Ceruloplasmin/hephaestin knockout mice model morphologic and molecular features of AMD
Open accessAbstract
PURPOSE: Iron is an essential element in human metabolism but also is a potent generator of oxidative damage with levels that increase with age. Several studies suggest that iron accumulation may be a factor in age-related macular degeneration (AMD). In prior studies, both iron overload and features of AMD were identified in mice deficient in the ferroxidase ceruloplasmin (Cp) and its homologue hephaestin (Heph) (double knockout, DKO). In this study, the location and timing of iron accumulation, the rate and reproducibility of retinal degeneration, and the roles of oxidative stress and complement activation were determined. METHODS: Morphologic analysis and histochemical iron detection by Perls' staining was performed on retina sections from DKO and control mice. Immunofluorescence and immunohistochemistry were performed with antibodies detecting activated complement factor C3, transferrin receptor, L-ferritin, and macrophages. Tissue iron levels were measured by atomic absorption spectrophotometry. Isoprostane F2alpha-VI, a specific marker of oxidative stress, was quantified in the tissue by gas chromatography/mass spectrometry. RESULTS: DKOs exhibited highly reproducible age-dependent iron overload, which plateaued at 6 months of age, with subsequent progressive retinal degeneration continuing to at least 12 months. The degeneration shared some features of AMD, including RPE hypertrophy and hyperplasia, photoreceptor degeneration, subretinal neovascularization, RPE lipofuscin accumulation, oxidative stress, and complement activation. CONCLUSIONS: DKOs have age-dependent iron accumulation followed by retinal degeneration modeling some of the morphologic and molecular features of AMD. Therefore, these mice are a good platform on which to test therapeutic agents for AMD, such as antioxidants, iron chelators, and antiangiogenic agents.
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Evidence of focal CNV was present in 75% of 12-13 month-old Cp−/−Heph−/Y mice and 50% of 7-9 month-old mice.
“Evidence of focal CNV was also present in 75% of 12–13 month-old mice and 50% of 7–9 month-old mice (Hahn et al., 2004; Hadziahmetovic et al., 2008).”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Hadziahmetovic et al., 2008
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Iron importers Zip8 and Zip14 are expressed in retina and regulated by retinal iron levels
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Ferroxidase Hephaestin's Cell-Autonomous Role in the Retinal Pigment Epithelium
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- Authors
- Hadziahmetovic, M., Dentchev, T., Song, Y., Haddad, N., He, X., Hahn, P., Pratico, D., Wen, R., Harris, Z. L., Lambris, J. D., Beard, J., & Dunaief, J. L.
- Affiliations
- University of Pennsylvania (US)
- Department of Pharmacology, Temple University, Philadelphia, Pennsylvania; the
- University of Miami (US)
- Johns Hopkins University (US)
- Pennsylvania State University (US)
- From the F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, and the
- ORCID
- Venue
- Investigative Opthalmology & Visual Science
- Published
- 2008-06-01
- Volume
- 49
- Issue
- 6
- Pages
- 2728
- ISSN
- 0146-0404 (ISSN-L)
- 1552-5783
- PMC
- PMC2569891
- OpenAlex
- W2081933988
- Cited by
- 121
- References
- 46
- Citations by year
- 2025: 3 · 2023: 1 · 2022: 5 · 2021: 6 · 2020: 6 · 2019: 3 · 2018: 6 · 2017: 5 · 2016: 3 · 2015: 14 · 2014: 12 · 2013: 6 · 2012: 14
- FWCI
- 12.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Investigative Ophthalmology & Visual Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Eye Institute (EY 015240, R01EY015240)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- age-related macular degeneration, ceruloplasmin, hephaestin, iron overload, retinal degeneration, oxidative stress, complement activation, retinal pigment epithelium, photoreceptor degeneration, subretinal neovascularization, lipofuscin, isoprostanes, iron chelators, antioxidants, anti-angiogenic therapy
- MeSH terms
- Animals, Apoferritins, Ceruloplasmin, Choroid, Complement Activation, Complement C3, Disease Models, Animal, Iron, Macrophages, Macular Degeneration, Gas Chromatography-Mass Spectrometry, Membrane Proteins, Mice, Inbred C57BL, Pigment Epithelium of Eye, Complement Factor B, Receptors, Transferrin, Retina, Spectrophotometry, Atomic, Dinoprost, Mice, Knockout, Oxidative Stress, Iron Overload, Mice
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