Departments of *Medicine and Bioregulatory Science and Molecular and Structure Biology, Graduate School of Medical Sciences, and Laboratory of Bio-function Analysis, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Correspondence to Dr. Toyoshi Inoguchi, Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Phone: 81-92-642-5284; Fax: 81-92-642-5287;
ABSTRACT. Hyperglycemia seems to be an important causative factorin the development of micro- and macrovascular complicationsin patients with diabetes. Several hypotheses have been proposedto explain the adverse effects of hyperglycemia on vascularcells. Both protein kinase C (PKC) activation and oxidativestress theories have increasingly received attention in recentyears. This article shows a PKC-dependent increase in oxidativestress in diabetic vascular tissues. High glucose level stimulatedreactive oxygen species (ROS) production via a PKC-dependentactivation of NAD(P)H oxidase in cultured aortic endothelialcells, smooth muscle cells, and renal mesangial cells. In addition,expression of NAD(P)H oxidase components were shown to be upregulatedin vascular tissues and kidney from animal models of diabetes.Furthermore, several agents that were expected to block themechanism of a PKC-dependent activation of NAD(P)H oxidase clearlyinhibited the increased oxidative stress in diabetic animals,as assessed by in vivo electron spin resonance method. Takentogether, these findings strongly suggest that the PKC-dependentactivation of NAD(P)H oxidase may be an essential mechanismresponsible for increased oxidative stress in diabetes. E-mail:toyoshi@intmed3.med.kyushu-u.ac.jp
Hyperglycemia seems to be an important causative factor in thedevelopment of micro- and macrovascular complications in patientswith diabetes (1,2). Various pathophysiological and biochemicalmechanisms have been proposed to explain the adverse effectsof hyperglycemia on vascular cells (3–6). Among variouspossible mechanisms, it is widely accepted that high glucoselevel and a diabetic state induce the persistent activationof the diacylglycerol (DAG)-protein kinase C (PKC) pathway inmicro- and macrovascular tissues of diabetic animals and ofpatients with diabetes (7–12). Because PKC is a criticalintracellular signaling molecule that can regulate many vascularfunctions, it is to be expected that activation of PKC may causealteration in various vascular functions in diabetes. However,accumulating evidence has shown that oxidative stress also mayplay a role in the development of diabetic vascular complications.A number of in vitro and in vivo studies suggest that the productionof reactive oxygen species (ROS) is increased in diabetes (13–16).It has been postulated that ROS production in diabetes may beenhanced by hyperglycemia through various mechanisms such asenhanced formation of glycation products (17), altered polyolpathway activity (18), and increased superoxide release frommitochondria (19). In contrast, attention is increasingly focusedon NAD(P)H oxidase as the most important source of ROS productionin blood vessels (20–23). Recent reports have implicatedthat this oxidase may be involved in the pathophysiology ofvarious vascular diseases, including hypercholesterolemia (24),atherosclerosis (25–27), and hypertension (28). In thisreview, we show that a PKC-dependent activation of NAD(P)H oxidasemay be an essential mechanism responsible for increased ROSproduction in diabetic vascular tissues. This may provide novelinsights into antioxidative therapy for preventing diabeticvascular complications.
Activation of PKC in Diabetic Vascular Tissues
In animals with chemically or genetically induced diabetes,the PKC activities in the membrane pool, which is the activefraction, have been shown to be elevated in many vascular tissuessuch as the aorta, heart, retina, and renal glomeruli by usand other investigators (7–11). In parallel with the changesin PKC activity, the total DAG level in these tissues has alsobeen shown to be increased. Because the total DAG level increasesin parallel with the PKC changes, these findings suggest thatdiabetes enhances the PKC activities by increasing total DAGlevel of the tissues. In cultured vascular cells, high glucoselevel also induces PKC activation in parallel with DAG change(7–12). The mechanism for the increased level of DAG byhigh glucose seems to be due to the ability of the glucose toincrease the de novo synthesis of DAG. The glucose-induced activationof the DAG-PKC pathway in the vascular cells probably couldbe linked to the dysfunction of vascular walls in diabetes.This notion has been supported by the increasing numbers ofstudies showing that many vascular abnormalities in retinal,renal, and cardiovascular tissues observed in diabetic animalscan be normalized by PKC inhibitors (12,29–33).
