Glyoxalase System as a Therapeutic Target against Diabetic Retinopathy

Abstract

Hyperglycemia, a defining characteristic of diabetes, combined with oxidative stress, results in the formation of advanced glycation end products (AGEs). AGEs are toxic compounds that have adverse effects on many tissues including the retina and lens. AGEs promote the formation of reactive oxygen species (ROS), which, in turn, boost the production of AGEs, resulting in positive feedback loops, a vicious cycle that compromises tissue fitness. Oxidative stress and the accumulation of AGEs are etiologically associated with the pathogenesis of multiple diseases including diabetic retinopathy (DR). DR is a devastating microvascular complication of diabetes mellitus and the leading cause of blindness in working-age adults. The onset and development of DR is multifactorial. Lowering AGEs accumulation may represent a potential therapeutic approach to slow this sight-threatening diabetic complication. To set DR in a physiological context, in this review we first describe relations between oxidative stress, formation of AGEs, and aging in several tissues of the eye, each of which is associated with a major age-related eye pathology. We summarize mechanisms of AGEs generation and anti-AGEs detoxifying systems. We specifically feature the potential of the glyoxalase system in the retina in the prevention of AGEs-associated damage linked to DR. We provide a comparative analysis of glyoxalase activity in different tissues from wild-type mice, supporting a major role for the glyoxalase system in the detoxification of AGEs in the retina, and present the manipulation of this system as a therapeutic strategy to prevent the onset of DR.

Biochemical Regulation of the Glyoxalase System in Response to Insulin Signaling

“…Importantly, the elevated level of MG in a Drosophila model may recapitulate the progression of type 2 diabetes, causing flies to become obese, insulin resistant, and hyperglycemic. This raises the question of whether elevated MG might be a cause of type 2 diabetes [ 12 , 13 ].…”

“…Increases in MG-derived AGEs were also found in experimental and clinical diabetes [ 17 , 18 ]. Furthermore, MG metabolism by the glyoxalase system has been linked to clinical microvascular complications, such as nephropathy, retinopathy, and neuropathy [ 13 , 19 , 20 ]. Clinical treatment against MG accumulation, such as insulin lispro, has an effect against diabetic nephropathy but only results in a 17% decrease in MG-derived AGEs [ 21 , 22 , 23 ].…”

Oxidative Stress and the Role of NADPH Oxidase in Glaucoma

“…Indeed, restoring the function of AGEs detoxifying enzyme glyoxalase (GLO) has been shown to prevent diabetic retinopathy injury [ 94 ]. While AGEs are sources of oxidative stress, the generated oxidant products have been known to promote the formation of AGEs, thus providing a positive feedback mechanism to enhance oxidative stress [ 92 ]. Apart from AGEs, NADPH oxidase-derived ROS have also shown to accelerate the synthesis of AGEs.…”

Selenomethionine (Se-Met) Induces the Cystine/Glutamate Exchanger SLC7A11 in Cultured Human Retinal Pigment Epithelial (RPE) Cells: Implications for Antioxidant Therapy in Aging Retina

“…System xc- is therefore a critical regulator of endogenous GSH synthesis, cellular redox balance, and ultimately cell fate [ 12 , 13 ]. As such, strategies to induce the expression and function of this transport system have a direct impact not only on the normal biology of RPE cells but also on the ability of these and other retinal cells to respond effectively to oxidative stress [ 12 , 14 ]. Thus, the potential therapeutic value of such strategies is high.…”