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R. Wong, P. Hahn, Z.L. Harris, J.L. Dunaief; Ceruloplasmin and Hephaestin Serve Overlapping Regulatory Functions in Ocular Iron Homeostasis . Invest. Ophthalmol. Vis. Sci. 2003;44(13):465.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Ceruloplasmin and hephaestin are ferroxidases important for the export of iron from cells to plasma. The purpose of this study was to investigate the roles of ceruloplasmin and hephaestin in regulating retinal iron levels. Methods: Mice deficient in ceruloplasmin (cp) were generated and crossed with the hephaestin-deficient (sla) mouse to generate cp-/-sla- mice. Iron levels in these eyes (cp-/-, sla-, and cp-/-sla-) were compared to wild-type by the enhanced Perl’s stain and by immunolabeling retinas for ferritin. Ultrastructural changes were examined by electron microscopy. Ceruloplasmin and hephaestin in the eye were localized by immunohistochemistry and Western analysis. Results: Substantial increases in iron were observed in the RPE and non-pigmented ciliary body epithelium of 5-6 month cp-/-sla- eyes only, whose retinas also had increases in both H- and L-ferritin. These increases appear to be age-dependent, as 4 week cp-/-sla- mice did not demonstrate increased iron. At the ultrastructural level, the RPE and ciliary bodies of 5 month cp-/-sla- eyes only contained electron-dense siderosomes, and the RPE was highly vacuolated. Both ceruloplasmin and hephaestin were present in Müller cells and the non-pigmented ciliary body epithelium. Conclusions: Ceruloplasmin and hephaestin thus serve overlapping functions in the regulation of retinal iron, such that combined deficiency results in age-dependent accumulation of iron in the RPE and ciliary body. As iron is a generator of potent free radicals, ceruloplasmin and hephaestin may serve to protect the retina against oxidative damage by removing excess iron. Iron accumulates in the RPE in some AMD eyes (Hahn P, ARVO abstract, submitted, 2003), and the cp-/-sla- mouse may provide a model of age-related macular degeneration and/or other retinal diseases.
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