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1 From the Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia; 2 Développement, Vieillissement et Pathologie de la Rétine, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U)450, Affiliée Centre National de la Recherche Scientifique (CNRS), Association Claude Bernard, Paris, France; 3 CNRS-Unité de Recherche Associée (URA)451, Chimie Nucléaire Analytique et Bioenvironmentale, Le Haut Vigneau, Bordeaux-Gradignan, France; and 4 Faculté X. Bichat, INSERM U409, Paris, France.
PURPOSE. To determine whether iron homeostasis disorder accompanies retinal degeneration in Royal College of Surgeons (RCS) rats.
METHODS. The presence of iron was revealed directly by proton-induced x-ray emission (PIXE) and indirectly by electron microscopy (EM). Ferritin, transferrin (Tf), and transferrin receptor (Tf-R) were localized by immunohistochemistry. Ferritin and Tf proteins were analyzed by Western blot analysis. Comparative study of Tf-R content was performed by slot-blot analysis and ferritin content was evaluated by enzyme-linked immunosorbent assay (ELISA). Ferritin and Tf-R expression was studied by reverse transcription–polymerase chain reaction (RT-PCR) and Tf expression by in situ hybridization (ISH). All studies were performed in RCS and control retinas from postnatal days (PN)20 to PN55.
RESULTS. PIXE analysis showed iron accumulation in outer retina of RCS rats in a time-dependent manner. EM studies revealed irregular iron inclusions on partially degenerated outer segments (OS) of photoreceptors and lamellar whorls at PN35 and very large iron deposits on membranes from a debris layer at PN55. No such deposits were found in the inner retina. Ferritin and Tf-R expression and protein levels seemed to be unaffected in the inner part of the retina. Iron accumulation was preceded by Tf degradation, as revealed by immunohistochemistry and Western blot analysis. Tf mRNA was detected in RCS rat retinal pigment epithelium (RPE) at all stages studied.
CONCLUSIONS. This study presents the first evidence for a correlation of iron homeostasis imbalance with the neurodegenerative state of the retina in RCS rats. The iron imbalance is not the underlying genetic defect but is the result of impaired RPE–photoreceptor interaction, which leads to debris accumulation and subsequent blockage of the outer retina’s iron delivery pathway. The increase of iron in the photoreceptor area may enhance the vulnerability of cells to oxidative stress.
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