Evidence of Oxidative Stress in the Pathogenesis of Fuchs Endothelial Corneal Dystrophy

Abstract

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 transferasemediated 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. Corneal endothelium (CE) is a monolayer of cells situated in the anterior chamber surface of the cornea; its primary function is to maintain the cornea in a state of deturgescence through sodium-activated ATPase pumping of water, thus, transparency. Fuchs endothelial corneal dystrophy (FECD) is the most common cause of endogenous corneal endothelial degeneration and is characterized by alterations in corneal endothelial cell morphology, progressive loss of CE cells, and concomitant accumulation of extracellular deposits in the basement membrane that eventually lead to corneal edema and opacity. Because CE does not divide in vivo, loss of endothelial cells seen in FECD is permanent. Corneal transplantation is the only treatment modality that can restore lost vision-rendering FECD the second most common cause of corneal transplants performed on the elderly (Ͼ60 years old) in the United States.2 Lack of knowledge of the mechanism of CE degeneration in FECD precludes the development of pharmacotherapeutics for this common and blinding condition.FECD has been termed a disorder of aging; it is a bilateral and slowly progressive disorder, typically appearing after the age of 60 years. FECD is usually a sporadic condition, but it can be inherited as an autosomal dominant trait.3-5 FECD is characterized by endo...

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

“…In this regard, mutations in TERE1 that reduce APOE binding may impair cholesterol and lipid recycling by APOE, and lead to elevated intracellular cholesterol via reduced efflux (Prack et al, 1994;Heeren et al, 2004;Abildayeva et al, 2006;Ha et al, 2009). It may also raise basal oxidative stress, consistent with recent reports regarding pathogenesis of SCD and other corneal dystrophies (Gatzioufas et al, 2010;Jurkunas et al, 2010).…”

Polymorphisms of the Apoptosis-Related FAS and FAS Ligand Genes in Keratoconus and Fuchs Endothelial Corneal Dystrophy

“…Oxidative stress and apoptosis are reported to play a role in the development of FECD particularly in regard to accelerated corneal endothelial cell loss (Borderie et al 2000;Li et al 2001;Buddi et al 2002;Szentmáry et al 2005;Engler et al 2010;Jurkunas et al 2010;Azizi et al 2011). This may be in part due to chronic ultraviolet (UV) light exposure (Inoki et al 2004).…”

“…Both association and linkage studies showed that a polymorphism in the transcription factor 4 (TCF4) gene was associated with FECD (Baratz et al 2010;Li et al 2011). Apoptosis was shown to be involved in the pathogenesis of KC and FECD (Mohan et al 1997;Cho et al 1999;Kim et al 1999;Borderie et al 2000;Li et al 2001;Kaldawy et al 2002;Gottsch et al 2003;Szentmáry et al 2005;Joyce et al 2009;Engler et al 2010;Jurkunas et al 2010). It was also shown that the FAS/FASLG system is expressed in the cornea and might have important functions in normal corneal physiology and in the pathophysiology of corneal diseases, including modulation of keratocyte apoptosis after epithelial injury (Wilson et al 1996).…”

What does the future hold for the treatment of Fuchs endothelial dystrophy; will ‘keratoplasty’ still be a valid procedure?

“…44 Interestingly, several authors have found evidence of increased apoptosis having a role in endothelial cell loss, as observed in FECD. 46,47 Furthermore, it was shown that the defense mechanism of FECD endothelium against oxidative stress-induced damage is impaired when compared with normal cells, 39,45,48,49 which is supported by the observed significant higher levels of (baseline) oxidative stressinduced damage, 43,45,48 and changes in endothelial cell morphology characteristic for oxidative stress. 50 These data suggest that chronic oxidative stress contributes to the pathophysiology of FECD, and that the decreased defense system renders FECD endothelial cells even more susceptible to oxidative stress-induced damage than normal cells already are.…”

“…[40][41][42] Corneal endothelial cells are thought to be especially vulnerable to oxidative stress-induced damage because they do not proliferate and have a high level of metabolic activity owing to their pump function. 39,43 Fortunately, these cells have several defense mechanisms against the detrimental effects of oxidative stress, 44,45 thereby reducing damage and promoting cell survival. However, if oxidative stress persists, the defense mechanisms fail, thereby allowing the cell to accumulate damage.…”