Abstract. Hyperglycemia seems to be an important causative factor in the development of micro-and macrovascular complications in patients with diabetes. Several hypotheses have been proposed to explain the adverse effects of hyperglycemia on vascular cells. Both protein kinase C (PKC) activation and oxidative stress theories have increasingly received attention in recent years. This article shows a PKC-dependent increase in oxidative stress in diabetic vascular tissues. High glucose level stimulated reactive oxygen species (ROS) production via a PKC-dependent activation of NAD(P)H oxidase in cultured aortic endothelial cells, smooth muscle cells, and renal mesangial cells. In addition, expression of NAD(P)H oxidase components were shown to be upregulated in vascular tissues and kidney from animal models of diabetes. Furthermore, several agents that were expected to block the mechanism of a PKCdependent activation of NAD(P)H oxidase clearly inhibited the increased oxidative stress in diabetic animals, as assessed by in vivo electron spin resonance method. Taken together, these findings strongly suggest that the PKC-dependent activation of NAD(P)H oxidase may be an essential mechanism responsible for increased oxidative stress in diabetes.Hyperglycemia seems to be an important causative factor in the development of micro-and macrovascular complications in patients with diabetes (1,2). Various pathophysiological and biochemical mechanisms have been proposed to explain the adverse effects of hyperglycemia on vascular cells (3-6). Among various possible mechanisms, it is widely accepted that high glucose level and a diabetic state induce the persistent activation of the diacylglycerol (DAG)-protein kinase C (PKC) pathway in micro-and macrovascular tissues of diabetic animals and of patients with diabetes (7-12). Because PKC is a critical intracellular signaling molecule that can regulate many vascular functions, it is to be expected that activation of PKC may cause alteration in various vascular functions in diabetes. However, accumulating evidence has shown that oxidative stress also may play a role in the development of diabetic vascular complications. A number of in vitro and in vivo studies suggest that the production of reactive oxygen species (ROS) is increased in diabetes (13-16). It has been postulated that ROS production in diabetes may be enhanced by hyperglycemia through various mechanisms such as enhanced formation of glycation products (17), altered polyol pathway activity (18), and increased superoxide release from mitochondria (19). In contrast, attention is increasingly focused on NAD(P)H oxidase as the most important source of ROS production in blood vessels (20 -23). Recent reports have implicated that this oxidase may be involved in the pathophysiology of various vascular diseases, including hypercholesterolemia (24), atherosclerosis (25-27), and hypertension (28). In this review, we show that a PKC-dependent activation of NAD(P)H oxidase may be an essential mechanism responsible for increased ROS ...

Oxidative stress may contribute to the pathogenesis of diabetic nephropathy. However, the detailed molecular mechanism remains uncertain. Here, we report oxidative mitochondrial DNA (mtDNA) damage and accumulation of mtDNA with a 4,834-bp deletion in kidney of streptozotocin-induced diabetic rats. At 8 weeks after the onset of diabetes, levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), which is a marker of oxidative DNA damage, were significantly increased in mtDNA from kidney of diabetic rats but not in nuclear DNA, suggesting the predominant damage of mtDNA. Semiquantitative analysis using PCR showed that the frequency of 4,834-bp deleted mtDNA was markedly increased in kidney of diabetic rats at 8 weeks, but it did not change at 4 weeks. Intervention by insulin treatment starting at 8 weeks rapidly normalized an increase in renal 8-OHdG levels of diabetic rats, but it did not reverse an increase in the frequency of deleted mtDNA. Our study demonstrated for the first time that oxidative mtDNA damage and subsequent mtDNA deletion may be accumulated in kidney of diabetic rats. This may be involved in the pathogenesis of diabetic nephropathy. Diabetes 51:1588 -1595, 2002 D iabetic nephropathy is the major cause of morbidity and mortality in diabetic patients. It is more rapidly liable to functional deterioration compared with other types of chronic renal disease and finally progresses to renal failure requiring dialysis therapy. Several mechanisms have been proposed for the pathogenesis of diabetic vascular complications that include nephropathy, such as hyperfiltration (1), increased production of advanced glycation end products (AGEs) (2), activation of protein kinase C (3-5), enhanced polyol pathway (6,7), and enhanced oxidative stress (8 -10). A number of in vitro and in vivo studies suggest that oxidative stress is increased in diabetic patients and animal models of diabetes (8 -14). Although enhanced oxidative stress may contribute to the initiation and development of diabetic nephropathy, the detailed molecular mechanism remains uncertain.In general, oxidative stress, including reactive oxygen species (ROS), can damage cellular macromolecules. Among the oxidative damages, base modifications, such as oxidation of deoxyguanosine to 8-hydroxy-2Ј-deoxyguanosine (8-OHdG) and subsequent mutations of mitochondrial DNA (mtDNA), have received increasing attention in recent years. It is widely accepted that mtDNA is 10 -20 times more vulnerable to oxidative damage and subsequent mutations than nuclear DNA (15-17). More than 50 pathogenic mtDNA mutations associated with or responsible for specific human diseases have been reported. Congenital mtDNA mutations as well as oxidative stress-induced mtDNA mutations may be related to the pathophysiology of various diseases. It has been shown that oxidative stress-induced mtDNA mutations may be related to aging-related organ dysfunction (18 -23) and several degenerative diseases (24,25). We speculated that enhanced oxidative stress might induce mtDNA damage and subsequent mtDNA...

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Normalization of low plasma levels of BCAA by oral supplementation can reduce anorexia and significantly improve overall nutritional status in elderly malnourished HD patients.

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Our findings indicate that high glucose concentrations may stimulate ROS production through PKC-dependent activation of NADPH oxidase, and induce MAP kinase phosphorylation subsequent to proliferation and type I collagen production by HSCs.

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