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

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 myoinositol, 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 cellular redox potential, resulting in an increase in the cytosolic ratio of NADH/NAD (Fig. 1). A number of well-designed animal model experiments were performed to test the role of AR in disease pathogenesis (6–12). Most of these studies reported accumulation of sorbitol (or galactitol in galactosemia model) in diabetic tissues, with AR inhibitors (ARIs) producing various degrees of improvement of microvascular and, in later studies, macrovascular complications. The polyol pathway, however, turned out to be very evasive. In multiple clinical trials, ARIs showed mixed success or failure in prevention and reversal of long-term diabetes complications (13,14). The short duration of these trials and the low potency (sorbinil) or toxicity (tolrestat) of the test agents used were identified as potential limitations that led to the negative results (15), which led to diminished enthusiasm for the polyol pathway as a therapeutic target. This rather dismal outlook for ARIs was quickly reversed by the outcome of the Aldose Reductase Inhibitor-Diabetes Complications Trial (16) that was performed in Japan. This study showed efficacy for a new ARI agent, epalrestat, in the treatment of diabetic peripheral neuropathy. Moreover, recent evidence has linked a genetic polymorphism in the AR gene with the susceptibility to diabetes complications. A restriction length polymorphism to an (A-C)n dinucleotide repeat of the microsatellite DNA 59 of the AR promoter has been identified in a population of Japanese and Chinese subjects with type 2 diabetes and was found to be associated with early-onset retinopathy but not nephropathy (17,18). The C-106T single nucleotide polymorphism in the AR promoter was identified as a susceptibility allele for diabetic retinopathy in Japanese type 2 diabetic patients (19). The new study by Vedantham et al. (20) in this issue demonstrates a novel role for polyol flux in diabetes. The authors previously showed that overexpression of AR accelerates diabetic atherosclerosis in mice overexpressing human AR (hAR) on an apolipoprotein (apo) E background (21). Using this mouse model and aortic endothelial cell culture studies, the new work demonstrates that a decrease in the cytosolic ratio of NADH/NAD due to increased polyol flux inhibits nicotinamide phosphoribosyl transferase (NAMPT), leading