P2X(7) Deficiency Attenuates Renal Injury in Experimental Glomerulonephritis

The P2X(7), receptor is a ligand-gated cation channel that is normally expressed by a variety of immune cells, including macrophages and lymphocytes. Because it leads to membrane blebbing, release of IL-1 beta, and cell death by apoptosis or necrosis, it is a potential therapeutic target for a variety of inflammatory diseases. Although the P2X(7) receptor is usually not detectable in normal renal tissue, we previously reported increased expression of both mRNA and protein in mesangial cells and macrophages infiltrating the glomeruli in animal models of anti body-mediated glomerulonephritis. In this study, we used P2X(7)-knockout mice in the same experimental model of glomerulonephritis and found that P2X(7) deficiency was significantly renoprotective compared with wild-type controls, evidenced by better renal function, a striking reduction in proteinuria, and decreased histologic glomerular injury. In addition, the selective P2X(7) antagonist A-438079 prevented the development of antibody-mediated glomerulonephritis in rats. These results support a proinflammatory role for P2X(7) in immune-mediated renal injury and suggest that the P2X(7) receptor is a potential therapeutic target.