- Zip14 -- Retina -- Iron -- Age-related macular degeneration (AMD) -- Ceruloplasmin -- Hephaestin -- Hepcidin; Ophthalmology -- Periodicals; Eye -- Periodicals; Œil -- Périodiques; Ophthalmology; Periodicals; Electronic journals; 612.8405
• DOI: 10.1016/j.exer.2016.12.008
• Languages: English
• ISSNs: 0014-4835

Abstract

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. Highlights: Upregulation of Zip8 and Zip14 may contribute to retinal iron overload. Zip8 and/or Zip14 protein is upregulated in mouse models of retinal iron overload. Zip8 and Zip14 are regulated on the post-transcriptional level in iron loaded retinas. Zip14 but not Zip8 protein levels are sensitive to intraocular holo-transferrin injection.