NDT Advance Access published online on October 1, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn530
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Regulation of connective tissue growth factor (CTGF) by hepatocyte growth factor in human tubular epithelial cells
1 Department of Nephrology and Hypertension, Medical Clinic 4 2 Nikolaus-Fiebiger-Center for Molecular Medicine, University Hospital of Erlangen-Nuremberg 3 Department of Urology, Waldkrankenhaus St Marien, 91054 Erlangen, Germany
Correspondence and offprint requests to: Margarete Goppelt-Struebe, Department of Nephrology and Hypertension, University Hospital of Erlangen-Nuremberg, Loschgestrasse 8, D-91054 Erlangen, Germany. Tel: +49-9131-8539201; Fax: +49-9131-8539202; E-mail: goppelt-struebe{at}rzmail.uni-erlangen.de
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Abstract |
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Background. Hepatocyte growth factor (HGF) is a pleiotropic protein with renoprotective functions, which have been attributed at least in part to its ability to counteract the profibrotic effects of transforming growth factor β (TGF-β). A major downstream mediator of TGF-β is connective tissue growth factor (CTGF). However, the molecular mechanisms of CTGF regulation by HGF have not yet been investigated.
Methods. CTGF expression was analysed in human primary tubular epithelial cells (hPTECs) and the cell line HKC-8 by western blotting. Morphological alterations were analysed by immunocytochemistry.
Results. HGF induced a transient expression of CTGF, which was maximal after 6 h and returned to baseline after 24 h. Coincubation with TGF-β increased CTGF protein at 6 h, whereas HGF significantly decreased CTGF induction by TGF-β after 24 h. Furthermore, HGF induced cell scattering associated with reorganization of focal adhesions and formation of lamellipodia and filopodia. The early induction of CTGF was linked to the HGF-mediated alterations of cell morphology. The PP2 inhibitor of Src-family kinases, which regulate focal adhesion turnover, reduced HGF-mediated upregulation of CTGF. In addition, inhibition of the Rho-kinase, which modulates the actin cytoskeleton, impaired CTGF expression. Combination of both inhibitors further decreased CTGF expression. Comparable inhibitory effects were obtained, when CTGF was induced by the combination of HGF and TGF-β.
Conclusions. We provide evidence for a dual effect of HGF on CTGF regulation in human tubular epithelial cells: transient upregulation of CTGF in the absence of TGF-β, which was related to alterations of cell morphology, and interference with TGF-β-mediated CTGF induction after prolonged incubation.
Keywords: actin cytoskeleton; connective tissue growth factor; focal adhesion; hepatocyte growth factor; transforming growth factor β
Received for publication: 3. 6.08
Accepted in revised form: 1. 9.08
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