P2X 7 accelerate tissue fibrosis via metalloproteinase 8-dependent macrophage infiltration in a murine model of unilateral ureteral obstruction.

Autor: Therkildsen JR; Department of Biomedicine, Aarhus University, Aarhus C, Denmark.; Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus N, Denmark., Tingskov SJ; Department of Clinical Medicine, Aarhus University, Aarhus C, Denmark., Jensen MS; Department of Clinical Medicine, Aarhus University, Aarhus C, Denmark., Praetorius H; Department of Biomedicine, Aarhus University, Aarhus C, Denmark., Nørregaard R; Department of Clinical Medicine, Aarhus University, Aarhus C, Denmark.
Jazyk: angličtina
Zdroj: Physiological reports [Physiol Rep] 2023 Nov; Vol. 11 (22), pp. e15878.
DOI: 10.14814/phy2.15878
Abstrakt: Renal fibrosis is tightly associated with chronic kidney disease, irrespective of the underlying pathogenesis. We previously demonstrated mild antifibrotic effects of targeting the P2X 7 receptor in a pyelonephritis model. Reduced P2X 7 R-activation elevated the neutrophil-to-macrophage ratio, resulting in less matrix accumulation without affecting the initial tissue healing. Here, we test if this P2X 7 R-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 P2X 7 -/- 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). P2X 7 R 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 P2X 7 -/- 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 P2X 7 -/- mice (p < 0.0008). Thus, the P2X 7 R is advocated as a late-stage fibrosis moderator by reducing neutrophil-dependent interstitial MMP8 release, resulting in less macrophage infiltration and reduced matrix accumulation.
(© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)
Databáze: MEDLINE
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