Abstract
Oxidative stress plays a critical role in age-related macular degeneration (AMD), and epithelial-mesenchymal transition (EMT) is involved in this process. The aim of this study was to investigate the protective effects of luteolin, a natural flavonoid with strong antioxidant activity, on H2O2-induced EMT in ARPE-19 cells. ARPE-19 cells were incubated with H2O2 at 200 μΜ to induce oxidative stress-associated injury. Cell viability assay showed that luteolin at 20 and 40 μM significantly promoted cell survival in H2O2-treated ARPE-19 cells. Luteolin also markedly protected ARPE-19 cells from H2O2-induced apoptosis. Cell migration assay presented that luteolin significantly reduced H2O2-induced migration in APRE-19 cells. EMT in ARPE-19 cells was detected by western blotting and immunofluorescence. The results showed that H2O2 significantly upregulated the expression of α-SMA and vimentin and downregulated the expression of ZO-1 and E-cadherin, while cells pretreated with luteolin showed a reversal. Meanwhile, the assessment of effects of luteolin on the Nrf2 pathway indicated that luteolin promoted Nrf2 nuclear translocation and upregulated the expressions of HO-1 and NQO-1. In addition, luteolin significantly increased the activities of SOD and GSH-PX and decreased intracellular levels of ROS and MDA in H2O2-treated ARPE-19 cells. Meanwhile, we observed that the expression of TGF-β2, p-AKT, and p-GSK-3β was upregulated in H2O2-treated ARPE-19 cells and downregulated in luteolin-treated cells, revealing that luteolin inhibited the activation of the AKT/GSK-3β pathway. However, these effects of luteolin were all annulled by transfecting ARPE-19 cells with Nrf2 siRNA. Our current data collectively indicated that inhibition of luteolin on EMT was induced by oxidative injury in ARPE-19 cell through the Nrf2 and AKT/GSK-3β pathway, suggesting that luteolin could be a potential drug for the treatment of dry AMD.
Highlights
Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly [1]
Our previous results showed that the viability of ARPE-19 cells treated with H2O2 at 200 μM decreased to 63% [24]
ARPE-19 cells exposed to H2O2 had significant apoptotic rate compared to control, but luteolin significantly reduced apoptosis. These data collectively indicated that luteolin effectively protected against cell death in ARPE-19 cells treated with H2O2
Summary
Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly [1]. AMD is a multifactorial degenerative disease of the retina. Susceptibility genes, environmental factors, chronic localized inflammation, and choroidal vascular dysfunction all play important roles in the onset and progression of AMD [2]. Retinal pigment epithelium (RPE) is a monolayer cell located between photoreceptors and Bruch’s membrane, characterized by cell-cell adhesion and apical-basal polarity arrangement. RPE transports nutrients from the choroidal capillary layer to the photoreceptors and phagocyte and digests photoreceptor outer segments, which is critical for keeping the photoreceptor function [3]. Abnormal distribution and dysfunction of RPE cells lead to retinal degeneration and eventually to loss of vision
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