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Volker Enzmann, Jasmin Balmer, Rahel Zulliger, Sebastian Wolf; Programmed cell death pathways in sodium iodate-induced retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):722.
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Programmed cell death (PCD) is a hallmark of several retinal diseases including aged-related macular degeneration. We have used the mouse model of sodium iodate (NaIO3)-induced retinal degeneration that displays features of the disease in order to investigate involved cell death pathways. NaIO3 is specifically toxic for the retinal pigment epithelium (RPE) and without the underlying RPE cells photoreceptors are undergoing cell death.
Adult C57/BL6 mice received a single i.v. injection of 25 mg/kg NaIO3 to induce retinal degeneration. Quantitative RT-PCR was applied to compare gene expression of specific PCD genes in RPE samples from NaIO3-treated and untreated animals. TUNEL staining was performed on paraffin sections to visualize PCD. Immunohistological staining using activated caspase antibodies as well as caspase activity assays were performed. Additionally, to investigate an involvement of calpains in NaIO3 induced degeneration calpain activity assay and substrate (PARP) immunostaining was performed.
Caspase-1 was significantly upregulated in the RPE cells at day 7 post injection (PI) and cathepsin S expression was increased at day 10, indicating that RPE cells are undergoing necrosis. TUNEL positive apoptotic photoreceptor cells were detected after administration of NaIO3 in the outer nuclear layer (ONL). Caspase 3 positive cells were found throughout the ONL. Photoreceptors were also positively stained for caspase 1 (inflammation), caspase 2 (activator caspase), caspase 9 (DNS damage/oxidative stress) and caspase 12 (endoplasmatic reticulum stress). Caspase activity assays performed on retinal tissue lysates confirmed activation at days 3 (caspase 3) and 10 PI (caspases 1, 2, 9 and 12). Calpain and PARP positive cells were also localized in the ONL, indicating an involvement of caspase in-dependent cell death pathways.
Sodium iodate induces RPE necrosis and subsequent photoreceptor apoptosis. Caspase-independent as well as caspase-dependent cell death is occurring in the NaIO3-induced retinal degeneration. Therefore, combinatory treatment might be necessary to prevent photoreceptor cells from undergoing apoptosis in the NaIO3 mouse model.
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