P2X7 accelerate tissue fibrosis via metalloproteinase 8-dependent macrophage infiltration in a murine model of unilateral ureteral obstruction

Jacob Rudjord Therkildsen, Stine Julie Tingskov, Michael Schou Jensen, Helle Praetorius*, Rikke Nørregaard

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Abstract

Renal fibrosis is tightly associated with chronic kidney disease, irrespective of the underlying pathogenesis. We previously demonstrated mild antifibrotic effects of targeting the P2X7 receptor in a pyelonephritis model. Reduced P2X7R-activation elevated the neutrophil-to-macrophage ratio, resulting in less matrix accumulation without affecting the initial tissue healing. Here, we test if this P2X7R-dependent modification of matrix accumulation also applies to a noninfectious fibrosis model of unilateral ureteral obstruction (7dUUO) and whether the response is gender-dependent. We found that P2X7−/− mice show reduced fibrosis compared to wild type after 7dUUO: the effect was most pronounced in females, with a 55% decrease in collagen deposition after 7dUUO (p < 0.0068). P2X7R deficiency did not affect early fibrosis markers (TGF-β, α-SMA) or the renal infiltration of neutrophils. However, a UUO-induced increase in macrophages was observed in wildtypes only (p < 0.001), leaving the P2X7−/− mice with ≈50% fewer CD68+ cells in the renal cortex (p = 0.018). In males, 7dUUO triggered an increase in diffusely interstitial scattering of the profibrotic, macrophage-attracting metalloproteinase MMP8 and showed significantly lower MMP8 tissue expression in both male and female P2X7−/− mice (p < 0.0008). Thus, the P2X7R is advocated as a late-stage fibrosis moderator by reducing neutrophil-dependent interstitial MMP8 release, resulting in less macrophage infiltration and reduced matrix accumulation.

OriginalsprogEngelsk
Artikelnummere15878
TidsskriftPhysiological Reports
Vol/bind11
Nummer22
ISSN2051-817X
DOI
StatusUdgivet - nov. 2023

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