ALTERATION OF GLOMERULAR-PERMEABILITY TO MACROMOLECULES INDUCED BY CROSS-LINKING OF BETA(1) INTEGRIN RECEPTORS

Altered glomerular epithelial cell attachment to the glomerular baseme nt membrane is an important pathogenetic factor in increased glomerula r permeability to proteins, We have previously presented evidence that antibodies reactive with integrin matrix receptors on glomerular epit helial cells inhibit adhesion of these cells and may be involved in th e production of proteinuria in vivo. Therefore, we utilized intact glo meruli in an in vitro system to directly assess the effect of anti-bet a(1)-integrin antibody on glomerular permeability. Permeability to alb umin (P-alb) was calculated from the volume response of glomeruli to a transcapillary oncotic gradient. Anti-beta(1)-integrin increased P-al b in a dose- and time-dependent manner. P-alb was increased to 0.70 +/ - 0.05 whereas normal rabbit IgG had no effect (0.10 +/- 0.04). F(ab') (2) fragments of antibody increased P-alb to a similar degree whereas Fab fragments had no effect (0.10 +/- 0.06). Cross-linking of Fab frag ments, however, with a second antibody restored their ability to incre ase P-alb (0.60 +/- 0.09), demonstrating the importance of integrin cr oss-linking in producing the observed effect, Intact, F(ab')(2) and Fa b fragments of anti-beta(1) antibody all inhibited adhesion of glomerc ular epithelial cells to fibronectin, laminin, and types I and IV coll agen, although the degree of inhibition by Fab fragments was significa ntly less on collagens. No cytotoxic effects were observed with anti-b eta(1) antibody or its fragments. These, results suggest that antibodi es to integrin matrix receptors on glomerular cells alter cell interac tions with the glomerular basement membrane and lead to increased glom erular permeability to proteins via a process that is initiated by int egrin cross-linking rather than through simple interference with cell adhesion per se.