Alteration of glomerular permeability to macromolecules induced by cross-linking of beta 1 integrin receptors.
Altered glomerular epithelial cell attachment to the glomerular basement membrane is an important pathogenetic factor in increased glomerular permeability to proteins. We have previously presented evidence that antibodies reactive with integrin matrix receptors on glomerular epithelial cells inhibit adhesion of these cells and may be involved in the production of proteinuria in vivo. Therefore, we utilized intact glomeruli in an in vitro system to directly assess the effect of anti-beta 1-integrin antibody on glomerular permeability. Permeability to albumin (Palb) was calculated from the volume response of glomeruli to a transcapillary oncotic gradient. Anti-beta 1-integrin increased Palb in a dose- and time-dependent manner. Palb 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 Palb to a similar degree whereas Fab fragments had no effect (0.10 +/- 0.06). Cross-linking of Fab fragments, however, with a second antibody restored their ability to increase Palb (0.60 +/- 0.09), demonstrating the importance of integrin cross-linking in producing the observed effect. Intact, F(ab')2 and Fab fragments of anti-beta 1 antibody all inhibited adhesion of glomerular epithelial cells to fibronectin, laminin, and types I and IV collagen, although the degree of inhibition by Fab fragments was significantly less on collagens. No cytotoxic effects were observed with anti-beta 1 antibody or its fragments. These results suggest that antibodies to integrin matrix receptors on glomerular cells alter cell interactions with the glomerular basement membrane and lead to increased glomerular permeability to proteins via a process that is initiated by integrin cross-linking rather than through simple interference with cell adhesion per se.
Adler
S
S
Department of Medicine, New York Medical College, Valhalla, USA.
Sharma
R
R
Savin
V J
VJ
Abbi
R
R
Eng
B
B
D000418:Albumins / Q000378:metabolism; D000818:Animals; D000937:Antigen-Antibody Reactions / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000648:ultrastructure; D019012:Integrin beta1 / Q000276:immunology*; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008854:Microscopy, Electron; D010539:Permeability / Q000187:drug effects; D011507:Proteinuria / Q000209:etiology; D051381:Rats; D017474:Receptors, Laminin / Q000187:drug effects*
D000418:Albumins; D003432:Cross-Linking Reagents; D019012:Integrin beta1; D017474:Receptors, Laminin