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. 2009 Jun;20(6):1275-81.
doi: 10.1681/ASN.2008060559. Epub 2009 Apr 23.

P2X7 deficiency attenuates renal injury in experimental glomerulonephritis

Simon R J Taylor  1 , Clare M Turner, James I Elliott, John McDaid, Reiko Hewitt, Jennifer Smith, Matthew C Pickering, Darren L Whitehouse, H Terence Cook, Geoffrey Burnstock, Charles D Pusey, Robert J Unwin, Frederick W K Tam
Affiliations

P2X7 deficiency attenuates renal injury in experimental glomerulonephritis

Simon R J Taylor et al. J Am Soc Nephrol. 2009 Jun.

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 VSports手机版. .

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Figures

Figure 1.
Figure 1.
Glomerular thrombosis, proteinuria, and serum creatinine levels in wild-type and P2X7−/− mice. (A through D) Representative low- and high-power microscopy of PAS-stained sections of kidneys from wild-type (A and B) and P2X7−/− (C and D) mice 9 d after administration of nephrotoxic serum. (E) P2X7−/− mouse kidneys showed significantly reduced glomerular thrombosis compared with the wild-type, confirmed by quantification of thrombosis scores. (F and G) Proteinuria was also significantly reduced in P2X7−/− mice killed 9d after administration of nephrotoxic serum compared with controls (F), as were serum creatinine levels (G).
Figure 2.
Figure 2.
Glomerular macrophage infiltration and urinary MCP-1 levels. (A) Urinary MCP-1 was significantly reduced in P2X7−/− mice compared with control (WT) mice. (B and C) Macrophage infiltration was similarly reduced in the P2X7−/− mice (B), with fewer CD68+ macrophages visible in glomerular cross-sections (GCS) from P2X7−/− than WT mice 9 d after administration of nephrotoxic serum (C). (D and E) In addition, C3 levels were unchanged between control and P2X7−/− mice (E), but fibrin deposition was significantly reduced (D).
Figure 3.
Figure 3.
Effect of early treatment with the P2X7 antagonist A-438079 on NTN in rats. (A) Rats treated with the 300-μmol/kg dose of A-438079 had a significant reduction in fibrinoid necrosis compared with vehicle-treated rats, whereas rats treated with the 100-μmol/kg dose showed only a trend toward lower levels of disease. (B) Similarly, rats treated with the higher dosage of A-438079 had a significant reduction in proteinuria compared with the vehicle-treated group, whereas rats treated with the lower dosage did not have significantly lower levels.
Figure 4.
Figure 4.
Effect of early treatment with the P2X7 antagonist A-438079 on infiltrating macrophages. Macrophage infiltration was assessed by immunoperoxidase staining using ED-1 mAb. (A) Glomeruli from vehicle-treated rats and those on the lower dosage of 100 μmol/kg A-438079 showed intense macrophage infiltration, whereas macrophage infiltration was significantly reduced in rats given the higher dosage of 300 μmol/kg of the P2X7 antagonist A-438079. (B) Macro-dosage of 300 μmol/kg of the P2X7 antagonist A-438079. (B) Macrophage infiltration as assessed by counting the number of infiltrating macrophages per GCS in 25 consecutive glomeruli confirmed these results.
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References

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