P2Xaccelerate tissue fibrosis via metalloproteinase 8-dependent macrophage infiltration in a murine model of unilateral ureteral obstruction.

Abstract

Renal fibrosis is tightly associated with chronic kidney disease, irrespective of the underlying pathogenesis. We previously demonstrated mild antifibrotic effects of targeting the P2Xreceptor in a pyelonephritis model. Reduced P2XR-activation elevated the neutrophil-to-macrophage ratio, resulting in less matrix accumulation without affecting the initial tissue healing. Here, we test if this P2XR-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 P2Xmice 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&#x2009;<&#x2009;0.0068). P2XR deficiency did not affect early fibrosis markers (TGF-&#x3b2;, &#x3b1;-SMA) or the renal infiltration of neutrophils. However, a UUO-induced increase in macrophages was observed in wildtypes only (p&#x2009;<&#x2009;0.001), leaving the P2Xmice with &#x2248;50% fewer CD68cells in the renal cortex (p&#x2009;=&#x2009;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 P2Xmice (p&#x2009;<&#x2009;0.0008). Thus, the P2XR is advocated as a late-stage fibrosis moderator by reducing neutrophil-dependent interstitial MMP8 release, resulting in less macrophage infiltration and reduced matrix accumulation.