Mette G. Christensen

TY - JOUR

T1 - Lack of P2X 7 Receptors Protects against Renal Fibrosis after Pyelonephritis with α-Hemolysin–Producing Escherichia coli

AU - Therkildsen, Jacob R.

AU - Christensen, Mette G.

AU - Tingskov, Stine J.

AU - Wehmöller, Julia

AU - Nørregaard, Rikke

AU - Praetorius, Helle A.

PY - 2019

Y1 - 2019

N2 - Severe urinary tract infections are commonly caused by sub-strains of Escherichia coli secreting the pore-forming virulence factor α-hemolysin (HlyA). Repeated or severe cases of pyelonephritis can cause renal scarring that subsequently can lead 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 signaling. Local ATP signaling and P2X 7 receptor activation play a key role in the development of tissue fibrosis. This study investigated the effect of P2X 7 receptors on infection-induced renal scarring in a murine model of pyelonephritis. Pyelonephritis was induced by injecting 100 million HlyA-producing, uropathogenic E. coli into the urinary bladder of BALB/cJ mice. A similar degree of pyelonephritis and mortality was confirmed at day 5 after infection in P2X 7 +/+ and P2X 7 −/− mice. Fibrosis was first observed 2 weeks after infection, and the data clearly demonstrated that P2X 7 −/− mice and mice exposed to the P2X 7 antagonist, brillian blue G, show markedly less renal fibrosis 14 days after infection compared with controls (P < 0.001). Immunohistochemistry revealed comparable early neutrophil infiltration in the renal cortex from P2X 7 +/+ and P2X 7 −/− mice. Interestingly, lack of P2X 7 receptors resulted in diminished macrophage infiltration and reduced neutrophil clearance in the cortex of P2X 7 −/− mice. Hence, this study suggests the P2X 7 receptor to be an appealing antifibrotic target after renal infections.

AB - Severe urinary tract infections are commonly caused by sub-strains of Escherichia coli secreting the pore-forming virulence factor α-hemolysin (HlyA). Repeated or severe cases of pyelonephritis can cause renal scarring that subsequently can lead 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 signaling. Local ATP signaling and P2X 7 receptor activation play a key role in the development of tissue fibrosis. This study investigated the effect of P2X 7 receptors on infection-induced renal scarring in a murine model of pyelonephritis. Pyelonephritis was induced by injecting 100 million HlyA-producing, uropathogenic E. coli into the urinary bladder of BALB/cJ mice. A similar degree of pyelonephritis and mortality was confirmed at day 5 after infection in P2X 7 +/+ and P2X 7 −/− mice. Fibrosis was first observed 2 weeks after infection, and the data clearly demonstrated that P2X 7 −/− mice and mice exposed to the P2X 7 antagonist, brillian blue G, show markedly less renal fibrosis 14 days after infection compared with controls (P < 0.001). Immunohistochemistry revealed comparable early neutrophil infiltration in the renal cortex from P2X 7 +/+ and P2X 7 −/− mice. Interestingly, lack of P2X 7 receptors resulted in diminished macrophage infiltration and reduced neutrophil clearance in the cortex of P2X 7 −/− mice. Hence, this study suggests the P2X 7 receptor to be an appealing antifibrotic target after renal infections.

UR - http://www.scopus.com/inward/record.url?scp=85065605871&partnerID=8YFLogxK

U2 - 10.1016/j.ajpath.2019.02.013

DO - 10.1016/j.ajpath.2019.02.013

M3 - Journal article

C2 - 30926332

AN - SCOPUS:85065605871

VL - 189

SP - 1201

EP - 1211

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 6

ER -