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K. Leung, K. K. Erickson, M. J. Seiler, J. M. Burke, C. J. Barnstable, J. Tombran-Tink; Age-Related Changes in the Expression of ZnT and ZIP Zinc Transporters Human RPE and Their Regulation by Neurotrophic Factors. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5544.
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© ARVO (1962-2015); The Authors (2016-present)
Zinc is an essential cofactor for normal cell function. Altered expression and function of zinc transporters may contribute to the pathogenesis of neurodegenerative disorders including macular degeneration. We recently reported that many zinc transporters are expressed in the human RPE cells. Here we examined the regulation of zinc transporters in the RPE with aging, the toxicity of zinc to these cells, and the effects of neurotrophic factors on RPE zinc uptake.
The expression of the ZnT and ZIP zinc transporters in young and old RPE cells was examined by PCR, immunocytochemistry, and western blot analysis. Zinc toxicity to the human RPE cell line, ARPE19, was determined using MTT, propidium iodide (PI), and TUNEL assays. Zn2+ uptake was visualized with Zinquin ethyl ester. The effects of the neurotrophic factors, BDNF, CNTF, GDNF, and PEDF, on the expression of zinc transporters were also examined.
Our studies show alteration in expression of several zinc transporters in RPE cells with aging. ZnT5 expression was not observed while ZnT6, ZIP1 and ZIP13 were the most abundantly expressed in all RPE samples. Addition of low concentrations of Zn2+ to ARPE19 cultures resulted in a dose-dependent increase in intracellular Zn2+ content in the cells and >30 nM Zn2+ induced necrosis with an LC50 = 117.4 nM. BDNF, CNTF, GDNF, and PEDF increased ZIP2, GDNF and PEDF increased ZnT2, and PEDF increased ZnT3 and ZnT8 expression. These neurotrophic factors also promoted Zn2+ uptake in the RPE.
The types of zinc transporters expressed by the RPE at different stages of development may play a key role in zinc homeostasis in the retina and in ocular health and diseases.
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