| Tgf-beta auto-induction and connective tissue growth factor expression in human renal tubule epithelial cells requires N-ras. | |
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MedLine Citation:
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PMID: 19494553 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND/AIMS: Transforming growth factor (TGF) beta is strongly implicated in the progression of renal fibrosis. TGFbeta1 is reported to cause epithelial-mesenchymal transition, inhibition of epithelial cell proliferation, increased apoptosis, auto-induction of TGFbeta production and induction of secondary mediators of tissue fibrosis such as connective tissue growth factor (CTGF, CCN2). The aims of this study were to investigate the role of the Ras/MAP kinase pathway in TGFbeta1 inhibition of proliferation, TGFbeta auto-induction and TGFbeta1-induced CTGF expression in HKC human renal tubule epithelial cells. METHODS AND RESULTS: TGFbeta1 (0-25 ng/ml) inhibited proliferation of HKC cells and at 25 ng/ml also induced apoptosis. After 5-10 min of incubation, TGFbeta1 increased cellular levels of phospho-ERK1/2 and phospho-AKT with a bell-shaped dose-response curve with a maximally effective concentration of 2.5 ng/ml. TGFbeta3 caused an increase in extracellular TGFbeta1, which was significantly reduced in the presence of PD 98059. TGFbeta1 increased cellular and secreted CTGF protein in HKC cells in a MEK-dependent manner. To identify the Ras isoform involved, specific antisense oligonucleotides targeted to Ha-Ras, Ki-Ras and N-Ras were employed. Only inhibition of N-Ras resulted in a significant reduction of auto-induced TGFbeta1 secretion and TGFbeta1-induced cellular and secreted CTGF. CONCLUSION: These results establish that the Ras/MAP kinase pathway, specifically through N-Ras, mediates TGFbeta1 auto-induction and TGFbeta1-induced CTGF expression in human renal tubule epithelial cells. |
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Authors:
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Mark E C Dockrell; Mysore K Phanish; Bruce M Hendry |
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Publication Detail:
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Type: Journal Article Date: 2009-06-01 |
Journal Detail:
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Title: Nephron. Experimental nephrology Volume: 112 ISSN: 1660-2129 ISO Abbreviation: Nephron Exp. Nephrol. Publication Date: 2009 |
Date Detail:
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Created Date: 2009-06-26 Completed Date: 2009-08-27 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 101159770 Medline TA: Nephron Exp Nephrol Country: Switzerland |
Other Details:
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Languages: eng Pagination: e71-9 Citation Subset: IM |
Copyright Information:
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Copyright 2009 S. Karger AG, Basel. |
Affiliation:
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Department of Renal Medicine, King's College London School of Medicine, London, UK. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Cell Proliferation
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drug effects Cells, Cultured Connective Tissue Growth Factor / biosynthesis* Epithelial Cells / metabolism Flavonoids / pharmacology Humans Kidney Tubules, Proximal MAP Kinase Signaling System / physiology Mitogen-Activated Protein Kinase 1 / metabolism Mitogen-Activated Protein Kinases / antagonists & inhibitors, metabolism Transforming Growth Factor beta1 / physiology*, secretion Transforming Growth Factor beta3 / physiology* ras Proteins / physiology* |
| Chemical | |
Reg. No./Substance:
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0/Flavonoids; 0/PD 98059; 0/Transforming Growth Factor beta1; 0/Transforming Growth Factor beta3; 139568-91-5/Connective Tissue Growth Factor; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 3.6.5.2/ras Proteins |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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