Advanced Glycation and Advanced Lipoxidation: Possible Role in Initiation and Progression of Diabetic Retinopathy

Alan   W.   Stitt; Norma      Frizzell; Suzanne   R.   Thorpe

Abstract

Diabetic retinopathy remains the most common microvascular complication suffered by diabetic patients and is the leading cause of registerable blindness in the working population of developed countries. The clinicopathological lesions of diabetic retinopathy have been well characterised and although a multitude of pathogenic mechanisms have been proposed, the underlying dysfunctional biochemical and molecular pathways that lead to initiation and progression of this complication remain largely unresolved. There is little doubt that the pathogenesis of diabetic retinopathy is highly complex and there is a pressing need to establish new therapeutic regimens that can effectively prevent or limit retinal microvascular cell dysfunction and death which is characteristic of the vasodegenerative stages of diabetic retinopathy. The formation and accumulation of advanced glycation endproducts (AGEs) and / or advanced lipoxidation endproducts (ALEs) are among several pathogenic mechanisms that may contribute to diabetic retinopathy. AGEs / ALEs can form on the amino groups of proteins, lipids and DNA through a number of complex pathways including non-enzymatic glycation by glucose and reaction with metabolic intermediates and reactive dicarbonyl intermediates. These reactions not only modify the structure and function of proteins, but also cause intra-molecular and intermolecular cross-link formation. AGEs / ALEs are known to accumulate in the diabetic retina where they may have important effects on retinal vascular cell function, as determined by a growing number of in vitro and in vivo studies. Evidence now points towards a pathogenic role for advanced glycation / lipoxidation in the initiation and progression of diabetic retinopathy and this review will examine the current state of knowledge of AGE / ALE-related pathology in the diabetic retina at a cellular and molecular level. It will also outline how recent pharmaceutical strategies to inhibit AGE / ALE formation or limit their pathogenic influence during chronic hyperglycaemia may play a significant role in the treatment of diabetic retinopathy.

Keywords: diabetic retinopathy, diabetes mellitus, lipoxidation reactions, glycation, hyperglycemia, age/ales, hplc, cornea