The role lipid aldehydes and ALEs in the pathogenesis of diabetic retinopathy.

Diabetic retinopathy is one of the most common causes of blindness in people of working age in developed countries. The retinal vasculature is central to the development of diabetic retinopathy, but there is accumulating evidence that neuroretinal dysfunction and degeneration also contributes to the aetiology and progression of this disease. The precise mechanisms through which diabetes causes neuroretinal dysfunction and degeneration remain to be fully established, but recent evidence from our own group has suggested that lipid aldehyde generation and the formation of advanced lipoxidation end-products (ALEs) plays a key contributory role. In the present talk, I will outline our recent data suggesting that the progressive and selective accumulation of the acrolein-derived ALE, FDP-lysine, in retinal Müller glial cells during diabetes is involved in the pathogenesis of neuroretinal dysfunction during diabetic retinopathy. More recent unpublished data will also be presented suggesting that FDP-lysine accumulation in the diabetic retina may occur primarily through a mechanism involving the downregulation of aldehyde detoxification enzymes. Current studies examining potential therapeutic strategies for preventing ALE accumulation in the diabetic retina will also be briefly discussed.