Profiling of anti-fibrotic signaling by hepatocyte growth factor in renal fibroblasts.
Hepatocyte growth factor (HGF) is a multifunctional growth factor affecting cell proliferation and differentiation. Due to its mitogenic potential, HGF plays an important role in tubular repair and regeneration after acute renal injury. However, recent reports have shown that HGF also acts as an anti-inflammatory and anti-fibrotic factor, affecting various cell types such as renal fibroblasts and triggering tubulointerstitial fibrosis of the kidney. The present study provides evidence that HGF stimulation of renal fibroblasts results in the activation of both the Erk1/2 and the Akt pathways. As previously shown, Erk1/2 phosphorylation results in Smad-linker phosphorylation, thereby antagonizing cellular signals induced by TGFbeta. By siRNA mediated silencing of the Erk1/2-Smad linkage, however, we now demonstrate that Akt signaling acts as an auxiliary pathway responsible for the anti-fibrotic effects of HGF. In order to define the anti-fibrotic function of HGF we performed comprehensive expression profiling of HGF-stimulated renal fibroblasts by microarray hybridization. Functional cluster analyses and quantitative PCR assays indicate that the HGF-stimulated pathways transfer the anti-fibrotic effects in renal interstitial fibroblasts by reducing expression of extracellular matrix proteins, various chemokines, and members of the CCN family.
Institute for Pathology, University Hospital Cologne, Kerpener Str. 62, 50924 Koeln, Germany.
Stephanie
S
Schievenbusch
Ingo
I
Strack
Melanie
M
Scheffler
Kerstin
K
Wennhold
Julia
J
Maurer
Roswitha
R
Nischt
Hans Peter
HP
Dienes
Margarete
M
Odenthal
D000818:Animals; D055511:CCN Intercellular Signaling Proteins / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011817:Rabbits; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000235:genetics
D055511:CCN Intercellular Signaling Proteins; D024042:Collagen Type I; C066855:HGF protein, human; D051785:Smad Proteins; D017228:Hepatocyte Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020782:Matrix Metalloproteinases