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We previously demonstrated mild antifibrotic effects of targeting the P2X<jats:sub>7<\/jats:sub> receptor in a pyelonephritis model. Reduced P2X<jats:sub>7<\/jats:sub>R\u2010activation elevated the neutrophil\u2010to\u2010macrophage ratio, resulting in less matrix accumulation without affecting the initial tissue healing. Here, we test if this P2X<jats:sub>7<\/jats:sub>R\u2010dependent modification of matrix accumulation also applies to a noninfectious fibrosis model of unilateral ureteral obstruction (7dUUO) and whether the response is gender\u2010dependent. We found that P2X<jats:sub>7<\/jats:sub><jats:sup>\u2212\/\u2212<\/jats:sup> 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 (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0068). P2X<jats:sub>7<\/jats:sub>R deficiency did not affect early fibrosis markers (TGF\u2010\u03b2, \u03b1\u2010SMA) or the renal infiltration of neutrophils. However, a UUO\u2010induced increase in macrophages was observed in wildtypes only (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), leaving the P2X<jats:sub>7<\/jats:sub><jats:sup>\u2212\/\u2212<\/jats:sup> mice with \u224850% fewer CD68<jats:sup>+<\/jats:sup> cells in the renal cortex (<jats:italic>p<\/jats:italic>\u2009=\u20090.018). In males, 7dUUO triggered an increase in diffusely interstitial scattering of the profibrotic, macrophage\u2010attracting metalloproteinase MMP8 and showed significantly lower MMP8 tissue expression in both male and female P2X<jats:sub>7<\/jats:sub><jats:sup>\u2212\/\u2212<\/jats:sup> mice (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0008). Thus, the P2X<jats:sub>7<\/jats:sub>R is advocated as a late\u2010stage fibrosis moderator by reducing neutrophil\u2010dependent interstitial MMP8 release, resulting in less macrophage infiltration and reduced matrix accumulation.<\/jats:p>","DOI":"10.14814\/phy2.15878","type":"journal-article","created":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T00:11:12Z","timestamp":1700871072000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>P2X<sub>7<\/sub><\/scp> accelerate tissue fibrosis via metalloproteinase 8\u2010dependent macrophage infiltration in a murine model of unilateral ureteral obstruction"],"prefix":"10.14814","volume":"11","author":[{"given":"Jacob Rudjord","family":"Therkildsen","sequence":"first","affiliation":[{"name":"Department of Biomedicine Aarhus University  Aarhus C Denmark"},{"name":"Department of Clinical Biochemistry Aarhus University Hospital  Aarhus N 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