Abstract
The retinal pigment epithelium (RPE), which is among the tissues in the body that are exposed to the highest levels of phagocytosis and oxidative stress, is dependent on autophagy function. Impaired autophagy and continuous cellular stress are associated with various disorders, such as dry age-related macular degeneration (AMD), a disease for which effective therapies are lacking. Cysteinyl leukotriene receptor (CysLTR) 1 is a potential modulator of autophagy; thus, the aim of this study was to investigate the role of CysLTR1 in autophagy regulation in the RPE cell line ARPE-19. The polarized ARPE-19 monolayer exhibited expression of CysLTR1, which was colocalized with β-tubulin III. In ARPE-19 cells, autophagic activity was rhythmically regulated and was increased upon CysLTR1 inhibition by Zafirlukast (ZK) treatment. H2O2 affected the proautophagic regulatory effect of ZK treatment depending on whether it was applied simultaneously with or prior to ZK treatment. Furthermore, mRNA levels of genes related to the leukotriene system, autophagy and the unfolded protein response were positively correlated. As CysLTR1 is involved in autophagy regulation under basal and oxidative stress conditions, a dysfunctional leukotriene system could negatively affect RPE functions. Therefore, CysLTR1 is a potential target for new treatment approaches for neurodegenerative disorders, such as AMD.
Highlights
The retinal pigment epithelium (RPE), which is among the tissues in the body that are exposed to the highest levels of phagocytosis and oxidative stress, is dependent on autophagy function
As endoplasmic reticulum (ER) stress induced by brefeldin A increases CysLTR1 expression[6], we investigated the effect of H2O2 as an ER stress inducer on CysLTR1 mRNA and protein expression in polarized ARPE-19 cells
RPE cells are exposed to high levels of phagocytosis and oxidative stress; functional autophagy is essential for ensuring the integrity of the R PE22
Summary
The retinal pigment epithelium (RPE), which is among the tissues in the body that are exposed to the highest levels of phagocytosis and oxidative stress, is dependent on autophagy function. It was reported that inhibition of ALOX5 by PEDF-R peptides increases the survival of RPE cells undergoing oxidative stress[5] This augmented survival of RPE cells could be explained by the recent finding that LTC4 induces an intracellular death-triggering mechanism in the late phase of the unfolded protein response (UPR) caused by excessive endoplasmic reticulum (ER) s tress[6]. As the inhibition of intracellular L TC4 receptor signaling keeps the cell in a prosurvival UPR state and moderate UPR activity induces autophagy to cope with ER stress, it seems obvious that leukotriene receptor antagonists could have the potential to regulate autophagy. Defective autophagic and lysosomal mechanisms can result in accumulation of damaged proteins, leading to cellular degeneration and cell death
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