Activation of the
renin-
angiotensin (Ang) system induces
inflammation via interaction between Ang II and type 1 receptor on leukocytes. The relevance of the new arm of the
renin-Ang system, namely Ang-converting
enzyme-2/Ang-(1-7)/Mas receptor, for inflammatory responses is not known and was investigated in this study. For this purpose, two experimental models were used: Ag-induced
arthritis (AIA) in mice and adjuvant-induced
arthritis (AdIA) in rats. Male C57BL/6 wild-type or Mas(-/-) mice were subjected to AIA and treated with Ang-(1-7), the Mas agonist
AVE 0991, or vehicle. AdIA was performed in female rats that were given
AVE 0991 or vehicle. In wild-type mice,
Mas protein is expressed in arthritic joints. Administration of
AVE 0991 or Ang-(1-7) decreased AIA-induced neutrophil accumulation, hypernociception, and production of TNF-α, IL-1β, and CXCL1. Histopathological analysis showed significant reduction of
inflammation. Mechanistically,
AVE 0991 reduced leukocyte rolling and adhesion, even when given after Ag challenge. Mas(-/-) mice subjected to AIA developed slightly more pronounced
inflammation, as observed by greater neutrophil accumulation and
cytokine release. Administration of
AVE 0991 was without effect in Mas(-/-) mice subjected to AIA. In rats, administration of
AVE 0991 decreased
edema, neutrophil accumulation, histopathological score, and production of IL-1β and CXCL1 induced by AdIA. Therefore, activation of Mas receptors decreases neutrophil influx and
cytokine production and causes significant amelioration of
arthritis in experimental models of
arthritis in rats and mice. This approach might represent a novel therapeutic opportunity for
arthritis.