Role of unfolded protein response dysregulation in oxidative injury of retinal pigment epithelial cells.
OBJECTIVE
Age-related macular degeneration (AMD), a major cause of legal blindness in the elderly, is associated with genetic and environmental risk factors, such as cigarette smoking. Recent evidence shows that cigarette smoke (CS) that contains high levels of potent oxidants preferably targets retinal pigment epithelium (RPE) leading to oxidative damage and apoptosis; however, the mechanisms are poorly understood. The present study aimed to investigate the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in CS-related RPE apoptosis.


RESULTS
ER stress and proapoptotic gene C/EBP homologous protein (CHOP) were induced in the RPE/choroid complex from mice exposed to CS for 2 weeks and in human RPE cells treated with hydroquinone, a potent oxidant found at high concentrations in CS. Suppressing ER stress or inhibiting CHOP activation by pharmacological chaperones or genetic approaches attenuated hydroquinone-induced RPE cell apoptosis. In contrast to enhanced CHOP activation, protein level of active X-box binding protein 1 (XBP1), a major regulator of the adaptive UPR, was reduced in hydroquinone-treated cells. Conditional knockout of XBP1 gene in the RPE resulted in caspase-12 activation, increased CHOP expression, and decreased antiapoptotic gene Bcl-2. Furthermore, XBP1-deficient RPE cells are more sensitive to oxidative damage induced by hydroquinone or NaIO3, a CS-unrelated chemical oxidant. Conversely, overexpressing XBP1 protected RPE cells and attenuated oxidative stress-induced RPE apoptosis.


CONCLUSIONS
These findings provide strong evidence suggesting an important role of ER stress and the UPR in CS-related oxidative injury of RPE cells. Thus, the modulation of the UPR signaling may provide a promising target for the treatment of AMD.
1 Department of Ophthalmology/Ross Eye Institute, University at Buffalo, The State University of New York , Buffalo, New York.
Chen
C
Chen
Marisol
M
Cano
Joshua J
JJ
Wang
Jingming
J
Li
Chuangxin
C
Huang
Qiang
Q
Yu
Terence P
TP
Herbert
James T
JT
Handa
Sarah X
SX
Zhang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D008268:Macular Degeneration / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010084:Oxidation-Reduction / Q000187:drug effects; D000071701:Regulatory Factor X Transcription Factors; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D012907:Smoking / Q000009:adverse effects; D013329:Structure-Activity Relationship; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects; D000071717:X-Box Binding Protein 1
C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; D006873:Hydroquinones; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D051742:Transcription Factor CHOP; C031927:hydroquinone