P2X7 Deficiency Attenuates Renal Injury in Experimental Glomerulonephritis

The P2X₇ 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-1β, and cell death by apoptosis or necrosis, it is a potential therapeutic target for a variety of inflammatory diseases. Although the P2X₇ 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 antibody-mediated glomerulonephritis. In this study, we used P2X₇-knockout mice in the same experimental model of glomerulonephritis and found that P2X₇ 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 P2X₇ antagonist A-438079 prevented the development of antibody-mediated glomerulonephritis in rats. These results support a proinflammatory role for P2X₇ in immune-mediated renal injury and suggest that the P2X₇ receptor is a potential therapeutic target.Glomerulonephritis (GN) is a major cause of end-stage kidney disease; current therapy usually involves relatively nonspecific immunosuppression with often serious adverse effects.¹ Glomerular deposition of antibodies directed against exogenous antigens or autoantigens, leading to immune complex–mediated inflammation and tissue injury, has been well documented in both experimental and clinical forms of GN.²The rat model of nephrotoxic nephritis (NTN) has demonstrated the importance of IL-1β in GN; renal levels of IL-1β are increased in this form of GN, and IL-1β has been shown to play an important role in glomerular crescent formation and in subsequent tubulointerstitial injury.³ Moreover, early and late treatment with an IL-1 receptor antagonist prevents the progression of crescentic GN.^4,5 Crescentic GN is also less severe in IL-1β^−/− or IL-18^−/− mice, and treatment with caspase inhibitors reduces renal inflammation and apoptosis—all consistent with a central role for IL-1β in this experimental model of GN.^6–8The ATP-sensitive P2X₇ receptor is a cation channel activated by high concentrations of extracellular ATP.⁹ Stimulation of this receptor is proinflammatory, causing release of inflammatory cytokines such as IL-1β and IL-18 from macrophages, changes in plasma membrane lipid distribution, and cell death by necrosis or apoptosis.^10,11 A central role for P2X₇ in IL-1β secretion via the Nacht Domain-, Leucine-Rich Repeat-, and PYD-Containing Protein 3 (NALP3) inflammasome has been shown in P2X₇-deficient mice.^12,13 This receptor also has significant prothrombotic effects,¹⁴ causing release of tissue factor–bearing microparticles.¹⁵ Indeed, P2X₇ is already considered to be a possible therapeutic target in inflammation, and antagonists are currently in Phase II clinical trials for the treatment of rheumatoid arthritis and chronic obstructive pulmonary disease; however, the role of this receptor in renal disease or injury is still unclear.¹⁶We previously reported an increase in glomerular expression of the P2X₇ receptor (at the mRNA and protein levels) in rats and mice with NTN induced by nephrotoxic globulin (NTG)—an established model of immune complex–mediated GN characterized by proteinuria, glomerular thrombosis, and tubulointerstitial injury—as well as in renal biopsy tissue from patients with lupus nephritis.^17,18 In this study, we used P2X₇-deficient mice and the selective P2X₇ antagonist A-438079 to examine in more detail the role of P2X₇ in the NTN model of GN.