The purpose of the present studies is to evaluate the effects of immune complexes (IC) formation and complement activation on the attachment of human glomerular cells to the extracellular matrix. Cell-matrix and cell-cell adhesion are mediated by a series of cell membrane proteins called integrins. By mediating cell-matrix adhesion, integrins influence cell morphology, cell proliferation and a variety of cell functions. In addition, certain integrins also function as receptors that is, binding to those integrins modify cell function. We recently demonstrated that several integrins are present in human glomerular cells and one of those integrins, a fibronectin (FN) receptor, mediate the binding of human mesangial cells (MC) to FN and the phagocytosis of FN coated particles. It is difficult to assess directly the relevance of cell-matrix adhesion to whole kidney function. However, previous studies have suggested that the attachment of glomerular epithelial cells to the glomerular basement membrane determines, at least in part, the selectivity permeability of the glomerular filter. Because IC and complement are common mediators of glomerular injury in humans, in preliminary studies we assessed whether those pathogenic events may produce alterations on the adhesion of MC to matrix. We showed that complement activation by IC result in detachment of MC from matrix, an event not associated with cell death. We also showed that MC-matrix detachment is an active process that requires new RNA and protein synthesis. In the present application, we propose to evaluate the mechanisms responsible for glomerular cell-matrix detachment after exposure to complement. Preliminary studies presented here and previous studies from our laboratory showed that complement activation increases glomerular cell synthesis of a variety of proteins. This effect of complement may have pathogenic relevance by increasing synthesis of proteins normally produced by glomerular cells, such as integrins and matrix proteins, and/or by inducing synthesis of new proteins, such as heat shock proteins. The effects of complement on the synthesis of these particular groups of proteins by glomerular cells will be evaluated here. These observations provide new insights into mechanisms by which complement activation can modify cell function and produce cell damage. Because cell-matrix adhesion plays a role in maintaining normal kidney structure and function, the present studies are likely to also give new insights into pathogenic mechanisms involved in complement-mediated glomerulonephritis.
