TGF-β1 activates MAP kinase in human mesangial cells: A possible role in collagen expression

Hayashida, Tomoko; Poncelet, Anne Christine; Hubchak, Susan; Schnaper, H. William

doi:10.1046/j.1523-1755.1999.00733.x

Cited by 185 publications

(186 citation statements)

References 43 publications

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“…The current paradigm for Smad regulation implicates multiple signaling pathways modulating Smad activity (18,19), as would likely be the case in the diabetic milieu. We previously reported that ERK enhances Smad activity in TGF-␤1 induction of collagen production (20,21). The observations in the present report indicate that, in addition to stimulating TGF-␤1 expression as has previously been reported (48), glucose-stimulated ERK could directly interact with the Smad pathway to enhance responses to TGF-␤1.…”

Section: Discussionsupporting

confidence: 86%

“…Human mesangial cells were isolated by differential sieving of minced human renal cortex as described previously and maintained with DMEM/Ham's F12 (glucose 16.5 mM) supplemented with 20% heat-inactivated FBS, glutamine, penicillin/streptomycin, sodium pyruvate, HEPES buffer, and 8 g/ml insulin (20). After 3 d of preconditioning to 6.5 mM glucose at the seventh passage, the cells were then passaged and cultured in DME containing 6.5 or 20 mM glucose for up to 72 h. Mannitol was used as an osmotic control.…”

Section: Cell Culture and Glucose Conditioningmentioning

confidence: 99%

“…The cells were harvested in reporter lysis buffer (Promega) after a 24-h incubation. Luciferase and ␤-galactosidase activities were measured as described previously (20). Each condition was tested in triplicate, and experiments were repeated at least three times for statistical analysis.…”

Section: Luciferase Assaymentioning

confidence: 99%

“…Recent findings indicate that this classical paradigm for TGF-␤ signaling may be more complex (19). In mesangial cells, TGF-␤1 activates both extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) mitogenactivated protein (MAP) kinase pathways (20). Preincubation with an ERK inhibitor reduces TGF-␤1-stimulated Smad phosphorylation and association, as well as collagen production and promoter activities, suggesting that ERK activity is necessary for an optimal response to TGF-␤1 (21).…”

mentioning

confidence: 99%

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High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

Hayashida¹,

Schnaper²

2004

Journal of the American Society of Nephrology

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Abstract. High ambient glucose activates intracellular signaling pathways to induce cytokines such as TGF-␤1 in the extracellular matrix accumulation of diabetic nephropathy. These same pathways also may directly modulate TGF-␤1 signaling. R-Smad phosphorylation, association with Smad4, and nuclear accumulation after TGF-␤1 treatment (1.0 ng/ml) were significantly higher in mesangial cells that were conditioned to 20 mM glucose for 72 h than mesangial cells in 6.5 mM glucose, suggesting that high glucose enhanced responsiveness to TGF-␤1. Neither TGF-␤1 bioactivity nor TGF-␤ receptor binding was significantly different between in 6.5 and 20 mM glucose-conditioned cultures. Furthermore, adding a neutralizing anti-TGF-␤1 antibody during glucose conditioning did not affect the enhanced Smad responsiveness, indicating that enhancement likely did not result from increased TGF-␤ expression. In contrast, a mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK inhibitor, PD98059, completely abrogated the effect of high glucose. Glucose stimulation of ERK was inhibited by the general protein kinase C (PKC) inhibitor calphostin C and by the PKC␦-specific inhibitor rottlerin, whereas Gö6976, an inhibitor of conventional PKC, had no effect on ERK activity. Specificity of the PKC inhibitors was further verified by PKC␤ and ␦ kinase assay. High glucose increased expression of several PKC isozymes, but only PKC␦ showed proportionally increased membrane translocation and kinase activity in cells that were conditioned to 20 mM glucose. Finally, both ERK and PKC␦ inhibition during glucose conditioning abrogated enhanced ␣1(I) collagen mRNA and promoter induction by TGF-␤1. Taken together, these data strongly suggest that heightened ERK and PKC␦ activity in high ambient glucose conditions interact with the Smad pathway, leading to enhanced responsiveness to TGF-␤1 and increased extracellular matrix production in mesangial cells.

