Activation of Protein Kinase C in Glomerular Cells in Diabetes: Mechanisms and Potential Links to the Pathogenesis of Diabetic Glomerulopathy

DeRubertis, Frederick R.; Craven, Patricia A.

doi:10.2337/diab.43.1.1

Cited by 241 publications

(96 citation statements)

References 41 publications

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“…Hyperglycemia can activate PKC, which in turn increases oxidative stress. These observations suggest that activation of the PKC system by hyperglycemia may be an important pathway by which glucotoxicity is transduced in susceptible cells in diabetes [27]. The increased availability of oxygen free radicals, such as superoxide anion, may expedite NO breakdown by rapid scavenging of NO to form peroxynitrite that finally decays into nitrite [28].…”

Section: Discussionmentioning

confidence: 99%

Effect of High Glucose on Nitric Oxide Production and Endothelial Nitric Oxide Synthase Protein Expression in Human Glomerular Endothelial Cells

Hoshiyama

Yao

et al. 2004

Nephron Exp Nephrol

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Background: Hyperglycemia directly contributes to the development of diabetic nephropathy. Nitric oxide (NO), a potent endothelium-derived vasodilator, has been suggested to participate in the regulation of renal blood flow, glomerular filtration rate, and mesangial matrix accumulation. Human vascular endothelial cells are known to exhibit functional heterogeneity, this prompted us to do the first study of NO bioavailability in human glomerular endothelial cells (HGECs), in response to high glucose exposure. Methods: NO release was examined by detecting nitrite generation by the Griess assay in HGECs exposed to control-level (5.5 mM) and high-level (15, 30 and 60 mM) glucose solutions at various time periods (24, 48 and 72 h) in the presence or absence of L-arginine (1 mM), or superoxide dismutase (SOD) (250 U/ml). In addition, we evaluated the effect of glucose on the expression of endothelial nitric oxide synthase (eNOS) in HGECs by Western blotting. Results: Final levels of nitrite generated in HGECs were reduced significantly, in a time- and concentration-dependent manner, after high glucose exposure. However, Western blot analysis revealed that eNOS protein expression was significantly upregulated at 12 h after exposure to high glucose concentrations (30 mM), reaching a peak at 48 h (twofold increase over baseline levels). The inhibitory effect of high glucose on NO production was restored by the addition of SOD. Addition of L-arginine (1 mM) to external media also reversed the inhibitory effect of high glucose on NO production of HGECs as well. Conclusions: The present study demonstrated that high glucose increased eNOS protein expression, but decreased NO release finally. Decreased NO bioavailability seems to be associated with overproduction of superoxide and L-arginine deficiency. These findings provide an important clue in clarifying the molecular basis of the mechanisms by which elevated glucose leads to an imbalance between NO and superoxide, resulting in impaired endothelial function. In addition, restoration of NO function by both administration of L-arginine and adequate intake of antioxidants suggests a potential supportive treatment for patients with diabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

Effect of High Glucose on Nitric Oxide Production and Endothelial Nitric Oxide Synthase Protein Expression in Human Glomerular Endothelial Cells

Hoshiyama

Yao

et al. 2004

Nephron Exp Nephrol

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“…Several studies including ours [35, 36] have established that high glucose concentrations increase protein kinase C activities in MCs as a consequence of increased de novo synthesis of diacylglycerol from glycolytic intermediates. It has been proposed [37, 38] that the increased production of extracellular matrix proteins from MCs by high glucose levels is largely due to enhanced protein kinase C activation presumably through the action of TGF-β. The other factors mediating stimulation of TGF-β expression in the diabetic kidney may involve advanced glycated end products [39], intraglomerular hemodynamic factors [40], or the renin-angiotensin system [41].…”

Section: Discussionmentioning

confidence: 99%

The Fibronectin Production Is Increased by Thrombospondin via Activation of TGF-β in Cultured Human Mesangial Cells

