Metal-catalyzed oxidation of extracellular matrix proteins disrupts integrin-mediated adhesion of mesangial cells.

We undertook the present study to determine whether oxidation of extracellular matrix could alter RGD (arginine-glycine-aspartic acid)-integrin interaction in mesangial cells. Mesangial cells demonstrated significantly less adhesion to matrix oxidized using a metal-catalyzed oxidation system and lost their typical spindle-shaped morphology. N-tert-butyl-alpha-phenylnitrone reversed in part both oxidation and impaired adhesion to matrix. Mesangial cells adhered to plates coated with GRGDSP but demonstrated impaired adhesion to oxidized GRGDSP. Oxidation of this peptide was demonstrated using immunoblot analysis with an antibody to dinitrophenylhydrazine bound to carbonyl groups on oxidized amino acid residues. This represents the first report demonstrating that oxidative modification of extracellular matrix impairs integrin-mediated adhesion and suggests that the mechanism may be oxidative modification of one or more amino acids in the RGD sequence. These data suggest a new mechanism by which cell-matrix interaction may be altered in disease states characterized by enhanced oxidative stress.