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Section: Discussionsupporting

confidence: 86%

Section: Cell Culture and Glucose Conditioningmentioning

confidence: 99%

Section: Luciferase Assaymentioning

confidence: 99%

mentioning

confidence: 99%

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High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

Hayashida¹,

Schnaper²

2004

Journal of the American Society of Nephrology

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“…In the present study we show that an experimental increase in plasma lipids increases CTGF mRNA and protein expression, so we can now include increased plasma FFA concentrations as one of the potential regulators of CTGF expression. There is evidence that CTGF mediates fibrotic changes in atherosclerotic plaques (37), mesangial expansion in models of diabetic nephropathy (38,39), fibrosis induced by cardiac myofibroblasts following myocardial infarction (40), and scleroderma and keloids (41). Of note, CTGF expression is increased in liver from Zucker obese rats in association with lipid abnormalities and fatty liver in this animal model of insulin resistance (36).…”

Section: Subjectmentioning

confidence: 79%

Lipid Infusion Decreases the Expression of Nuclear Encoded Mitochondrial Genes and Increases the Expression of Extracellular Matrix Genes in Human Skeletal Muscle

Richardson

Kashyap

Bajaj

et al. 2005

Journal of Biological Chemistry

226

200

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The association between elevated plasma free fatty acid (FFA) concentrations and insulin resistance is well known. Although the cause and effect relationship between FFAs and insulin resistance is complex, plasma FFA is negatively correlated with the expression of peroxisome proliferator activated receptor-␥ cofactor-1 (PGC-1) and nuclear encoded mitochondrial genes. To test whether this association is causal, we infused a triglyceride emulsion (or saline as control) into healthy subjects to increase plasma FFA for 48 h followed by muscle biopsies, microarray analysis, quantitative real time PCR, and immunoblots. Lipid infusion increased plasma FFA concentration from 0.48 ؎ 0.02 to 1.73 ؎ 0.43 mM and decreased insulin-stimulated glucose disposal from 8.82 ؎ 0.69 to 6.67 ؎ 0.66 mg/kg⅐min, both with p < 0.05. PGC-1 mRNA, along with mRNAs for a number of nuclear encoded mitochondrial genes, were reduced by lipid infusion (p < 0.05). Microarray analysis also revealed that lipid infusion caused a significant overexpression of extracellular matrix genes and connective tissue growth factor. Quantitative reverse transcription PCR showed that the mRNA expression of collagens and multiple extracellular matrix genes was higher after the lipid infusion (p < 0.05). Immunoblot analysis revealed that lipid infusion also increased the expression of collagens and the connective tissue growth factor protein. These data suggest that an experimental increase in FFAs decreases the expression of PGC-1 and nuclear encoded mitochondrial genes and also increases the expression of extracellular matrix genes in a manner reminiscent of inflammation.

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TGF-β1 enhances SDF-1α-induced chemotaxis and homing of naive T cells by up-regulating CXCR4 expression and downstream cytoskeletal effector molecules

et al. 2002

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The migration of immunocytes within the extracellular matrix (ECM) is influenced by the activation state of the incoming cell and its responses to the presence of chemokines and cytokines. We studied the regulatory role of TGF‐β1 on T cell homing to secondary lymphatic organs, such as the spleen, and chemotaxis within an ECM‐like environment in using an ECM‐like 3‐dimensional gel system designed to follow the migration of individual leukocytes along chemokine gradients in real time. The numbers of migrating naive, but not memory T cells toward SDF‐1α markedly increased after pre‐incubating the cells with TGF‐β1 (0.25 ng / ml) for 24 h. The mechanisms underlying TGFβ1‐modulated migration involve the up‐regulation of the expression of the SDF‐1α receptor CXCR4, the enhancement of the SDF‐1α‐induced actin polymerization, and increased phosphorylation of Pyk2, a focal adhesion kinase involved in integrin‐mediated lymphocyte migration, adhesion and interactions with ECM. Interestingly, priming of naive human T cells with TGF‐β1 increased homing of these cells to the spleen of NOD / SCID mice in a CXCR4‐dependent manner. We propose that theeffect of TGF‐β1 on the chemotaxis of naive T cells may be important in the locomotion of naive T cells toward SDF‐1α‐rich niches.

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TGF-β1 activates MAP kinase in human mesangial cells: A possible role in collagen expression

Cited by 185 publications

References 43 publications

High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

Lipid Infusion Decreases the Expression of Nuclear Encoded Mitochondrial Genes and Increases the Expression of Extracellular Matrix Genes in Human Skeletal Muscle

TGF-β1 enhances SDF-1α-induced chemotaxis and homing of naive T cells by up-regulating CXCR4 expression and downstream cytoskeletal effector molecules

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