Document Detail


Heparanase and syndecan-1 interplay orchestrates fibroblast growth factor-2-induced epithelial-mesenchymal transition in renal tubular cells.
MedLine Citation:
PMID:  22102278     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Valentina Masola; Giovanni Gambaro; Elena Tibaldi; Anna Maria Brunati; Alessandra Gastaldello; Angela D'Angelo; Maurizio Onisto; Antonio Lupo
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Publication Detail:
Type:  Journal Article     Date:  2011-11-18
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-01-09     Completed Date:  2012-02-27     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1478-88     Citation Subset:  IM    
Affiliation:
Department of Experimental Biomedical Sciences, University of Padova, 35122 Padova, Italy.
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MeSH Terms
Descriptor/Qualifier:
Autocrine Communication / 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:
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
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