New insights into the pathogenic role of advanced glycation in diabetic retinopathy

Abstract

Abstract Purpose Retinopathy is the most common microvascular complication of diabetes. The clinicopathology of microvascular lesions and neuroglial dysfunction in the diabetic retina have been extensively studied, although the relative contribution of various biochemical sequelae of hyperglycaemia remains ill‐defined. The formation and accumulation of advanced glycation endproducts (AGEs) is an important pathogenic pathway in the progression of diabetic retinopathy although some of the cellular and molecular pathologies initiated by these adducts in retinal cells remain unknown. Methods This presentation will cover several aspects of AGE‐linked retinal pathology and demonstrate opportunities for therapeutic intervention. The studies outlined will cover a wide range of molecular cell biology approaches using appropriate in vitro and in vivo model systems. Results It will be demonstrated that AGEs form in vivo in the diabetic retina through the reaction of alpha‐oxaloaldehydes leading to significant modifications of retinal proteins. Evidence will be presented to demonstrate that these AGEs act as significant effectors of retinal vascular and neuroglial cell dysfunction, leading to pro‐inflammatory responses, growth factor imbalance and, ultimately, neurovascular lesions such as blood retinal barrier dysfunction and microvascular degeneration. The protective role of novel AGE‐inhibitors will also be shown. Conclusion Evidence now points towards a pathogenic role for advanced glycation in the initiation and progression of diabetic retinopathy and this review lecture will outline the current state of knowledge of AGE‐related pathology in the retina at a cellular and molecular level.