Dysfunction of the retinal pigment epithelium with age: Increased iron decreases phagocytosis and lysosomal activity

Purpose: Iron accumulation with age in the retinal pigment pithelium (RPE) may be one important source of oxidative stress that contributes to age-related macular degeneration (AMD). Young and old rodent RPE/choroid were compared to assess iron homeostasis during normal aging and the effects of increased iron on the functions of retinal pigment epithelial cells. Methods: The iron level, mRNA expression, and protein level of iron-regulatory molecules in RPE/choroid were quantitatively compared between young and old animals. To test the effects of increased intracellular iron on the functions of retinal pigment epithelial cells, in vitro ARPE-19 cells were treated with high levels of iron and assessed for phagocytosis activity and lysosomal activity. Results: Iron level was significantly increased in the aged RPE/choroid. Ferritin and ceruloplasmin mRNAs were significantly increased in the aged RPE/choroid, whereas transferrin, transferrin receptor, and ferroportin mRNAs did not change with age. At the protein level, decreased transferrin and transferrin receptor, increased ferritin and ceruloplasmin, and unchanged ferroportin were observed in the aged RPE/choroid. Exposure of ARPE-19 cells to increased iron markedly decreased phagocytosis activity, interrupted cathepsin D processing, and reduced cathepsin D activity in retinal pigment epithelial cells. Conclusions: The RPE/choroid of aged animals demonstrates iron accumulation and associated alterations in iron homeostasis. Iron accumulation with age may impair the phagocytosis and lysosomal functions of retinal pigment epithelial cells in the aged RPE/choroid. Therefore, age-related changes of iron homeostasis in the RPE could increase the susceptibility of the tissue to genetic mutations associated with AMD.