The role of purinergic P2X7 receptors in the inflammation and fibrosis of unilateral ureteral obstruction in mice

Abstract

Receptors of the P2X7 type have been demonstrated in granulocytes, monocytes/macrophages, B and T lymphocytes, and have been involved in several cellular mechanisms including those related to inflammation and immunological response. This study attempted to investigate the role of these receptors on the inflammatory and fibrogenic response in the kidneys of unilateral ureteral obstruction (UUO), by using P2X7 knockout mice (-/-). C57Bl6 mice were submitted to left UUO and killed after 7 and 14 days. Histopathology using hematoxylin-eosin, periodic-acid Schiff and Sirius-red staining, immunohistochemistry for macrophages, myofibroblasts, transforming growth factor-beta (TGF-beta)1 and P2X7, and immunofluorescence for apoptotic cells (terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick-end labeling) were performed. Protocols were as follows: (1) control; (2) sham; (3) control P2X7 (-/-); (4) sham P2X7 (-/-); (5) UUO wild type (WT); (6) UUO P2X7 (-/-). Myofibroblasts and Sirius-red staining were significantly lower in UUO P2X7 (-/-) mice at days 7 and 14, compared to UUO WT. Kidneys from UUO P2X7 (-/-) mice showed reduced number of inflammatory cells at day 14 but not at day 7, compared to UUO WT. TGF-beta1 was less in UUO P2X7 (-/-) mice at days 7 and 14 when compared to UUO WT. Macrophage infiltration and tubular apoptosis were lower in UUO P2X7 (-/-) at day 14 but not at day 7, compared to UUO WT. P2X7 was expressed only in tubular epithelial cells at day 7 of UUO WT mice. These findings constitute the first evidence that P2X7 receptors are implicated in macrophage infiltration, collagen deposition and apoptosis in response to ureteral obstruction in mice.

The role of P2X7 receptors in tissue fibrosis: a brief review

“…P2X 7 R-deficient mice exhibited markedly reduced lung inflammation with reduced fibrosis [54,55]. P2X 7 R promotes macrophage infiltration and collagen deposition contributing to the inflammation and fibrosis of unilateral ureteral obstruction in mice [62]. In accordance, results suggested that P2X 7 R activity was present in animal models of liver injury and fibrosis, and contributed to fibrogenesis [71,72].…”

“…Moreover, Solini and colleagues [61] demonstrated the importance of P2X 7 R activation in TGF-β1 secretion and ECM production from mesangial cells. In addition, tubulo-interstitial damage and fibrosis induced after unilateral ureteral obstruction (UUO) are attenuated in the absence of P2X 7 R. Indeed, P2X 7 R (-/-) knockout UUO mice have a lower population of myofibroblasts, diminished collagen deposition, and decreased TGF-β1 expression in the renal interstitium compared to wildtype UUO mice [62]. These data indicate that myofibroblasts may be stimulated by P2X 7 R activation either directly, or indirectly in response to cell injury via IL-1β activation which promotes fibroblast proliferation and collagen production.…”

CD39 overexpression does not attenuate renal fibrosis in the unilateral ureteric obstructive model of chronic kidney disease

“…ATP is the ligand for both the P2X7 and P2X4 receptors and in the UUO model, these interactions have opposing effects: P2X7KO mice develop less fibrosis whereas P2X4KO mice have an exaggerated fibrotic response compared to WT mice [7][8][9][10]. Similarly, there is also conflicting evidence for a role for adenosine receptors in the pathogenesis of the UUO model.…”

The Inflammasomes in Kidney Disease

“…25,63,74 Consistent with these data, P2X 7 Ϫ/Ϫ mice exhibit less tubular injury and reduced inflammation and fibrosis after UUO compared with wild-type mice. 78 In addition to ATP, other cellular factors also activate the NLRP3 inflammasome and play a role in chronic kidney disease, including the extracellular matrix components biglycan, hyaluronan. 75,76 In the case of biglycan, mice deficient in this extracellular matrix protein are resistant to injury after UUO.…”