Abstract
Herein, we have investigated retinal cell-death pathways in response to the retina toxin sodium iodate (NaIO3) both in vivo and in vitro. C57/BL6 mice were treated with a single intravenous injection of NaIO3 (35 mg/kg). Morphological changes in the retina post NaIO3 injection in comparison to untreated controls were assessed using electron microscopy. Cell death was determined by TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining. The activation of caspases and calpain was measured using immunohistochemistry. Additionally, cytotoxicity and apoptosis in retinal pigment epithelial (RPE) cells, primary retinal cells, and the cone photoreceptor (PRC) cell line 661W were assessed in vitro after NaIO3 treatment using the ApoToxGlo™ assay. The 7-AAD/Annexin-V staining was performed and necrostatin (Nec-1) was administered to the NaIO3-treated cells to confirm the results. In vivo, degenerating RPE cells displayed a rounded shape and retracted microvilli, whereas PRCs featured apoptotic nuclei. Caspase and calpain activity was significantly upregulated in retinal sections and protein samples from NaIO3-treated animals. In vitro, NaIO3 induced necrosis in RPE cells and apoptosis in PRCs. Furthermore, Nec-1 significantly decreased NaIO3-induced RPE cell death, but had no rescue effect on treated PRCs. In summary, several different cell-death pathways are activated in retinal cells as a result of NaIO3.
Highlights
Age-related macular degeneration (AMD) is the main cause of blindness in the elderly in industrialized countries
We provide evidence that, in retinal pigment epithelium (RPE) cells, NaIO3 treatment resulted in necrosis in the absence of caspase-dependent conventional cell death, whereas it triggered caspase-dependent apoptosis in the cone photoreceptor cell line 661W
The microvilli are wrapped around the outer segments of the photoreceptors, corresponding to the physiological situation in which shed outer segments are phagocytized by RPE
Summary
Age-related macular degeneration (AMD) is the main cause of blindness in the elderly in industrialized countries. The dry form of AMD is characterized by the disease-associated formation of drusen, which represent debris accumulating between the Bruch’s membrane and the basal lamina of the retinal pigment epithelium (RPE). The sodium iodate (NaIO3) model of pharmacologically induced retinal degeneration, known to display AMD-associated features, was widely used to further understand the cell-death mechanisms in RPE and photoreceptors (PRC) [1,2,3]. In this model, the progression and onset of the degeneration can be modulated, facilitating the design of a potential therapeutic strategy to repopulate the damaged
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