PKC-Dependent Activation of NAD(P)H Oxidase Induced by High Glucose
The role of oxidative stress in atherogenesis has received increasingattention in recent years. Oxidative modification of lipoproteinsis critical for atheromatous lesion formation. In addition,ROS reacts with nitric oxide, resulting in loss of nitric oxide’santiatherogenic properties. ROS affect a large number of varioussignaling pathways and proteins and cause DNA damage in vasculartissues. Recent reports have indicated that vascular NAD(P)Hoxidase–driven ROS production may play a role in the pathophysiologyof various vascular diseases, including hypercholesterolemia,atherosclerosis, and hypertension. Therefore, we examined therole of NAD(P)H oxidase in high glucose level–inducedROS production in cultured aortic endothelial cells, smoothmuscle cells, and renal mesangial cells using electron spinresonance (ESR) spectroscopy (34). Exposure of cultured vascularcells to high glucose level (400 mg/dl) for 72 h significantlyincreased ROS production as compared with low glucose level(100 mg/dl). Treatment of the cells with PMA, a protein kinaseC (PKC) activator, for 3 h also increased it. In addition, suchincreases by high glucose level or PMA were restored to controlvalues by diphenylene iodonium (an NAD[P]H oxidase inhibitor)and calphostin C or GF109203X (a PKC inhibitor). In contrast,other inhibitors of flavoproteins, such as xanthine oxidase(oxyprinal), nitric oxide synthase (l-N-monomethyl arginine),and mitochondrial electron transport chain oxidase (rotenone),were ineffective. These results suggest that high glucose levelstimulates ROS production via a PKC-dependent activation ofNAD(P)H oxidases in vascular cells and renal mesangial cells(Figure 1). To explore the molecular mechanism, we examinedthe effect of high glucose level on the small GTP-binding proteinRac-1 activity, which is a key regulator of NAD(P)H oxidasein many cells (35), including vascular tissues. In parallelwith the NAD(P)H oxidase activity, high glucose level inducedan activation of Rac-1 and this activation was inhibited byPKC inhibitors (unpublished data). These results suggest thatthe molecular mechanism underlying high glucose–inducedNAD(P)H oxidase activation may be via a PKC-dependent activationof Rac-1.
Figure 1. Mechanism for increased ROS production induced by diabetes and insulin-resistant state.
The insulin-resistant state as well as diabetes is linked withatherosclerosis. One of the metabolic features of insulin resistanceis a defect in the insulin-mediated lowering action of fattyacids. We found that not only high glucose level but also saturatednonesterified fatty acids (NEFA) can stimulate de novo DAG synthesisand PKC activity in cultured aortic endothelial cells (EC) (36)and smooth muscle cells (37) and subsequently induce the increasein ROS production via a PKC-dependent activation of NAD(P)Hoxidase (34) (Figure 1). The elevated concentration of plasmaNEFA in patients with obesity or an insulin-resistant statemay induce the increase in ROS production. This notion is consistentwith the previous findings showing that raising plasma NEFAelevates vascular resistance, raises BP (38), and impairs thelower extremity vascular endothelium-dependent vasodilation(39). Thus, high glucose–induced or elevated NEFA–inducedPKC-dependent activation of NAD(P)H oxidase may cause the increasedROS production in patients with diabetes or an insulin-resistantstate.
Upregulation of NAD(P)H Oxidase Components in Diabetic Vascular Tissues and Kidney
Several reports have recently shown that the expression of NAD(P)Hoxidase subunit proteins (p22phox, p47phox, or p67phox) is upregulatedin aorta from animal models of diabetes (40,41) and in saphenousvein and internal mammary artery from patients with diabetesand coronary artery disease (42). Furthermore, this enzyme-drivensuperoxide production was reported to be involved in vasculardysfunction such as impaired endothelium-dependent vasodilationfound in type 2 diabetes animal model (41). These results furthersupport the idea that vascular NAD(P)H oxidase may play a rolein the pathogenesis of macroangiopathy associated with diabetes.
