Evidence of oxidative stress in the pathogenesis of fuchs endothelial corneal dystrophy.
Fuchs endothelial corneal dystrophy (FECD) is a progressive, blinding disease characterized by corneal endothelial (CE) cell apoptosis. Corneal transplantation is the only measure currently available to restore vision in these patients. Despite the identification of some genetic factors, the pathophysiology of FECD remains unclear. In this study, we observed a decrease in the antioxidant response element-driven antioxidants in FECD corneal endothelium. We further demonstrated that nuclear factor erythroid 2-related factor 2, a transcription factor known to bind the antioxidant response element and activate antioxidant defense, is down-regulated in FECD endothelium. Importantly, we detected significantly higher levels of oxidative DNA damage and apoptosis in FECD endothelium compared with normal controls and pseudophakic bullous keratopathy (iatrogenic CE cell loss) specimens. A marker of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, colocalized to mitochondria, indicating that the mitochondrial genome is the specific target of oxidative stress in FECD. Oxidative DNA damage was not detected in pseudophakic bullous keratopathy corneas, whereas it colocalized with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells in FECD samples. Ex vivo, oxidative stress caused characteristic morphological changes and apoptosis of CE, suggestive of findings that characterize FECD in vivo. Together, these data suggest that suboptimal nuclear factor erythroid 2-related factor 2-regulated defenses may account for oxidant-antioxidant imbalance in FECD, which in turn leads to oxidative DNA damage and apoptosis. This study provides evidence that oxidative stress plays a key role in FECD pathogenesis.
Jurkunas
Ula V
UV
Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114, USA. ula_jurkunas@meei.harvard.edu
Bitar
Maya S
MS
Funaki
Toshinari
T
Azizi
Behrooz
B
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D016039:Corneal Transplantation; D004249:DNA Damage; D004728:Endothelium, Corneal / Q000166:cytology / Q000187:drug effects / Q000473:pathology* / Q000601:surgery; D005642:Fuchs' Endothelial Dystrophy / Q000473:pathology* / Q000503:physiopathology* / Q000601:surgery; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress
D000975:Antioxidants; D016877:Oxidants; D006861:Hydrogen Peroxide