PKC and high glucose stimulate collagen alpha 1 (IV) transcriptional activity in a reporter mesangial cell line

Fumo, Peter; Kuncio, Gerald S.; Ziyadeh, Fuad N.

doi:10.1152/ajprenal.1994.267.4.f632

Cited by 46 publications

(44 citation statements)

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“…5,9,[41][42][43] Glucoseinduced TGF-␤ expression might directly contribute to increased expression of TGF-␤ in the vascular wall under hyperglycemic conditions. In fact, the in vitro findings of TGF-␤ induction by high glucose concentrations are accompanied by in vivo studies demonstrating increased TGF-␤ expression during hyperglycemia in animal models of diabetes.…”

Section: Discussionmentioning

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

Hypertension

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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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Section: Discussionmentioning

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

Hypertension

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“…3C). These data are particularly interesting given the evidence that high glucose induces de novo diacylglycerol synthesis and subsequent PKC activation in a variety of cell types, including mesangial cells (34,35). In fact, PKC has been identified as a potential therapeutic target in the treatment of diabetic complications (36,37).…”

Section: Enhanced Ctgf Expression In Renal Cortex and Isolated Glomermentioning

confidence: 98%

Suppression Subtractive Hybridization Identifies High Glucose Levels as a Stimulus for Expression of Connective Tissue Growth Factor and Other Genes in Human Mesangial Cells

Murphy¹,

Godson²,

Cannon³

et al. 1999

Journal of Biological Chemistry

371

302

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Accumulation of mesangial matrix is a pivotal event in the pathophysiology of diabetic nephropathy. The molecular triggers for matrix production are still being defined. Here, suppression subtractive hybridization identified 15 genes differentially induced when primary human mesangial cells are exposed to high glucose (30 mM versus 5 mM) in vitro. These genes included (a) known regulators of mesangial cell activation in diabetic nephropathy (fibronectin, caldesmon, thrombospondin, and plasminogen activator inhibitor-1), (b) novel genes, and (c) known genes whose induction by high glucose has not been reported. Prominent among the latter were genes encoding cytoskeleton-associated proteins and connective tissue growth factor (CTGF), a modulator of fibroblast matrix production. In parallel experiments, elevated CTGF mRNA levels were demonstrated in glomeruli of rats with streptozotocin-induced diabetic nephropathy. Mannitol provoked less mesangial cell CTGF expression in vitro than high glucose, excluding hyperosmolality as the key stimulus. The addition of recombinant CTGF to cultured mesangial cells enhanced expression of extracellular matrix proteins. High glucose stimulated expression of transforming growth factor ␤1 (TGF-␤1), and addition of TGF-␤1 to mesangial cells triggered CTGF expression. CTGF expression induced by high glucose was partially suppressed by anti-TGF-␤1 antibody and by the protein kinase C inhibitor GF 109203X. Together, these data suggest that 1) high glucose stimulates mesangial CTGF expression by TGF␤1-dependent and protein kinase C dependent pathways, and 2) CTGF may be a mediator of TGF␤1-driven matrix production within a diabetic milieu.

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“…In addition, it has been amply demonstrated that MCs in tissue culture increase the production of fibronectin, laminin, collagen type IV as well as mRNA levels for these matrix proteins when incubated in the presence of supraphysiological concentrations of glucose (7,(15)(16)(17)(18). Although it has been suggested that the increase in matrix synthesis may be partially due to the osmolar effect caused by high glucose concentrations (18), most of the evidence accumulated thus far indicates that the change is related to the metabolism of glucose (16,19,20). Glucose enters MCs by a facilitated diffusion process which is independent of insulin action (21).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of glucose transporters in rat mesangial cells cultured in a normal glucose milieu mimics the diabetic phenotype.

Heilig

Concepcion²,

Riser³

et al. 1995

J. Clin. Invest.

254

212

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An environment of high glucose concentration stimulates the synthesis of extracellular matrix (ECM) in mesangial cell (MC) cultures. This may result from a similar increase in intracellular glucose concentration. We theorized that increased uptake, rather than glucose concentration per se is the major determinant of exaggerated ECM formation. To test this, we compared the effects of 35 mM glucose on ECM synthesis in normal MCs with those of 8 mM glucose in the same cells overexpressing the glucose transporter GLUT1 (MCGT1). Increasing medium glucose from 8 to 35 mM caused normal MCs to increase total collagen synthesis and catabolism, with a net 81-90% increase in accumulation. MCs transduced with the human GLUT] gene (MCGT1) grown in 8 mM glucose had a 10-fold greater GLUT1 protein expression and a 1.9, 2.1, and 2.5-fold increase in cell myo-inositol, lactate production, and cell sorbitol content, respectively, as compared to control MCs transduced with bacterial f8-galactosidase (MCLacZ). MCGT1 also demonstrated increased glucose uptake (5-fold) and increased net utilization (43-fold), and greater synthesis of individual ECM components than MCLacZ. In addition, total collagen synthesis and catabolism were also enhanced with a net collagen accumulation 111-118% greater than controls. Thus, glucose transport activity is an important modulator of ECM formation by MCs; the presence of high extracellular glucose concentrations is not necessarily required for the stimulation of matrix synthesis. (J.

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PKC and high glucose stimulate collagen alpha 1 (IV) transcriptional activity in a reporter mesangial cell line

Cited by 46 publications

References 0 publications

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

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

Suppression Subtractive Hybridization Identifies High Glucose Levels as a Stimulus for Expression of Connective Tissue Growth Factor and Other Genes in Human Mesangial Cells

Overexpression of glucose transporters in rat mesangial cells cultured in a normal glucose milieu mimics the diabetic phenotype.

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