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-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.
Taylor
Simon R J
SR
MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom.
Turner
Clare M
CM
Elliott
James I
JI
McDaid
John
J
Hewitt
Reiko
R
Smith
Jennifer
J
Pickering
Matthew C
MC
Whitehouse
Darren L
DL
Cook
H Terence
HT
Burnstock
Geoffrey
G
Pusey
Charles D
CD
Unwin
Robert J
RJ
Tam
Frederick W K
FW
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
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