Abstract
Abstract: :
Purpose: Ceruloplasmin (Cp) and its homolog hephaestin (Heph) are ferroxidases that facilitate iron export from cells into plasma. Patients with aceruloplasminemia have retinal degeneration whose mechanism has yet to be elucidated. The aim of the current study is to generate a model of this retinal degeneration and determine whether Cp and Heph play a role in retinal iron homeostasis. Methods: Mice deficient in Cp and/or Heph were generated. Normal retinal expression and localization of Cp and Heph were determined by RT–PCR, Western analysis, and immunohistochemistry. In eyes deficient in Cp and/or Heph, iron accumulation was assessed by the Perls’ stain for iron, and morphologic changes were visualized by histochemical and ultrastructural analysis of sectioned eyes. Results: In normal eyes, Cp and Heph localized to Müller glia and retinal pigment epithelium (RPE), a blood–brain barrier. Mice deficient in both Cp and Heph, but not each individually, had a striking, age dependent increase in RPE and retinal iron. The iron storage protein ferritin also increased in Cp–/–Heph–/– retinas. Old Cp–/–Heph–/– mice had RPE hypertrophy, hyperplasia and death, photoreceptor degeneration, subretinal neovascularization, and sub–RPE long–spaced collagen deposits, providing a model of some features of both aceruloplasminemia and age–related macular degeneration. Conclusions: These data demonstrate the importance of Cp and Heph in retinal iron homeostasis and provide a model of iron overload–induced retinal degeneration with neovascularization to test the therapeutic efficacy of iron chelators and anti–angiogenic agents.
Keywords: cell death/apoptosis • oxidation/oxidative or free radical damage • retinal degenerations: cell biology