期刊
TOXICOLOGY LETTERS
卷 322, 期 -, 页码 77-86出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2020.01.005
关键词
All-trans-retinal; Retinal pigment epithelial cell; Oxidative stress; Autophagy; Autophagic cell death; Endoplasmic reticulum stress
类别
资金
- National Natural Science Foundation of China [81801424]
- Zhejiang Provincial Natural Science Foundation of China [LQ17H120001]
- Medical Science and Technology Program of Zhejiang Province [2016KYA195, 2017KY714, 2015KYB429]
- 211 Talents Training Program of Taizhou
Failure of all-trans-retinal (atRAL) clearance contributes to retina degeneration. However, whether autophagy can be activated by excess atRAL accumulation in retinal pigment epithelial (RPE) cells is not known. This study showed that atRAL provoked mitochondria-associated reactive oxygen species (ROS) production, activated the nuclear factor (erythroid-derived 2)-like 2 and apoptosis in a human RPE cell line, ARPE-19 cells. Moreover, we found that autophagic flux was functionally activated after atRAL treatment. The antioxidant N-acetylcysteine attenuated the expression of autophagy markers, suggesting that ROS triggered atRAL-activated autophagy. In addition, autophagic cell death was observed in atRAL-treated RPE cells, while inhibition of autophagy with 3-methyladenine or LC3, Beclin1, p62 silencing ameliorated atRAL-induced cytotoxicity. Suppression of autophagy quenched mitochondrial ROS and inhibited HO-1 and gamma-GCSh expression, indicating that atRAL-activated autophagy enhances intracellular oxidative stress, thereby promoting RPE cell apoptosis. Furthermore, we found that inhibiting endoplasmic reticulum (ER) stress suppressed atRAL-induced mitochondrial ROS generation, subsequently attenuated autophagy and apoptosis in RPE cells. Taken together, these results suggest that atRAL-induced oxidative stress and ER stress modulate autophagy, which may contribute to RPE degeneration. There may be positive feedback regulatory mechanisms between atRAL-induced oxidative stress and autophagy or ER stress.
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