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Kidney Week

Abstract: TH-PO950

Lack of P2X7 Receptors Protects Against Pyelonephritis Associated Renal Fibrosis

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms


  • Therkildsen, Jacob Rudjord, Aarhus University, Aarhus C, Denmark
  • Christensen, Mette G., Aarhus University, Aarhus C, Denmark
  • Pedersen, Stine Julie Tingskov, Aarhus University, Aarhus C, Denmark
  • Norregaard, Rikke, Aarhus University, Aarhus C, Denmark
  • Praetorius, Helle A., Aarhus University, Aarhus C, Denmark

Severe urinary tract infections are regularly caused by sub-strains of E. coli secreting the pore-forming virulence factor α-haemolysin (HlyA). Repeated cases of pyelonephritis can cause marked renal scarring that subsequently leads to progressive failure. We have previously demonstrated that HlyA releases cellular ATP directly through its membrane pore and that acute HlyA-induced cell damage is completely prevented by blocking ATP-signalling. Moreover, there is substantial evidence that local ATP signalling and P2X7 receptor activation plays a key role in the development of tissue fibrosis. This study investigates the effect of P2X7 receptors in infection-induced renal scarring in a murine model of pyelonephritis.


Pyelonephritis was induced by injecting 100 mill HlyA-producing, uropathogenic E. coli into the urinary bladder of balb/c mice. Pyelonephritis was confirmed by culture of the right kidney at day 5 post infection with concomitant high levels of proinflammatory cytokines (IL-6 and IL-1b) a response similar in both P2X7+/+ and P2X7-/- mice.


Lack of P2X7 receptor did not influence on the mortality in the mice exposed to bacteria (ntotal = 131). Fibrosis was first observed 2 weeks post infection. Our data clearly demonstrate that P2X7-/- mice showed markedly less renal fibrosis following a similar degree of infection compared to P2X7+/+ controls (p<0.001), reducing the renal scarring from 1.153 ± 0.0755 mm-2 to 0.296 ± 0.036 mm-2 (fibrotic areas/mm2 in the cortex). Similarly, a P2X7 antagonist BBG reduced the formation of fibrosis (p<0.001) to 0.3810 ± 0.03532 mm-2 in the cortex. Immunohistochemistry revealed comparable degree of neutrophil infiltration in kidneys from P2X7+/+ and P2X7-/- mice, with diminished macrophage infiltration and reduced neutrophil clearance in P2X7-/- mice or mice treated with BBG compared to controls.


Hence this study suggests the P2X7 receptor to be an appealing antifibrotic target following renal infections.


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