| Heparanase and syndecan-1 interplay orchestrates fibroblast growth factor-2-induced epithelial-mesenchymal transition in renal tubular cells. | |
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MedLine Citation:
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PMID: 22102278 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The epithelial-mesenchymal transition (EMT) of proximal tubular epithelial cells (PTECs) into myofibroblasts contributes to the establishment of fibrosis that leads to end stage renal disease. FGF-2 induces EMT in PTECs. Because the interaction between FGF-2 and its receptor is mediated by heparan sulfate (HS) and syndecans, we speculated that a deranged HS/syndecans regulation impairs FGF-2 activity. Heparanase is crucial for the correct turnover of HS/syndecans. The aim of the present study was to assess the role of heparanase on epithelial-mesenchymal transition induced by FGF-2 in renal tubular cells. In human kidney 2 (HK2) PTEC cultures, although FGF-2 induces EMT in the wild-type clone, it is ineffective in heparanase-silenced cells. The FGF-2 induced EMT is through a stable activation of PI3K/AKT which is only transient in heparanase-silenced cells. In PTECs, FGF-2 induces an autocrine loop which sustains its signal through multiple mechanisms (reduction in syndecan-1, increase in heparanase, and matrix metalloproteinase 9). Thus, heparanase is necessary for FGF-2 to produce EMT in PTECs and to sustain FGF-2 intracellular signaling. Heparanase contributes to a synergistic loop for handling syndecan-1, facilitating FGF-2 induced-EMT. In conclusion, heparanase plays a role in the tubular-interstitial compartment favoring the FGF-2-dependent EMT of tubular cells. Hence, heparanase is an interesting pharmacological target for the prevention of renal fibrosis. |
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Authors:
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Valentina Masola; Giovanni Gambaro; Elena Tibaldi; Anna Maria Brunati; Alessandra Gastaldello; Angela D'Angelo; Maurizio Onisto; Antonio Lupo |
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Publication Detail:
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Type: Journal Article Date: 2011-11-18 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 287 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-01-09 Completed Date: 2012-02-27 Revised Date: 2013-02-20 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 1478-88 Citation Subset: IM |
Affiliation:
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Department of Experimental Biomedical Sciences, University of Padova, 35122 Padova, Italy. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Autocrine Communication
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genetics Cell Line Enzyme Activation / genetics Epithelial-Mesenchymal Transition* Fibroblast Growth Factor 2 / genetics, metabolism* Fibrosis Glucuronidase / genetics, metabolism* Humans Kidney Failure, Chronic / metabolism*, pathology Kidney Tubules / metabolism*, pathology Phosphatidylinositol 3-Kinases / genetics, metabolism Proto-Oncogene Proteins c-akt / genetics, metabolism Receptor, Fibroblast Growth Factor, Type 2 / genetics, metabolism Signal Transduction / genetics Syndecan-1 / genetics, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/SDC1 protein, human; 0/Syndecan-1; 103107-01-3/Fibroblast Growth Factor 2; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.10.1/Receptor, Fibroblast Growth Factor, Type 2; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.2.1.-/heparanase; EC 3.2.1.31/Glucuronidase |
| Comments/Corrections | |
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