Prevention of cadmium accumulation in retinal pigment epithelium with manganese and zinc

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the elderly. Risk factors include old age, female gender, obesity, smoking, low dietary intakes of antioxidants and increased exposure to the toxic metal cadmium (Cd²⁺). Supplementation with high-dose zinc (80 mg) provides some protection, but the mechanism(s) underlying such protection has not been fully elucidated. The present study had a focus on the human retinal pigment epithelial (RPE) cell line ARPE-19 in an attempt to demonstrate a reduction in intracellular Cd²⁺ effect associated with heme oxygenase-1 (HO-1) expression by co-exposure with zinc (Zn²⁺) or manganese (Mn²⁺), which is known to be a more potent inhibitor of Cd²⁺ uptake than Zn²⁺. Our results indicated that co-exposure of 10 μM Cd²⁺ with 5 μM Mn²⁺ reduced the intracellular Cd²⁺ effect by 50-60%, possibly by limiting the amounts of Cd²⁺ entering cells through Mn²⁺ transporter protein (ZIP8). A similar reduction in a Cd²⁺ effect was achieved by co-exposure with 20 μM Zn²⁺ while co-exposure with 5 and 10 μM Zn²⁺ ions was ineffective. Mn²⁺ ions as low as 2.5 μM were found to cause an increase in HO-1 mRNA expression levels in ARPE-19 cells, demonstrating for the first time that Mn²⁺ is an inducer of HO-1. Mn²⁺ ions at 1 μM induced HO-1 mRNA expression in the HEK293 human embryonic kidney cells. In contrast, Zn²⁺ in 5, 10 or 20 μM concentrations did not induce expression of HO-1 in ARPE-19 cells or any other cells tested. These data suggest the superiority of Mn²⁺ over Zn²⁺ in preventing Cd²⁺ uptake and accumulation in RPE to toxic levels. Further, induction of HO-1 by Mn²⁺ could provide RPE with some resistance to enhanced oxidative stress arising from Cd²⁺ accumulation in RPE as HO-1 is one of the frontline cellular antioxidant defense mechanisms.