Repressing c-Jun N-terminal kinase signaling mitigates retinal pigment epithelium degeneration in mice with failure to clear all-trans-retinal

• Published in: Experimental eye research 2022-01, Vol.214, p.108877-108877, Article 108877
• Main Authors: Tao, Lei, He, Danxue, Liao, Chunyan, Cai, Binxiang, Chen, Chao, Wang, Yan, Chen, Jingmeng, Liu, Zuguo, Wu, Yalin
• Format: Article
• Language: English
• Subjects: Alcohol Oxidoreductases - genetics; Alcohol Oxidoreductases - metabolism; Animals; Apoptosis; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Blotting, Western; c-Jun N-Terminal kinase (JNK); Caspase 3 - metabolism; Cells, Cultured; Chromatography, High Pressure Liquid; Endoplasmic reticulum stress; Endoplasmic Reticulum Stress - physiology; Fluorescent Antibody Technique, Indirect; Humans; In Situ Nick-End Labeling; JNK Mitogen-Activated Protein Kinases - metabolism; Macular degeneration; Mice; Mice, Inbred C57BL; Mice, Knockout; Reactive oxygen species; Reactive Oxygen Species - metabolism; Retinal Degeneration - metabolism; Retinal Degeneration - pathology; Retinal Degeneration - prevention & control; Retinal pigment epithelium; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - pathology; Retinaldehyde - metabolism; Signal Transduction - physiology; Stargardt's disease; Zonula Occludens-1 Protein - metabolism
• ISSN: 0014-4835; 1096-0007
• DOI: 10.1016/j.exer.2021.108877

Retinal pigment epithelium (RPE) cell apoptosis arising from all-trans-retinal (atRAL) is in close contact with the etiology of dry age-related macular degeneration (AMD) and autosomal recessive Stargardt's disease (STGD1), but its underlying mechanisms remain elusive. In this study, we reported that c-Jun N-terminal kinase (JNK) activation facilitated atRAL-induced apoptosis of RPE cells. Reactive oxygen species production and endoplasmic reticulum stress were identified as two of major upstream events responsible for activating JNK signaling in atRAL-loaded RPE cells. Inhibiting JNK signaling rescued RPE cells from apoptosis induced by atRAL through attenuating caspase-3 activation leading to poly-ADP-ribose polymerase (PARP) cleavage, and DNA damage response. Abca4−/−Rdh8−/− mice upon light exposure exhibit rapidly increased accumulation of atRAL in the retina, and display severe RPE degeneration, a primary attribute of dry AMD and STGD1. Reducing JNK signaling by intraperitoneally injected JNK–IN-8 was highly effective in preventing RPE atrophy and apoptosis in light-exposed Abca4−/−Rdh8−/− mice. These findings afford a further understanding for contribution of JNK activation by atRAL to retinal damage. •JNK activation in response to atRAL promoted apoptosis of RPE cells.•ROS production and ER stress were responsible for activating JNK signaling in atRAL-loaded RPE cells.•Inhibiting JNK signaling prevented RPE atrophy and apoptosis in retinopathies characterized by disrupted atRAL clearance.