AR is an enzyme involved in conversion of glucose

AR is an enzyme involved in conversion of glucose into sorbitol using NADPH as a cofactor [46]. This AR polyol pathway generates sorbitol accumulation and NADPH depletion. NADPH participates in detoxification via glutathione (GSH) reductase pathway [47]. Therefore, reduction of NADPH attenuates removal of reactive oxygen species (ROS), suggesting that increased influx of AR polyol pathway causes oxidative stress. Diabetic patients have higher risks to develop organ complications such as nephropathy [48], cardiomyopathy [49] and peripheral neuropathy [50]. Previous data suggested that these diabetic complications could be due to AR elevation in these patients [51]. In the diabetic eye, cataract [52] and retinopathy [53] are major complications causing vision loss. Other than oxidative stress, AR polyol pathway also accelerates advanced glycation end-product (AGE) formation by producing fructose, which forms AGE much faster than glucose [54]. A study observed the increase of AGE in retina causes ocular inflammation by inducing RMG activation [19]. Accordingly, blockade of AR polyol pathway could play a protective role in retina by preventing AGE-induced inflammation. NF-κB signaling pathway is one of the mechanisms that explain how AR induces inflammation. Many studies reported that down-regulation of AR either by genetic or enzymatic methods suppresses NF-κB activation in macrophages [30], [31] or in a mouse uveitis model [27]. Under cellular activation, NF-κB would be acetylated then translocated into nucleus to bind to transcriptional Exemestane of DNA, further inducing inflammatory signaling [55]. However, the activity of acetyl-NF-κB could be attenuated due to deacetylation by sirtulin-1, which is an NAD+-dependent deacetylase [56]. AR polyol pathway is involved in NAD + consumption in conversion of sorbitol into fructose by sorbitol dehydrogenase (SDH) [46]. Increased influx of AR polyol pathway results in reduction of NAD+, which would be expected to reduce sirtulin deacetylase activity. We, therefore, suspect that less deacetylase activity causes more acetyl-NF-κB accumulation in nucleus and remains higher inflammatory signaling production. Many studies showed that AR plays a role in eye pathogenesis including retinopathy. However, few studies mentioned that AR contributes to eye pathogenesis via immune cells. Here we report the first study regarding the role of AR in RMG activation in vivo. Our results point to AR as an attractive drugable target for suppressing inflammation in the eye. Future studies are required to determine if inhibition of AR is an effective strategy for prevention of ocular inflammation in a variety of disease settings such as diabetes and uveitis.
Conflict of interest statement
Acknowledgments This study is supported by NIH grants EY005856 and EY021498.
Introduction Cataract is one of the major causes of blindness in diabetic patients in developing countries. Aldose reductase (AR) is a key enzyme in the intracellular polyol pathway, responsible for the development of diabetic cataract. The contribution of AR during chronic hyperglycemia is reported to be enhanced as compared to euglycemic conditions where it play a minor role [1], [2]. AR catalyzes the reduction of glucose to sorbitol, which causes an accumulation of sorbitol in lens which results in increase in osmotic pressure, and thereby swelling of the tissues [3]. Thus, by inhibiting aldose reductase localized in lens epithelial cells, it may be possible to prevent cataract progression especially in diabetic conditions. A number of aldose reductase inhibitors have been studied experimentally in animal studies for their efficacy in diabetic complications like epalrestat, fidarestat, ranirestat, zenarestat, sorbinil and tolrestat [4]. Despite numerous efforts, only a few drugs have succeeded to reach into clinical trials, but some of them are still associated with unacceptable side effects, as well as poor pharmacokinetics [5]. Thus, there is a need to develop aldose reductase inhibitors with potent efficacy and fewer side effects. Currently natural products are in demand for the treatment of diabetes and its complications [6].