Matrix protein synthesis by glomerular mesangial cells in culture: Effects of transforming growth factor β (TGFβ) and platelet‐derived growth factor (PDGF) on fibronectin and collagen type IV mRNA

Hänsch, Gertrud Maria; Wagner, C.; Bürger, Antje; Dong, Wenjie; Staehler, G.; Stoeck, Michael

doi:10.1002/jcp.1041630304

Cited by 58 publications

(31 citation statements)

References 24 publications

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“…PDGF-BB, secreted by glomerular cells as well as activated platelets and macrophages, is the most potent mitogen for mesangial cells in vitro and in vivo (36). Moreover, PDGF has been shown to be induced by TGF-␤ and to mediate TGF-␤-induced accumulation of collagen IV and fibronectin (32). Also, VEGF has been reported to enhance collagen synthesis via the activation of ERK (3).…”

Section: Discussionmentioning

confidence: 99%

Bradykinin reduces growth factor-induced glomerular ERK1/2 phosphorylation

Cellier

Mage

Duchêne

et al. 2003

American Journal of Physiology-Renal Physiology

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Several experimental data report both mitogenic and antimitogenic effects of bradykinin (BK). To conciliate these apparent opposite effects, we hypothesized that, depending on cell context activation, BK could reduce the mitogenic effect of growth factors. Therefore, in the present study we assessed the existence of possible negative cross talk between BK and potential pathogenic growth factors in freshly isolated rat glomeruli (IG). Next, we determined whether this cross talk could be pharmacologically recruited during angiotensin-converting enzyme (ACE) inhibition in the diabetic rat. In IG from normal rats, BK, via activation of the B2 kinin receptor (B2R), causes a transient stimulation of ERK1/2 phosphorylation, whereas it inhibits ERK1/2 phosphorylation induced by IGF-1, PDGF-BB, VEGF, or basic FGF. The reduction of growth factor-induced ERK1/2 phosphorylation is abolished by an inhibitor of tyrosine phosphatase. In glomeruli from diabetic rats, hyperglycemia increased the phosphorylation level of ERK-1/2 as well as oxidative stress. The reversal of these events by ACE inhibition is mediated via B2R activation. These observations are consistent with a potential therapeutic role of BK and B2R during glomerulosclerosis.

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Section: Discussionmentioning

confidence: 99%

Bradykinin reduces growth factor-induced glomerular ERK1/2 phosphorylation

Cellier

Mage

Duchêne

et al. 2003

American Journal of Physiology-Renal Physiology

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“…To assess the role of TGF-␤ in modulating actin cytoskeletal regulatory protein gene expression in mesangial cells, cells were serum-starved for 24 h and then cultured in the presence or absence of TGF-␤ (10 ng/ml, 24 h). Interestingly, TGF-␤ did not mimic the effects of exposure to high glucose on the expression of genes encoding actin cytoskeletal regulatory proteins, whereas fibronectin, a well defined TGF-␤-responsive gene (10,35), was induced (Fig. 1B).…”

Section: Enhanced Expression Of Actin Cytoskeletal Regulatory Genes Imentioning

confidence: 98%

High Glucose-altered Gene Expression in Mesangial Cells

Clarkson¹,

Murphy²,

Gupta³

et al. 2002

Journal of Biological Chemistry

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High extracellular glucose plays a pivotal role in the pathophysiology of diabetic nephropathy. Here we report 200 genes, identified using suppression-subtractive hybridization, that are differentially expressed when human mesangial cells are propagated in high ambient glucose in vitro. The major functional classes of genes identified included modulators and products of extracellular matrix protein metabolism, regulators of cell growth and turnover, and a cohort of actin cytoskeleton regulatory proteins. Actin cytoskeletal disassembly is a prominent feature of diabetic nephropathy. The induction of actin cytoskeleton regulatory gene expression by high glucose was attenuated by the inhibitor of reactive oxygen species generation, carbonyl cyanide m-chlorophenylhydrazone but not by the protein kinase C inhibitor GF 109203X and was not mimicked by the addition of transforming growth factor ␤. Enhanced expression of actin cytoskeleton regulatory genes was also observed following disruption of the mesangial cell actin cytoskeleton by cytochalasin D. In aggregate, these results suggest that the induction of genes encoding actin cytoskeleton regulatory proteins (a) is a prominent component of the mesangial cell transcriptomic response in diabetic nephropathy and (b) is dependent on oxidative stress, is independent of protein kinase C and transforming growth factor-␤, and represents an adaptive response to actin cytoskeleton disassembly. Diabetic nephropathy (DN)1 accounts for over one-third of all new cases of end stage renal failure in Western society (1).Glomerulosclerosis is the pathological hallmark of DN and reflects, in large part, altered mesangial cell matrix metabolism (2-6). The latter is triggered, in turn, by the complex interplay of metabolic and hemodynamic stress (2-6). Putative mediators of high glucose-induced mesangial cell dysfunction include oxidative stress, glomerular hypertension, protein kinase C (PKC) activation, transforming growth factor (TGF-␤), cell sorbitol accumulation, and advanced glycosylation end products (2-7). The molecular components of the mesangial cell response to high glucose stress are still being defined. With the completion of the human genome project, the monitoring of changes in the cellular transcriptome in response to diseasemimicking stimuli provides a powerful methodology for dissecting the molecular basis of disease. Here we employed a PCRbased technique, namely suppression-subtractive hybridization (SSH), to assess the influence of high extracellular glucose on gene expression by cultured human mesangial cells. This technique has the advantage over most other PCR-based techniques, such as differential display PCR, of including a normalization step that removes bias for the more abundant cellular transcripts. SSH may be more sensitive than most currently available oligonucleotide microarray systems, being able to detect relatively small changes in gene expression down to 1.5-fold as judged by Northern blot analysis. SSH identified some 200 genes that are differentiall...

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“…These phosphorylated Smad2 and Smad3 proteins then can associate with Smad4 (common Smad), and this complex translocates to the nucleus, leading to gene regulation. MC express Smad2/3, Smad4, and Smad7 (inhibitory Smad), which mediate TGF-␤-induced gene expression, including that of ECM genes such as plasminogen activator-1 and type I collagen (11,13,(17)(18)(19). There is also evidence that, apart from the Smad pathway, the matrix-inducing actions of TGF-␤ may also be mediated via activation of mitogenactivated protein kinases (MAPK) (20).…”

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confidence: 99%