Zinc transport from the endoplasmic reticulum to the cytoplasm via Zip7 is necessary for barrier dysfunction mediated by inflammatory signaling in RPE cells

Abstract

Inflammatory signaling induces barrier dysfunction in retinal-pigmented epithelium (RPE) cells and plays a role in the pathology of age-related macular degeneration (AMD). We studied the role of Zn flux from the endoplasmic reticulum (ER) to the cytoplasm via Zip7 during inflammatory signaling in RPE cells. In ARPE-19 cells, Zip7 inhibition reduced impedance loss, FITC-dextran permeability and cytokine induction caused by challenge with IL-1β/TNF-α. Zip7 inhibition in iPS-derived RPE cells challenged with TNF- α reduced barrier loss in TER assays. In ARPE-19 cells, a Zn ionophore restored cytokine induction and barrier loss in cells challenged with IL-1 β /TNF- α despite Zip7 inhibition. A cell permeable Zn chelator demonstrated that Zn is essential for IL-1 β /TNF- α signaling. ER stress caused by Zip7 inhibition in ARPE-19 cells was found to partially contribute to reducing barrier dysfunction caused by IL-1 β /TNF- α. Overall, it was shown that Zn flux through Zip7 from the ER to the cytoplasm plays a critical role in driving barrier dysfunction caused by inflammatory cytokines in RPE cells.

Modulation of Adverse Health Effects of Environmental Cadmium Exposure by Zinc and Its Transporters

“…Dysregulated metal homeostasis, evident from reduced levels of Zn and Cu in the RPE and choroid complex, may also be a contributing factor [151]. Like data for UROtsa cells (Table 3), various ZIP and ZnT are expressed in adult human RPE cells and the ARPE-19 cell line, which provide entry routes for both Zn and Cd [152][153][154][155].…”