With respect to diabetic microangiopathy, one report showedthat the activity of NAD(P)H oxidase was increased in the retinaof diabetic rats and that this might be involved in the developmentof diabetic retinopathy (43). We examined the expression ofessential subunits of NAD(P)H oxidase, NOX-4 and p22phox, inthe kidney from streptozotocin-induced diabetic rats (44). Thelevels of mRNA of both NOX4 and p22phox expression were significantlyincreased in the kidney from diabetic rats as compared withcontrol rats. Immunohistochemical analysis showed that the expressionof NOX4 and p22phox were clearly increased in both distal tubularcells and glomeruli from diabetic rats. Both the localizationand the expression levels of these components were in parallelwith those of 8-hydroxy-deoxyguanosine that is a marker of ROS-inducedDNA damage. Interventive insulin treatment for 2 wk completelyrestored the increased levels of these components in diabetickidney to control levels in parallel with the normalizationof 8-hydroxy-deoxyguanosine level. These results suggest thatthe expression of NAD(P)H oxidase subunits NOX4 and p22phoxare upregulated in the kidney of diabetic rats and that NAD(P)H-dependentoverproduction of ROS may cause DNA damage in diabetic renaltissues. Vascular NAD(P)H oxidase may play an essential rolein the development of diabetic microangiopathy such as nephropathy.However, further studies should be done to prove the role ofPKC in the upregulated expression of this oxidase in macro-and microvascular tissues in vivo.
Antioxidative Agents Targeting the Mechanism of PKC-Dependent Activation of NAD(P)H Oxidase
Inhibition of oxidative stress using various antioxidants hasshown some success at preventing the diabetic vascular complicationsin animal models. However, results of studies in humans havegenerally been negative. One possible reason for its ineffectivenessis that radical scavengers such as vitamin E may serve not onlyas an antioxidant but also as a pro-oxidant. For example, vitaminE reacts with radicals and subsequently generates tocopheroxylradicals. Another problem in antioxidative therapy is the lackof a direct and sensitive method to evaluate oxidative stressin vivo. Here we used the in vivo ESR method to evaluate theeffect of various agents on the increased ROS production indiabetic animals. This in vivo ESR method has been recentlydeveloped for a noninvasive, sensitive in vivo measurement offree radical generation in living animals. Free radicals suchas ROS have unpaired electrons, which can be detected selectivelyand sensitively by ESR spectroscopy. However, conventional ESRspectrometers have significant limitations for analysis in livinganimals because the high-frequency microwaves used are absorbedby water, resulting in the development of fever. Recently, Utsumiet al. and other investigators (45–47) showed that a combinationof a low-frequency ESR spectrometer with nitroxide radicalsas probes enables a sensitive, real-time in vivo measurementof free radicals in living animals. Using this method, we examinedwhether several agents that are expected to block the processof activation of NAD(P)H oxidase really normalize the increasedoxidative stress in diabetic animals. We first examined theeffect of PKC inhibitor on the increased ROS production in streptozotocin-induceddiabetic rats. The increased ROS production in diabetic ratsat 2 and 4 wk after onset of diabetes was confirmed by in vivoESR measurement. Acute administration of the PKC inhibitor CGP41251(50 mg/kg) significantly inhibited the increased ROS productionin diabetic rats, clearly suggesting the role of PKC in theincreased ROS production in diabetes (unpublished data). PKCinhibitor may inhibit ROS production in diabetes via its inhibitoryeffect on high glucose–induced activation of NADPH oxidases.For clinical use, however, long-term in vivo use of non–isoform-specificPKC inhibitors could be potentially harmful. Among various isoforms,preferential activation of the PKC- isoform is reported to occurin many vascular tissues in the diabetic states (8,31). Presently,one of the most promising specific inhibitors of PKC- is LY333531.Oral administration of LY333531 to diabetic rats has been reportedto prevent the increased albumin excretion, elevated glomerularfiltration, and abnormal retinal hemodynamics (31). Clinicaltrials are now ongoing to assess the effects of PKC- inhibitionon diabetic retinopathy and neuropathy. The beneficial effectsof PKC- specific inhibitor might be also at least in part dueto its inhibitory effect on oxidative stress. Further investigationinto the antioxidative properties of this agent is imperative.
The effect of the 3-hydroxy-3-methylglutaryl CoA reductase inhibitors(statins) on cardiovascular diseases is mainly attributed totheir cholesterol-lowering properties, but accumulating evidencehas shown that some beneficial effects of these agents may beindependent of plasma cholesterol levels. Notably, recent reportshave revealed that statins may inhibit ROS production in vascularcells probably via inhibition of angiotensin II–inducedNAD(P)H oxidase activation (48,49). Therefore, we expected thatstatins might also inhibit the high glucose–induced NAD(P)Hoxidase activation and finally prevent the increase in ROS productionin diabetes. Oral administration of pitavastatin for 2 wk normalizedthe increased ROS production in diabetic rats to control levels(unpublished data). For activation of NAD(P)H oxidase, activeRac has to be anchored in the membrane via its geranylgeranyltail. Statins may inhibit the high glucose–induced activationof Rac by inhibiting the geranylgeranylation-dependent translocationof Rac from the cytosol to the cell membrane. This notion maybe supported by several clinical studies showing that statinsprevent a decline in renal function and cause a decrease inalbumin excretion in diabetic nephropathy (50,51). These beneficialeffects of statins for diabetic nephropathy may be explainedby their antioxidative properties rather than their cholesterol-loweringeffect.
