Protective effect of zinc against A2E-induced toxicity in ARPE19 cells: Possible involvement of lysosomal acidification
- Dry age-related macular degeneration (AMD) is characterized by the accumulation of insoluble extracellular aggregates called drusen and the degeneration of photoreceptor cells and retinal pigment epithelium (RPE) cells. It has been proposed that dysfunctional lysosomes in the RPE cells contribute to the pathology of dry AMD by hindering the degradation of shed photoreceptor membranes. We have previously shown that raising the intracellular zinc levels can restore the lysosomal acidity and degradative functions of lysosomes. In the present study, we examined the effects of zinc on lysosomal alkalization and dysfunction in an in vitro model of AMD.
We used A2E (a lipofuscin derivative) to induce lysosomal dysfunction in a human RPE cell line (ARPE-19) and quantitatively assessed the A2E-induced cell death by measuring the amount of lactate dehydrogenase (LDH) released into the culture medium. The lysosomal pH of the cells treated with a zinc ionophore was measured using pHrodo™ Red-AM. In addition, we observed the effects of zinc on the lysosomal acidity and degradative functions in A2E-treated ARPE19 cells.
Twenty-four hours after A2E treatment, the ARPE19 cells showed a significant amount of cell death, increased A2E accumulation, and decreased pHrodo™ Red AM signals compared to the control cells. Moreover, the zinc ionophore decreased the amount of A2E autofluorescence and restored the lysosomal pH to the acidic range. Following treatment of the ARPE19 cells with the zinc ionophore, A2E-induced cell death was significantly reduced.
These results support the possibility that adequate levels of zinc may help to overcome the cytotoxic effects of A2E or lysosomal alkalinizing agents, both of which may contribute to the pathogenesis of AMD.
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- Dry age-related macular degeneration (dry AMD); retinal pigment epithelium (RPE); lysosome; zinc; ARPE-19 cells
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