Aldose Reductase Meets Histone Acetylation: A New Role for an Old Player

Abstract

With diabetes reaching epidemic proportions, there is an urgent need for reliable treatment strategies for microvascular (retinopathy, neuropathy, and nephropathy) and macrovascular (coronary heart disease and stroke) diabetes complications. The role of diabetic hyperglycemia in the development of complications has been extensively studied and a number of biochemical pathways activated by hyperglycemia have been identified. Among these, the polyol pathway is perhaps the most investigated and the most controversial pathway. The initial discovery by Ruth van Heyningen (1) of high sorbitol levels in diabetic rat lenses over 50 years ago followed by studies by Jin Kinoshita (2) laid the foundation for the polyol hypothesis in the pathogenesis of diabetes complications. This hypothesis asserts that diabetes complications result, in part, from direct or indirect consequences of sorbitol production from excess glucose by aldose reductase (AR). AR catalyzes the reduction of glucose to sorbitol, the accumulation of which has been postulated to alter the metabolism of myo -inositol, a six-carbon cyclic polyol, in nerve, ocular, and renal tissues (3,4). Depletion of myo -inositol reduces its incorporation into cellular phosphoinositide pools, resulting in chronic elevation of diacylglycerol (DAG), the chief physiological activator of protein kinase C (PKC) (5). Increased oxidation of sorbitol to fructose may also alter …