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1ß1 Integrin-Mediated Collagen Matrix Remodeling by Rat Mesangial Cells Is Differentially Regulated by Transforming Growth Factor-ß and Platelet-Derived Growth Factor-BB

SHOJI KAGAMI^*, SHUJI KONDO^*, KLEMENS LÖSTER, WERNER REUTTER, TAKASHI KUHARA^*, KOJI YASUTOMO^* and YASUHIRO KURODA^*

^* Department of Pediatrics, School of Medicine, University of Tokushima, Tokushima, Japan
Institut für Molekularbiologie und Biochemie, Freie Universitat Berlin, Berlin-Dahlem, Germany.

Correspondence to Dr. Shoji Kagami, Department of Pediatrics, School of Medicine, University of Tokushima, Kuramoto-cho-3-chome, Tokushima 770-8503, Japan. Phone: 011 81 886 31 3111; Fax: 011 81 886 31 8697; E-mail: kagami{at}medclin.clin.med.tokushima-u.ac.jp

Abstract. Pathologic remodeling of mesangial matrix after glomerular injury is the central biologic feature of glomerular scarring (sclerosis). Transforming growth factor-ß (TGF-ß) and platelet-derived growth factor (PDGF)-BB have been implicated in the development of glomerular scarring in rat and human glomerulonephritis. To clarify molecular and cellular mechanisms involved in abnormal mesangial remodeling, this study focused on the role of 1ß1 integrin, a collagen/laminin receptor, in rat mesangial cells, using collagen gel contraction as an experimental model of in vivo collagen matrix remodeling and scar formation. In addition, the influence of TGF-ß and PDGF-BB on mesangial cell (MC)-mediated collagen gel contraction in association with the 1ß1 integrin expression was evaluated. Integrin function blocking studies using anti-1, ß1 subunit antibodies indicated that MC-1ß1 integrin is essentially required not only for collagen-dependent adhesion/migration, but also for gel contraction. Protein synthesis and mRNA analysis experiments demonstrated that TGF-ß, but not PDGF-BB, increases the expression of 1ß1 integrin in mesangial cells cultured on plastic surface and in collagen gels. The upregulation of 1ß1 integrin expression by TGF-ß correlated with increases in gel contraction and collagen-dependent adhesion but not migration of mesangial cells. On the other hand, PDGF-BB enhanced MC-mediated gel contraction and migration without affecting cell adhesion to collagen I. Growth factor-induced collagen-dependent adhesion, migration, and gel contraction were significantly attenuated by incubation with anti-1, ß1 subunit antibodies. Thus, these data indicate that 1ß1 integrin-mediated collagen matrix remodeling can be modulated by TGF-ß and PDGF-BB via different mechanisms. 1ß1 integrin-mediated mesangial matrix remodeling induced by TGF-ß or PDGF-BB may be a pathogenic mechanism leading to glomerular scarring.

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