Oxidative stress and diabetic retinopathy: Pathophysiological mechanisms and treatment perspectives

Abstract

Retinopathy is one of the most severe ocular complications of diabetes and is a leading cause of acquired blindness in young adults. The cellular components of the retina are highly coordinated but very susceptible to the hyperglycemic environment. The microvasculature of the retina responds to hyperglycemic milieu through a number of biochemical changes, including increased oxidative stress and polyol pathway, PKC activation and advanced glycation end product formation. Oxidative stress is considered as one of the crucial contributors in the pathogenesis of diabetic retinopathy, but oxidative stress appears to be highly interrelated with other biochemical imbalances that lead to structural and functional changes and accelerated loss of capillary cells in the retinal microvasculature and, ultimately, pathological evidence of the disease. One such potential connection that links oxidative stress to metabolic alterations is gyceraldehyde-3-phosphate dehydrogenase whose activity is impaired in diabetes, and that results in activation of other major pathways implicated in the pathogenesis of diabetic retinopathy. Alterations associated with oxidative stress offer many potential therapeutic targets making this an area of great interest to the development of safe and effective treatments for diabetic retinopathy. Animal models of diabetic retinopathy have shown beneficial effects of antioxidants on the development of retinopathy, but clinical trials (though very limited in numbers) have provided somewhat ambiguous results. Although antioxidants are being used for other chronic diseases, controlled clinical trials are warranted to investigate potential beneficial effects of antioxidants in the development of retinopathy in diabetic patients.

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

“…155 Consumption of dark chocolate is associated with blood pressure reduction associated with a reduction in oxidative stress and increase in nitric oxide bioavailability, 156 both abnormalities that have been involved in the pathogenesis of diabetic nephropathy and retinopathy. 67,[85][86][87][88][93][94][95][97][98][99]156 Finally, in experimental diabetes, the use of green tea was associated with an improvement in diabetic nephropathy and retinopathy and associated with a reduction in oxidative stress. 91, 157 The usefulness of these dietary approaches in diabetic patients with hypertension and nephropathy or retinopathy that are on standard treatment deserves to be tested in larger clinical trials.…”

“…92 Further corroborating the contribution of hypertension to retinal damage in diabetic SHR, we have demonstrated that anti-hypertensive treatment either with losartan (an AT1 receptor blocker, ARB) or with triple therapies (hydralazine, reserpine and hydrochlorothiazide) abolished these effects. 84 In the retina, a number of studies have shown that there is an increase in oxidative markers after the induction of DM, 67,[93][94][95] but the concomitance of diabetes and hypertension evoked earlier oxidative retinal damage characterized by an increase in nitrotyrosine and 8-OHdG in retinal tissue from short-term STZ-induced DM in SHRs. [96][97][98][99] These oxidative markers were the consequence of an increase in superoxide production and depletion of the gluthationereduced antioxidant system in the retinal tissue.…”

Associations of FPG, A1C and disease duration with protein markers of oxidative damage and antioxidative defense in type 2 diabetes and diabetic retinopathy

“…7 Globally, DM is the leading cause of blindness, especially in developing countries. 8,9 Hyperglycemia, glycation of hemoglobin, and duration of diabetes disease are among multiple factors involved in the development of diabetic retinopathy (DR). 9,10 In addition, retinal ischemia and OS are important processes in developing DR. Of much importance, it has been reported that hyperglycemia per se lead to increased generation of FRs and OS.…”

“…8,9 Hyperglycemia, glycation of hemoglobin, and duration of diabetes disease are among multiple factors involved in the development of diabetic retinopathy (DR). 9,10 In addition, retinal ischemia and OS are important processes in developing DR. Of much importance, it has been reported that hyperglycemia per se lead to increased generation of FRs and OS. 11,12 The status of OS in health and disease is determined by an array of oxidative damage markers and antioxidant defense systems.…”

Role of matrix metalloproteinase-2 and -9 in the development of diabetic retinopathy

“…Considerable experimental evidence, generated in both tissue culture and animal models, indicate that in diabetes, retinal cells undergoes accelerated apoptosis and induces acellular capillaries and pericyte ghosts in retinal vasculature by unknown mechanism [12][13][14]. Over the last several years, multiple mechanisms on the altered cell signaling pathways and its components, including oxidative stress and polyol pathway, protein kinase C (PKC), and mitogen-activated protein kinases (MAPK) in the microvasculature of the diabetic retina have been shown [15][16][17][18][19][20][21][22][23]. Understanding on such mechanistic pathways might help to develop future adjuvant therapies for diabetic retinopathy.…”