Recent epidemiologic studies have established that angiotensinII–converting enzyme inhibitors (ACEI) and angiotensinII receptor blockers (ARB) have a protective effect on the developmentof diabetic nephropathy (52–54). One report showed thatACEI and ARB prevented the development of albuminuria in streptozotocin-induceddiabetic rats in parallel with the prevention of increased expressionof p47phox component of NAD(P)H oxidase and its oxidative products(55). We also found that oral administration of Olmesartan (3mg/kg) for 3 d partially inhibited the increased ROS productionin diabetic rats by in vivo ESR measurement (unpublished data).Although the beneficial effects of ACEI and ARB on diabeticnephropathy are thought to be secondary to changes in glomerularhemodynamics, these results suggest that antioxidative propertiesof these drugs may also play an important role.
The inhibition of increased oxidative stress in diabetes bythese agents strongly supports the notion that the PKC-dependentactivation of NAD(P)H oxidase may be a main source of ROS productionin diabetes. The mechanism of PKC-dependent activation of vascularNAD(P)H oxidase may be a new target of antioxidative therapyfor preventing the diabetic vascular complications (Figure 2).
We showed here that a PKC-dependent activation of vascular NAD(P)Hoxidase may play a major role in the increase in ROS productionin diabetes and finally may contribute to the onset or developmentof diabetic micro- or macrovascular complications. Such a mechanismmay be a new target of antioxidative therapy for preventingdiabetic vascular complications.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Research(no. 11671126) from the Ministry of Education, Science and Culture,Japan, and the Takeda Medical Fund. This work was performedin part at Kyushu University Station for Collaborative Research.
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R. Ouedraogo, X. Wu, S.-Q. Xu, L. Fuchsel, H. Motoshima, K. Mahadev, K. Hough, R. Scalia, and B. J. Goldstein Adiponectin Suppression of High-Glucose-Induced Reactive Oxygen Species in Vascular Endothelial Cells: Evidence for Involvement of a cAMP Signaling Pathway
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C. Premanand, M. Rema, M. Z. Sameer, M. Sujatha, and M. Balasubramanyam Effect of Curcumin on Proliferation of Human Retinal Endothelial Cells under In Vitro Conditions
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L. Xia, H. Wang, H. J. Goldberg, S. Munk, I. G. Fantus, and C. I. Whiteside Mesangial cell NADPH oxidase upregulation in high glucose is protein kinase C dependent and required for collagen IV expression
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M. Trivedi and M. F. Lokhandwala Rosiglitazone restores renal D1A receptor-Gs protein coupling by reducing receptor hyperphosphorylation in obese rats
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J.-K. Min, Y.-M. Kim, S. W. Kim, M.-C. Kwon, Y.-Y. Kong, I. K. Hwang, M. H. Won, J. Rho, and Y.-G. Kwon TNF-Related Activation-Induced Cytokine Enhances Leukocyte Adhesiveness: Induction of ICAM-1 and VCAM-1 via TNF Receptor-Associated Factor and Protein Kinase C-Dependent NF-{kappa}B Activation in Endothelial Cells
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T. Thum and J. Bauersachs Spotlight on endothelial progenitor cell inhibitors: short review
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T. Thum and J. Bauersachs Spotlight on endothelial progenitor cell inhibitors: short review
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H. J. Han, Y. J. Lee, S. H. Park, J. H. Lee, and M. Taub High glucose-induced oxidative stress inhibits Na+/glucose cotransporter activity in renal proximal tubule cells
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I. Talior, T. Tennenbaum, T. Kuroki, and H. Eldar-Finkelman PKC-{delta}-dependent activation of oxidative stress in adipocytes of obese and insulin-resistant mice: role for NADPH oxidase
Am J Physiol Endocrinol Metab,
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[Abstract][Full Text][PDF]
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Abstract
Introduction
isoform is reported to occur in many vascular tissues in the diabetic states (8,31). Presently, one of the most promising specific inhibitors of PKC-
