PDGF-BB enhances α1β1 integrin-mediated activation of the ERK/AP-1 pathway involved in collagen matrix remodeling by rat mesangial cells

• Published in: Journal of cellular physiology Vol. 198; no. 3; pp. 470 - 478
• Main Authors: Kagami, Shoji, Urushihara, Maki, Kitamura, Akiko, Kondo, Shuji, Hisayama, Tetsuhiro, Kitamura, Masanori, Löster, Klemens, Reutter, Werner, Kuroda, Yasuhiro
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.03.2004
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.10433

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 α1β1 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‐α1‐ or anti‐β1‐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 α1β1 integrin‐dependent MC migration to collagen I. These results indicated that PDGF‐BB enhances α1β1 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 α1β1 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. J. Cell. Physiol. 198: 470–478, 2004© 2003 Wiley‐Liss, Inc.