REGULATION OF SURVIVAL AND DEATH OF MESANGIAL CELLS BY EXTRACELLULAR-MATRIX

Background. Cell-matrix interactions exert major effects on such pheno typic features as cell growth and differentiation. Apoptosis is an act ive form of cell death that is crucial for maintaining the appropriate number uf cells as well as the organization of tissue. Recently, it h as been suggested that apoptosis of the mesangial cells (MC) is import ant in glomerular remodeling after injury. The MC are surrounded by an extracellular matrix (ECM) in vivo. Since in disease conditions the m esangial matrix is altered quantitatively and qualitatively, it is of intel est to determine whether cell-matrix interactions may influence apoptosis of the MC. Methods. We first investigated the differences in the susceptibility to apoptotic stimuli of the MC cultured on various ECM components (type I collagen. fibronectin, basement membrane matri x), We then determined whether the inhibition of MC-matrix interaction s would affect apoptosis. Finally. interactions between MC and matrix were disrupted by the inhibition of beta(1)-integrin expression with a ntisense oligonucleotides (ODN). Results. When MC were cultured on typ e I collagen or fibronectin and deprived of serum for eight hours, the extracted DNA horn the MC demonstrated an internucleosomal ladder pat tern on gel electrophoresis that constituted the biochemical character istics of apoptosis. However, no ladder pattern was apparent when MC w ere cultured on basement membrane matrix. The attachment of cells was completely inhibited when the MC were cultured on agarose-coated dishe s for 24 hours. Gel electrophoresis of DNA extracted from these cells showed a ladder pattern. However. the MC attached to the substratum di d not show any apoptosis. MC showed an increase in apoptotic cell deat h after treatment with antisense ODN against beta(1)-integrin molecule . Conclusions. These results indicate that normal ECR I may prevent th e MC from undergoing apoptosis and serve as a survival factor for MC. Signals from ECM that prevent apoptosis may be mediated by beta(1)-int egrin molecules.