LAUSR

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. HighlightsUpregulation 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.