Pathologic remodeling of mesangial matrix after glomerular injury is the central
biologic feature of glomerular
scarring (
sclerosis).
Transforming growth factor-beta (
TGF-beta) 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
alpha1beta1 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-beta and
PDGF-BB on mesangial cell (MC)-mediated
collagen gel contraction in association with the
alpha1beta1 integrin expression was evaluated.
Integrin function blocking studies using anti-alpha1, beta1 subunit
antibodies indicated that MC-alpha1beta1
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-beta, but not
PDGF-BB, increases the expression of
alpha1beta1 integrin in mesangial cells cultured on
plastic surface and in
collagen gels. The upregulation of
alpha1beta1 integrin expression by
TGF-beta 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-alpha1, beta1 subunit
antibodies. Thus, these data indicate that
alpha1beta1 integrin-mediated
collagen matrix remodeling can be modulated by
TGF-beta and
PDGF-BB via different mechanisms.
Alpha1 integrin-mediated mesangial matrix remodeling induced by
TGF-beta or
PDGF-BB may be a pathogenic mechanism leading to glomerular
scarring.