Tada

Isogai²

1998

Nephron

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Thrombospondin (TSP) is a multifunctional glycoprotein that is synthesized by a variety of cells including mesangial cells (MCs). To clarify the effect of TSP on the pathogenesis of diabetic nephropathy, we studied the effect of glucose concentrations on TSP synthesis in cultured human MCs. Thereafter, the effects of TSP on the activation of transforming growth factor beta (TGF-β) and fibronectin production were investigated in MCs. Incubating MCs with elevated glucose levels for 6 days resulted in an increase in TSP synthesis, measured by an enzyme-linked immunosorbent assay, both in culture media and cell layers. Treatment of MCs with TSP (final concentrations 1 and 5 µg/ml) for 24 h resulted in an increase (1.3- and 2.1-fold, respectively) in active TGF-β, which was determined with an enzyme-linked immunosorbent assay using TGF-β-soluble receptor type II, in the culture media without having any effect on the production of total TGF-β. Exposure of MCs to TSP caused enhancement of fibronectin production in both media and cell layers in a TSP dose-dependent manner with the maximum at a TSP concentration of 1 µg/ml. The TSP-induced increase in fibronectin production from MCs was completely prevented by concomitant treatment with 10 µg/ml anti-TGF-β neutralizing antibody. These results indicate that the TSP production is promoted by a high ambient glucose concentration in human MCs and that TSP, in turn, causes an increase in fibronectin production via activation of TGF-β.

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“…These include increased polyol pathway activity [141]and associated changes in intracellular redox state [142], increased diacylglycerol synthesis, with consequent activation of specific PKC isoforms [6, 143, 144]increased non-enzymatic glycation of both intracellular and extracellular proteins, and increased formation of reactive oxygen species.…”

Section: Discussionmentioning

confidence: 99%

Role of Growth Factors in the Development of Diabetic Complications

Chiarelli

Santilli

Mohn³

2000

Horm Res Paediatr

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The structural changes characterising diabetic microangiopathy, which may be referred to as ’abnormal growth’ and ’impaired regeneration’, strongly suggest a role for a number of aberrantly expressed growth factors, possibly acting in combination, in the development of these complications. This initial speculation has been supported by the detection of increased concentrations of several growth factors in the target tissues of diabetic long-term complications, and by enhanced expression of these growth factors consequent to the activation of the biochemical pathways linking hyperglycaemia to microvascular changes: the polyol pathway; non-enzymatic glycation of proteins; vasoactive hormones; oxidative stress, and hyperglycaemic pseudohypoxia. As to nephropathy, insulin-like growth factor I (IGF-I) seems to be implicated in the earlier stages of the disease, while transforming growth factor β (TGFβ) is involved both in the early and later stages, being responsible, at least in part, for extracellular matrix (ECM) accumulation. Vascular endothelial growth factor (VEGF) plays a pivotal role both in non-proliferative and proliferative retinopathy. Finally, deficiency of several neurotrophic factors, namely nerve growth factor (NGF) and IGF-I has been related to the degeneration or impaired regeneration occurring in diabetic neuropathy. Knowledge of the involvement of growth factors in diabetic microangiopathy opens the way to new therapeutic interventions aimed at blocking the deleterious actions of several growth factors.

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Activation of Protein Kinase C in Glomerular Cells in Diabetes: Mechanisms and Potential Links to the Pathogenesis of Diabetic Glomerulopathy

Cited by 241 publications

References 41 publications

Effect of High Glucose on Nitric Oxide Production and Endothelial Nitric Oxide Synthase Protein Expression in Human Glomerular Endothelial Cells

Effect of High Glucose on Nitric Oxide Production and Endothelial Nitric Oxide Synthase Protein Expression in Human Glomerular Endothelial Cells

The Fibronectin Production Is Increased by Thrombospondin via Activation of TGF-β in Cultured Human Mesangial Cells

Role of Growth Factors in the Development of Diabetic Complications

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