alpha 1 beta 1 integrin-mediated collagen matrix remodeling by rat mesangial cells is differentially regulated by transforming growth factor-beta andplatelet-derived growth factor-BB

Pathologic remodeling of mesangial matrix after glomerular injury is the ce ntral biologic feature of glomerular scarring (sclerosis). Transforming gro wth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF)-BB hav e been implicated in the development of glomerular scarring in rat and huma n glomerulonephritis. To clarify molecular and cellular mechanisms involved in abnormal mesangial remodeling, this study focused on the role of alpha 1 beta 1 integrin, a collagen/laminin receptor, in rat mesangial cells, usi ng collagen gel contraction as an experimental model of in vivo collagen ma trix remodeling and scar formation. In addition, the influence of TGF-beta and PDGF-BB on mesangial cell (MC)-mediated collagen gel contraction in ass ociation with the alpha 1 beta 1 integrin expression was evaluated. Integri n function blocking studies using anti-alpha 1, beta 1 subunit antibodies i ndicated that MC-alpha 1 beta 1 integrin is essentially required not only f or collagen-dependent adhesion/migration, but also for gel contraction. Pro tein synthesis and mRNA analysis experiments demonstrated that TGF-P, but n ot PDGF-BB, increases the expression of alpha 1 beta 1 integrin in mesangia l cells cultured on plastic surface and in collagen gels. The upregulation of alpha 1 beta 1 integrin expression by TGF-beta correlated with increases in gel contraction and collagen-dependent adhesion but not migration of me sangial cells. On the other hand, PDGF-BB enhanced MC-mediated gel contract ion and migration without affecting cell adhesion to collagen I. Growth fac tor-induced collagen-dependent adhesion, migration, and gel contraction wer e significantly attenuated by incubation with anti-alpha 1, beta 1 subunit antibodies. Thus, these data indicate that alpha 1 beta 1 integrin-mediated collagen matrix remodeling can be modulated by TGF-beta and PDGF-BB via di fferent mechanisms. alpha 1 beta 1 integrin-mediated mesangial matrix remod eling induced by TGF-beta or PDGF-BB may be a pathogenic mechanism leading to glomerular scarring.