ZIP2 and ZIP4 mediate age-related zinc fluxes across the retinal pigment epithelium

Decreases in systemic and cellular levels of zinc (Zn²⁺) during normal aging correlate with several agerelated pathologies including age-related macular degeneration. Zn²⁺ homeostasis in tissues is not only dependent on dietary intake but also on optimal expression and function of its influx (ZIP) and efflux (ZnT) transporters. We recently showed that many of the Zn²⁺ transporters are expressed by the retinal pigment epithelial (RPE) cells. In this study, we present evidence that RPE cells contain less endogenous Zn²⁺ with increased aging and transport this ion vectorially with greater transport from the basal to apical direction. Expression of two Zn²⁺ influx transporters, ZIP2 and ZIP4, is reduced as a function of RPE age. Gene silencing of ZIP2 and ZIP4 in RPE cells from young donors or their overexpression in cells from older donors confirms that these two transporters are essential in controlling Zn²⁺influx and sequestration in RPE cells. Both transporters are distributed on the basal surface of the RPE where they are likely to control Zn²⁺ homeostasis in the outer retina.