Activation of Protein Kinase C Isoforms and Its Impact on Diabetic Complications

Geraldes, Pedro; King, George L.

doi:10.1161/circresaha.110.217117

Cited by 779 publications

(641 citation statements)

References 154 publications

(146 reference statements)

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“…6). It is well recognised that hyperglycaemia causes activation of PKCβ2 in the heart and subsequent activation of NADPH oxidase [29]. In the current study, PKCβ2 production and p22 phox expression were increased in diabetic Ntg hearts but not diabetic caPI3K hearts.…”

Section: Discussionsupporting

confidence: 45%

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Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

et al. 2012

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Aims/hypothesis Diabetic cardiomyopathy is characterised by diastolic dysfunction, oxidative stress, fibrosis, apoptosis and pathological cardiomyocyte hypertrophy. Phosphoinositide 3-kinase (PI3K)(p110α) is a cardioprotective kinase, but its role in the diabetic heart is unknown. The aim of this study was to assess whether PI3K(p110α) plays a critical role in the induction of diabetic cardiomyopathy, and whether increasing PI3K(p110α) activity in the heart can prevent the development of cardiac dysfunction in a setting of diabetes.Methods Type 1 diabetes was induced with streptozotocin in adult male cardiac-specific transgenic mice with increased PI3K(p110α) activity (constitutively active PI3K [p110α], caPI3K] or decreased PI3K(p110α) activity (dominantnegative PI3K [p110α], dnPI3K) and non-transgenic (Ntg) mice for 12 weeks. Cardiac function, histological and molecular analyses were performed. Results Diabetic Ntg mice displayed diastolic dysfunction and increased cardiomyocyte size, expression of atrial and B-type natriuretic peptides (Anp, Bnp), fibrosis and apoptosis, as well as increased superoxide generation and increased protein kinase C β2 (PKCβ2), p22 phox and apoptosis signalregulating kinase 1 (Ask1) expression. Diabetic dnPI3K mice displayed an exaggerated cardiomyopathy phenotype compared with diabetic Ntg mice. In contrast, diabetic caPI3K mice were protected against diastolic dysfunction, pathological cardiomyocyte hypertrophy, fibrosis and apoptosis. Protection in diabetic caPI3K mice was associated with attenuation of left ventricular superoxide generation, attenuated Anp, Bnp, PKCβ2, Ask1 and p22 phox expression, and elevated AKT. Further, in cardiomyocyte-like cells, increased PI3K(p110α) activity suppressed high glucose-induced superoxide generation and enhanced mitochondrial function. Conclusions/interpretation These results demonstrate that reduced PI3K activity accelerates the development of diabetic cardiomyopathy, and that enhanced PI3K(p110α) activity can prevent adverse cardiac remodelling and dysfunction in a setting of diabetes.

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Section: Discussionsupporting

confidence: 45%

“…4a). A large body of evidence has demonstrated that hyperglycaemia leads to activation of PKCβ2 in the heart and subsequent activation of NADPH oxidase [29]. PKCβ2 protein production was increased in diabetic Ntg hearts compared with non-diabetic Ntg hearts (Fig.…”

Section: Resultsmentioning

confidence: 93%

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

et al. 2012

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“…Alternatively, redox imbalance can also lead to activation of PKC, which then would modulate expression of TGF-␤1. For instance, PKC activation is reversed by antioxidants and by administration of PKC inhibitors, and that reduces TGF-␤-mediated expression of ECM proteins and thereby ameliorates microvascular complications of diabetes (61,62). However, at this point, it is unknown whether the pathogenetic role of the G-X pathway in tubulo-interstitial fibrosis is mediated by the profibrogenic cytokine, TGF-␤1.…”

Section: Discussionmentioning

confidence: 99%

myo-Inositol Oxygenase Overexpression Accentuates Generation of Reactive Oxygen Species and Exacerbates Cellular Injury following High Glucose Ambience

Sun

Dutta

Xie

et al. 2016

Journal of Biological Chemistry

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increased ROS generation, depleted reduced glutathione, reduced GSH/GSSG ratio, and enhanced adaptive changes in the profile of the antioxidant defense system. These changes were also accompanied by mitochondrial dysfunctions, DNA damage and induction of apoptosis, accentuated activity of profibrogenic cytokine, and expression of fibronectin, the latter two being the major hallmarks of DN. These perturbations were largely blocked by various ROS inhibitors (Mito Q, diphenyleneiodonium chloride, and N-acetylcysteine) and MIOX/NOX4 siRNA. In conclusion, this study highlights a novel mechanism where MIOX under HG ambience exacerbates renal injury during the progression of diabetic nephropathy following the generation of excessive ROS via an unexplored G-X pathway.

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“…Moreover, we and others reported previously that d-α-tocopherol prevents the activation of the DAG-PKC pathway in diabetic vascular tissues, including renal glomeruli through the enhancement of DGK (6,7,11), acting as a regulator of PKC activity (18). Thus, the activation of DGK may have therapeutic potential for preventing diabetic vascular complications.…”

Section: Discussionmentioning

confidence: 71%

Reversal of redox-dependent inhibition of diacylglycerol kinase by antioxidants in mesangial cells exposed to high glucose

et al. 2011

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Abstract. Activation of the diacylglycerol (DAG)-protein kinase C (PKC) pathway is one of the pathomechanisms of diabetic nephropathy. We previously reported that d-α-tocopherol, well known as an antioxidant, enhances diacylglycerol kinase (DGK) activity, leading to the reduction of excess DAG accumulation and PKC activation in the glomeruli of streptozotocin-induced diabetic rats. However, it remains to be determined whether the effect of d-α-tocopherol on DGK activity is exerted through its antioxidative action. DAG contents, PKC and membranous DGK activity were measured in cultured human glomerular mesangial cells under normal (5.5 mM) or high glucose (27.5 mM) conditions in the presence or absence of two antioxidants (50 μM d-α-tocopherol and probucol). Mesangial cells were exposed to hydrogen peroxide (H 2 O 2 ) (10-1000 μM) in the presence or absence of 300 U/ml catalase, followed by measurement of DGK activity. Both antioxidants restored the high glucose-induced decrease in DGK activity, resulting in the reduction of high glucose-induced activation of the DAG-PKC pathway. In mesangial cells exposed to H 2 O 2 at various concentrations, DGK activity decreased in a dose-dependent manner. The addition of antioxidative enzyme catalase to the cells reversed the H 2 O 2 -mediated down-regulation of DGK activity. In conclusion, DGK activity is reduced by oxidative stress in human mesangial cells cultured under high glucose conditions. Antioxidants, including d-α-tocopherol and probucol may improve hyperglycemia-induced DAG-PKC activation by enhancing DGK activity.

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Activation of Protein Kinase C Isoforms and Its Impact on Diabetic Complications

Cited by 779 publications

References 154 publications

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

myo-Inositol Oxygenase Overexpression Accentuates Generation of Reactive Oxygen Species and Exacerbates Cellular Injury following High Glucose Ambience

Reversal of redox-dependent inhibition of diacylglycerol kinase by antioxidants in mesangial cells exposed to high glucose

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