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

Receptors of the P2X(7) 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 P2X(7) 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 P2X(7), 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 P2X(7) (-/-); (4) sham P2X(7) (-/-); (5) UUO wild type (WT); (6) UUO P2X(7) (-/-). Myofibroblasts and Sirius-red staining were significantly lower in UUO P2X(7) (-/-) mice at days 7 and 14, compared to UUO WT. Kidneys from UUO P2X(7) (-/-) mice showed reduced number of inflammatory cells at day 14 but not at day 7, compared to UUO WT. TGF-beta(1) was less in UUO P2X(7) (-/-) mice at days 7 and 14 when compared to UUO WT. Macrophage infiltration and tubular apoptosis were lower in UUO P2X(7) (-/-) at day 14 but not at day 7, compared to UUO WT. P2X(7) was expressed only in tubular epithelial cells at day 7 of UUO WT mice. These findings constitute the first evidence that P2X(7) receptors are implicated in macrophage infiltration, collagen deposition and apoptosis in response to ureteral obstruction in mice.