Continuous exposure to non-lethal doses of sodium iodate induces retinal pigment epithelial cell dysfunction.

Xiao-Yu Zhang,Di Wu,Di Cao,Shaodan Zhang,Yumeng Wang,Sun On Chan,Kwok Ping Chan,Tsz Kin Ng,Jasmine Sum Yee Yung,Jian Xiong Wang,Mårten Erik Brelén,Chi Pui Pang

doi:10.1038/srep37279

Abstract

Age-related macular degeneration (AMD), characterized by progressive degeneration of retinal pigment epithelium (RPE), is the major cause of irreversible blindness and visual impairment in elderly population. We previously established a RPE degeneration model using an acute high dose sodium iodate to induce oxidative stress. Here we report findings on a prolonged treatment of low doses of sodium iodate on human RPE cells (ARPE-19). RPE cells were treated continuously with low doses (2–10 mM) of sodium iodate for 5 days. Low doses (2–5 mM) of sodium iodate did not reduce RPE cell viability, which is contrasting to cell apoptosis in 10 mM treatment. These low doses are sufficient to retard RPE cell migration and reduced expression of cell junction protein ZO-1. Phagocytotic activity of RPE cells was attenuated by sodium iodate dose-dependently. Sodium iodate also increased expression of FGF-2, but suppressed expression of IL-8, PDGF, TIMP-2 and VEGF. Furthermore, HTRA1 and epithelial-to-mesenchymal transition marker proteins were downregulated, whereas PERK and LC3B-II proteins were upregulated after sodium iodate treatment. These results suggested that prolonged exposure to non-lethal doses of oxidative stress induces RPE cell dysfunctions that resemble conditions in AMD. This model can be used for future drug/treatment investigation on AMD.

Highlights

The sodium iodate-induced ARPE-19 cell death in vitro has been shown to be associated with increased levels of reactive oxygen species (ROS) and interleukin-8 (IL-8)[14]
We hypothesized that a prolonged exposure of sub-lethal doses of sodium iodate in human retinal pigment epithelium (RPE) cells (ARPE-19), instead of triggering massive cell death as in acute high dose exposure, affects cellular functions in RPE cells that are closely related to pathophysiological conditions of neovascular Age-related macular degeneration (AMD), which include maintenance of cell integrity, wound healing ability, phagocytotic activity and angiogenic factor expression
Sodium iodate at 1, 2 and 5 mM enhanced the viability of ARPE-19 cells by 160.32%, 188.56% and 84.33% at Day 5 when compared to the control, whereas 10 and 20 mM sodium iodate reduced cell viability by 63.81% and 98.51%, respectively (p < 0.001; Fig. 1B)

Summary

Introduction

The sodium iodate-induced ARPE-19 cell death in vitro has been shown to be associated with increased levels of reactive oxygen species (ROS) and interleukin-8 (IL-8)[14]. Other studies have shown that 5 days exposure of 8 mM tert-butylhydroperoxide (TBHP) induces premature senescence in ARPE-19 cells, and rendering the cells become pro-angiogenic[17]. This treatment upregulates expression of drusen-related molecular chaperones and pro-angiogenic factors[18]. We hypothesized that a prolonged exposure of sub-lethal doses of sodium iodate in human RPE cells (ARPE-19), instead of triggering massive cell death as in acute high dose exposure, affects cellular functions in RPE cells that are closely related to pathophysiological conditions of neovascular AMD, which include maintenance of cell integrity, wound healing ability, phagocytotic activity and angiogenic factor expression

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Conclusion