Metal-catalyzed oxidation of extracellular matrix proteins promotes human mesangial cell apoptosis and is associated with enhanced expression of Bax and caspase activation

Oxidative injury in glomerular disease may oxidize extracellular matrix proteins which might modulate their interaction with mesangial cells and thereby account for the hypocellularity seen in advanced glomerulosclerosis. In this study we evaluated whether oxidation of extracellular matrix could modulate human mesangial cell apoptosis. Human mesangial cells were seeded onto plates coated with unmodified (control) or oxidized Matrigel, laminin, or type IV collagen. Mesangial cell apoptosis was increased on oxidized Matrigel as well as on oxidized laminin and type IV collagen. Mesangial cells behaved similarly on plates coated with control and oxidized forms of the integrin ligand-containing peptide GRGDSP. Cells on oxidized matrix demonstrated enhanced expression of Bax, increased fragmentation of PARP, and diminished apoptosis in the presence of the interleukin-1 beta converting enzyme inhibitor Ac-Tyr-Val-Ala-Asp-aldehyde. These data suggest that oxidation of extracellular matrix proteins may enhance human mesangial cell apoptosis via a mechanism that appears to involve enhanced expression of Bax and caspase activation. This may account for irreversible mesangial hypocellularity in glomerulosclerosis.