Abstract. Diabetes causes increased oxidative stress, which is thought to play an important role in the pathogenesis of various diabetic complications. However, the source of the hyperglycemia-induced oxidative stress is not clear. It was found that the polyol pathway is the major contributor to oxidative stress in the lenses and nerves of diabetic mice. The first enzyme in the pathway, aldose reductase (AR), reduces glucose to sorbitol, which is then converted to fructose by sorbitol dehydrogenase (SDH). Transgenic mice that overexpress AR specifically in their lenses showed a significant increase in oxidative stress when they became hyperglycemic, as indicated by a decrease in GSH and an increase in malondialdehyde in their lenses. Introducing an SDH-deficient mutation into these transgenic mice significantly normalized the GSH and malondialdehyde levels. These results indicate that both enzymes of the polyol pathway contributed to hyperglycemia-induced oxidative stress in the lens. In the wild-type mice, diabetes caused a significant decrease in GSH in their sciatic nerves, indicative of oxidative stress. In the AR null mutant mice, diabetes did not lead to any decrease in the nerve GSH level. These results indicate that similar to the situation in the lens, AR is also the major contributor to hyperglycemia-induced oxidative stress in the nerve. Although increased flux of glucose through the polyol pathway leads to diabetic lesions in both the lenses and nerve, the mechanisms may be different. AR-induced osmotic stress seems to be the cause of diabetic cataract, whereas AR-induced oxidative stress is probably the cause of neuronal dysfunction.Diabetes causes increased oxidative stress in various tissues as evidenced by increased levels of oxidized DNA, proteins, and lipids. Besides damaging the functions of these molecules, oxidative stress also triggers a series of cellular responses, including the activation of protein kinase C (PKC) (1,2), transcription factor NF-B (3), and JNK stress-associated kinases (4), and so forth. Inappropriate activation of these important regulatory molecules would have deleterious effects on cellular functions, and it is thought to contribute to the pathogenesis of various diabetic complications (5). However, it is not clear how hyperglycemia leads to increased oxidative stress. It is most likely the combined effects of increased levels of reactive oxygen species (ROS) and decreased capacity of the cellular antioxidant defense system. Glucose auto-oxidation (6), nonenzymatic glycation (7), and the interaction between glycated products and their receptors (8), overproduction of ROS by mitochondria (9), and the polyol pathway (10,11) all are potential sources of hyperglycemia-induced oxidative stress. This report focuses on the contribution of the polyol pathway to oxidative stress.The polyol pathway consists of two enzymes. The first enzyme, aldose reductase (AR), reduces glucose to sorbitol with the aid of its co-factor NADPH, and the second enzyme, sorbitol dehydrogenase (SDH),...
Aldose reductase (AR) has been implicated in the etiology of diabetic cataract, as well as in other complications. However, the role of AR in these complications remains controversial because the strongest supporting evidence is drawn from the use of AR inhibitors for which specificity in vivo cannot be ascertained. To settle this issue we developed transgenic mice that overexpress AR in their lens epithelial cells and found that they become susceptible to the development of diabetic and galactose cataracts. When the sorbitol dehydrogenase-deficient mutation is also present in these transgenic mice, greater accumulation of sorbitol and further acceleration of diabetic cataract develop. These genetic studies demonstrated convincingly that accumulation of polyols from the reduction of hexose by AR leads to the formation of sugar cataracts.Diabetic complications such as neuropathy, nephropathy, retinopathy, and cataract, etc., occur in both insulin-dependent and noninsulin-dependent diabetes mellitus. Hyperglycemia has long been suspected as the cause of these manifestations, and the results of the Diabetic Control and Complications Trial (1) appear to confirm it. However, by what mechanism elevated blood glucose leads to these complications is unclear. One theory implicates the polyol pathway as a cause of diabetic cataract because of the discovery of polyols in cataractous lenses (2) and the identification of aldose reductase (AR) that reduces various sugars to their polyols (3, 4). AR reduces glucose to sorbitol, which is then converted to fructose by sorbitol dehydrogenase (SorD). Because sorbitol does not readily diffuse out of cells and its oxidation to fructose is slow, the accumulation of sorbitol under the hyperglycemic state would increase the intracellular osmotic pressure, leading to swelling and eventual rupture of the lens fiber cells (5). The involvement of AR in diabetic cataract is supported by the fact that animals such as rats and dogs that have high levels of this enzyme in their lenses are prone to develop diabetic cataract, whereas mice that have low lens AR activity are not (6). Rats and dogs also develop galactose-induced cataracts more readily than diabetes-induced cataracts (7). This fact agrees with the polyol model because galactose is a better substrate than glucose for AR in vitro, and its reduction product galactitol is not further converted to other metabolites, resulting in faster buildup of this polyol. Additional evidence for the polyol model came from the fact that several AR inhibitors could suppress cataract formation in experimentally induced diabetic animals (8-10). However, these drugs may inhibit AR by nonspecific hydrophobic interactions (11,12), and their beneficial effects may be derived from the inhibition of other enzymes. The strongest challenge to the polyol model is the fact that kinetic analyses (13, 14) and x-ray crystallographic studies (15) indicated that AR has a very low affinity for glucose and galactose, and it has not been demonstrated directly that...
