PDGF-BB enhances alpha1beta1 integrin-mediated activation of the ERK/AP-1 pathway involved in collagen matrix remodeling by rat mesangial cells.

Abstract

Platelet-derived growth factor-BB (PDGF-BB) has been implicated in the pathogenesis of progressive glomerulonephritis (GN). Previous studies have reported that PDGF-BB stimulates mesangial cells (MCs)-induced collagen matrix remodeling through enhancement of alpha1beta1 integrin-dependent migratory activity. To determine the cell signaling pathway responsible for abnormal MC-related mesangial matrix remodeling in progressive GN, we studied the involvement of the extracellular signal-regulated kinase (ERK)/activator protein-1 (AP-1) pathway in PDGF-BB-enhanced collagen gel contraction. Western blotting and gel shift assay revealed that MC-induced gel contraction resulted in ERK activation in parallel with that of AP-1 binding, peaking at 4 h and lasting at least for 24 h. Application of the MEK inhibitor, U0126, and the c-jun/AP-1 inhibitor, curcumin, inhibited gel contraction and AP-1 activity, respectively, dose dependently. PDGF-BB enhanced not only gel contraction but ERK phosphorylation and AP-1 activity by MCs. Marked inhibitory effects on PDGF-BB-induced gel contraction and ERK/AP-1 activity were observed in the presence of either function blocking anti-alpha1- or anti-beta1-integrin antibody or U0126. Consistently, AP-1-inactive MCs expressing a dominant-negative mutant of c-jun showed a significant decrease of PDGF-BB-induced gel contraction as compared with mock-transfected MCs. Finally, migration assay showed that ERK/AP-1 activity is required for PDGF-BB-stimulated alpha1beta1 integrin-dependent MC migration to collagen I. These results indicated that PDGF-BB enhances alpha1beta1 integrin-mediated collagen matrix reorganization through the activation of the ERK/AP-1 pathway that is crucial for MC migration. We conclude that the ERK/AP-1 pathway plays an important role in PDGF-BB-induced alpha1beta1 integrin-dependent collagen matrix remodeling; therefore, the inhibition of its pathway may provide a novel approach to regulate abnormal collagen matrix remodeling in progressive GN.

• Authors: Shoji Kagami, Maki Urushihara, Akiko Kitamura, Shuji Kondo, Tetsuhiro Hisayama, Masanori Kitamura, Klemens Löster, Werner Reutter, Yasuhiro Kuroda
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 198 Issue 3 Pg. 470-8 (Mar 2004) ISSN: 0021-9541 [Print] United States
• PMID: 14755552 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2003 Wiley-Liss, Inc.

Chemical References

• Butadienes
• Enzyme Inhibitors
• Integrin alpha1beta1
• Nitriles
• Platelet-Derived Growth Factor
• Proto-Oncogene Proteins c-sis
• Transcription Factor AP-1
• U 0126
• Becaplermin
• Collagen
• Mitogen-Activated Protein Kinases
• Curcumin

Topics

• Animals
• Becaplermin
• Blotting, Western
• Butadienes (pharmacology)
• Cell Movement (physiology)
• Collagen (drug effects, metabolism)
• Curcumin (pharmacology)
• Dose-Response Relationship, Drug
• Electrophoretic Mobility Shift Assay
• Enzyme Activation (physiology)
• Enzyme Inhibitors (pharmacology)
• Extracellular Matrix (drug effects, metabolism)
• Genes, jun
• Glomerular Mesangium (cytology, metabolism)
• Glomerulonephritis (physiopathology)
• Integrin alpha1beta1 (metabolism)
• Mitogen-Activated Protein Kinases (drug effects, metabolism)
• Mutation
• Nitriles (pharmacology)
• Platelet-Derived Growth Factor (physiology)
• Proto-Oncogene Proteins c-sis
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (physiology)
• Transcription Factor AP-1 (drug effects, metabolism)
• Transfection