期刊
PHYSIOLOGICAL REPORTS
卷 11, 期 22, 页码 -出版社
WILEY
DOI: 10.14814/phy2.15878
关键词
antifibrotic; gender difference; macrophage; Metalloprotease 8; P2X(7); renal fibrosis
类别
P2X(7) receptor plays a regulatory role in late-stage fibrosis by reducing neutrophil-dependent interstitial MMP8 release, resulting in less macrophage infiltration and reduced matrix accumulation.
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-beta, alpha-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 approximate to 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.
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