In 15-month-old db/db mice, signs of diabetic retinopathy, including blood-retinal barrier breakdown, loss of pericytes, neuro-retinal apoptosis, glial reactivation, and proliferation of blood vessels, were evident. These changes in the diabetic retina were associated with increased expression of aldose reductase (AR). To further understand the role of AR in the pathogenesis of diabetic retinopathy, we generated db/db mice with an AR null mutation (AR ؊/؊ db/db). AR deficiency led to fewer retinal blood vessels with IgG leakage, suggesting that AR may contribute to blood-retinal barrier breakdown. AR deficiency also prevented diabetes-induced reduction of platelet/endothelial cell adhesion molecule-1 expression and increased expression of vascular endothelial growth factor, which may have contributed to blood-retinal barrier breakdown. In addition, long-term diabetes-induced neuro-retinal stress and apoptosis and proliferation of blood vessels were less prominent in AR ؊/؊ db/db mice. These findings indicate that AR is responsible for the early events in the pathogenesis of diabetic retinopathy, leading to a cascade of retinal lesions, including blood-retinal barrier breakdown, loss of pericytes, neuro-retinal apoptosis, glial reactivation, and neovascularization. Diabetes 54:3119 -3125, 2005
The roles of caveolin-1 (cav-1) in regulating blood-brain barrier (BBB) permeability are unclear yet. We previously reported that cav-1 was down-regulated and the production of nitric oxide (NO) induced the loss of cav-1 in focal cerebral ischemia and reperfusion injury. The present study aims to address whether the loss of cav-1 impacts on BBB permeability and matrix metalloproteinases (MMPs) activity during cerebral ischemia-reperfusion injury. We found that focal cerebral ischemia-reperfusion down-regulated the expression of cav-1 in isolated cortex microvessels, hippocampus, and cortex of ischemic brain. The down-regulation of cav-1 was correlated with the increased MMP-2 and -9 activities, decreased tight junction (TJ) protein zonula occludens (ZO)-1 expression and enhanced BBB permeability. Treatment of N Gnitro-L-arginine methyl ester [L-NAME, a non-selective nitric oxide synthase (NOS) inhibitor] reserved the expression of cav-1, inhibited MMPs activity, and reduced BBB permeability.To elucidate the roles of cav-1 in regulating MMPs and BBB permeability, we used two approaches including cav-1 knockdown in cultured brain microvascular endothelial cells (BMECs) in vitro and cav-1 knockout (KO) mice in vivo. Cav-1 knockdown remarkably increased MMPs activity in BMECs. Meanwhile, with focal cerebral ischemia-reperfusion, cav-1 deficiency mice displayed higher MMPs activities and BBB permeability than wild-type mice. Interestingly, the effects of L-NAME on MMPs activity and BBB permeability was partly reversed in cav-1 deficiency mice. These results, when taken together, suggest that cav-1 plays important roles in regulating MMPs activity and BBB permeability in focal cerebral ischemia and reperfusion injury. The effects of L-NAME on MMPs activity and BBB permeability are partly mediated by preservation of cav-1. Keywords: blood-brain barrier, caveolin-1, ischemia, nitric oxide synthase.
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