High glucose-induced TGF-beta 1 regulates mesangial production of heparan sulfate proteoglycan

Kolm, Verena; Sauer, Ulrich; Olgemooller, B.; Schleicher, Erwin

doi:10.1152/ajprenal.1996.270.5.f812

Cited by 44 publications

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“…High glucose concentrations increase TGF- . Further, increased glucose concentrations in vitro stimulate TGF-b mRNA expression and bioactivity, cellular hypertrophy and collagen transcription in proximal tubules [89] in addition to increased mesangial production of heparan sulphate proteoglycan [96].…”

Section: In Vitro Evidence For Tgf-b Effects On Kidney Cellsmentioning

confidence: 99%

Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease

2000

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Section: In Vitro Evidence For Tgf-b Effects On Kidney Cellsmentioning

confidence: 99%

Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease

2000

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“…The results of the Diabetes Control and Complications Trial have shown that strict prevention of hyperglycemia can prevent the onset and progression of diabetic nephropathy (4). In vivo and in vitro studies provide evidence that ambient high glucose induces the synthesis of extracellular matrix components (e.g., fibronectin) in glomerular and proximal tubular cells (5)(6)(7)(8)(9). There is ample evidence that the increased rate of glucose metabolism promotes the pathological changes in diabetic nephropathy (5,10).…”

mentioning

confidence: 99%

“…The hyperglycemia-induced TGF-␤ stimulates the production of fibronectin and other matrix proteins in mesangial and other renal cells (8,9,22). Activation of protein kinase C (PKC) isoforms (7,10,23), the hexosamine biosynthetic pathway (24,25), and the extracellular signalrelated kinase (ERK) 1 and 2 (26,27) and p38 mitogenactivated protein kinase (MAPK) pathway (28,29) have been implicated in the enhanced expression of TGF-␤1 and matrix proteins.…”

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confidence: 99%

Evidence for a Novel TGF-β1−Independent Mechanism of Fibronectin Production in Mesangial Cells Overexpressing Glucose Transporters

et al. 2003

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Recent experimental work indicates that the hyperglycemia-induced increase in mesangial matrix production, which is a hallmark in the development of diabetic nephropathy, is mediated by increased expression of GLUT1. Mesangial cells stably transfected with human GLUT1 mimic the effect of hyperglycemia on the production of the extracellular matrix proteins, particularly fibronectin, when cultured under normoglycemic conditions. Our investigation of the molecular mechanism of this effect has revealed that the enhanced fibronectin production was not mediated by the prosclerotic cytokine transforming growth factor (TGF)-␤1. We found markedly increased nuclear content in Jun proteins, leading to enhanced DNA-binding activity of activating protein 1 (AP-1). AP-1 inhibition reduced fibronectin production in a dosage-dependent manner. Moreover, inhibition of classic protein kinase C (PKC) isoforms prevented both the activation of AP-1 and the enhanced fibronectin production. In contrast to mesangial cells exposed to high glucose, no activation of the hexosamine biosynthetic, p38, or extracellular signal-related kinase 1 and 2 mitogen-activated protein kinase pathways nor any increase in TGF-␤1 synthesis could be detected, which could be explained by the absence of oxidative stress in cells transfected with the human GLUT1 gene. Our data indicate that increased glucose uptake and metabolism induce PKC-dependent AP-1 activation that is sufficient for enhanced fibronectin production, but not for increased TGF-␤1 expression.

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“…3,4 The possible importance of TGF-␤1 in diabetic nephropathy has been demonstrated in vitro by glucose-induced upregulation of this cytokine in different cell types. [5][6][7][8][9][10][11][12][13] Increased TGF-␤1 expression has also been demonstrated in diabetic animal models and human patients. 14,15 TGF-␤ binds specific serine/threonine kinase type I and type II receptors.…”

mentioning

confidence: 99%

Glucose-Induced TGF-β1 and TGF-β Receptor-1 Expression in Vascular Smooth Muscle Cells Is Mediated by Protein Kinase C-α

Lindschau

Quass²,

Menne³

et al. 2003

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Abstract-Sclerosis and increased matrix expression in diabetes are mediated by glucose-induced transforming growth factor (TGF)-␤1 expression. The intracellular effects of high glucose occur at least in part by way of protein kinase C (PKC). We previously described a role for PKC-␣ in glucose-induced permeability. We now investigated the hypothesis that glucose-induced expression of TGF-␤1 and its receptors (TGF-␤-R1 and -R2) are mediated by activation of this PKC isoform. TGF-␤1 and TGF-␤-R expressions were determined in vascular smooth muscle cells (VSMCs) by immunocytochemistry and Western blotting. PKC isoforms were assessed by confocal microscopy. PKC isoforms were inhibited with antisense oligodeoxynucleotides. PKC-␣ was upregulated by overexpression or microinjection. High glucose (20 mmol/L) increased VSMC TGF-␤1 and TGF-␤-R1 expression but not TGF-␤-R2 expression. PKC inhibitors and specific PKC-␣ downregulation by antisense treatment prevented this effect, whereas antisense treatment against PKC-␤, -⑀, and -had no influence. PKC-␣ overexpression increased TGF-␤1 and TGF-␤-R1 expression but not TGF-␤-R2 expression. PKC-␣ microinjection into individual VSMCs also increased TGF-␤1 and TGF-␤-R immunofluorescence. Last, VSMCs from PKC-␣-deficient mice did not respond to high glucose compared with VSMCs from wild-type mice. We propose that high glucose-induced TGF-␤1 and TGF-␤-R1 expression is mediated by PKC-␣. Our findings suggest an autocrine feedback mechanism and a possible role for PKC-␣ in diabetic vascular disease. Key Words: glucose Ⅲ growth substances Ⅲ protein kinases Ⅲ diabetes Ⅲ muscle, vascular, smooth Ⅲ atherosclerosis R enal hypertrophy, basement membrane thickening, and extracellular matrix accumulation characterize diabetic nephropathy. 1 Several cytokines with fibrogenic potential contribute to this, particularly transforming growth factor (TGF)-␤1. 2 TGF-␤1 increases matrix synthesis, inhibits matrix degradation, upregulates adhesion molecules, and enhances chemoattraction. 3,4 The possible importance of TGF-␤1 in diabetic nephropathy has been demonstrated in vitro by glucose-induced upregulation of this cytokine in different cell types. 5-13 Increased TGF-␤1 expression has also been demonstrated in diabetic animal models and human patients. 14,15 TGF-␤ binds specific serine/threonine kinase type I and type II receptors. The receptors form heteromeric cell surface complexes with TGF-␤. 16,17 The type II receptor determines ligand specificity, whereas the type I receptor interacts with the type II receptor and might not have a specific ligand. The type II receptor, likely in conjunction with the type I receptor, is probably required for the antiproliferative effect, whereas the type I receptor is the probable mediator of extracellular gene expression. 16,17 High glucose upregulates TGF-␤1 receptors in vitro and in vivo. 18,19 Hyperglycemia might mediate the effect of protein kinase C (PKC) activation. 20 -24 PKC consists of several isoforms with distinct cellular functions and different ex...

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High glucose-induced TGF-beta 1 regulates mesangial production of heparan sulfate proteoglycan

Cited by 44 publications

References 0 publications

Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease

Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease

Evidence for a Novel TGF-β1−Independent Mechanism of Fibronectin Production in Mesangial Cells Overexpressing Glucose Transporters

Glucose-Induced TGF-β1 and TGF-β Receptor-1 Expression in Vascular Smooth Muscle Cells Is Mediated by Protein Kinase C-α

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