title: P2X7 deficiency attenuates renal injury in experimental glomerulonephritis.
abstract: 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-1beta, 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.
authors.affiliation: MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom.
authors.forename: Simon R J
authors.initials: SR
authors.lastname: Taylor
authors.forename: Clare M
authors.initials: CM
authors.lastname: Turner
authors.forename: James I
authors.initials: JI
authors.lastname: Elliott
authors.forename: John
authors.initials: J
authors.lastname: McDaid
authors.forename: Reiko
authors.initials: R
authors.lastname: Hewitt
authors.forename: Jennifer
authors.initials: J
authors.lastname: Smith
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Pickering
authors.forename: Darren L
authors.initials: DL
authors.lastname: Whitehouse
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Burnstock
authors.forename: Charles D
authors.initials: CD
authors.lastname: Pusey
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Unwin
authors.forename: Frederick W K
authors.initials: FW
authors.lastname: Tam
mesh_terms: D000818:Animals; D005260:Female; D005921:Glomerulonephritis / Q000503:physiopathology* / Q000517:prevention & control; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058919:Purinergic P2 Receptor Antagonists; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058486:Receptors, Purinergic P2X7; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C523668:3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine; C546469:P2rx7 protein, mouse; D058919:Purinergic P2 Receptor Antagonists; D011725:Pyridines; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D013777:Tetrazoles