Anti-Inflammatory Effects of the Activation of the Angiotensin-(1–7) Receptor, Mas, in Experimental Models of Arthritis

Abstract

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.

Telmisartan acts through the modulation of ACE-2/ANG 1–7/mas receptor in rats with dilated cardiomyopathy induced by experimental autoimmune myocarditis

“…Further, ANG 1-7 or captopril treatment reduced the expression of several inflammation genes involved in the NF-kB signaling pathway; as a result, it reduced cardiac ischemia-induced dysfunction in diabetic hypertensive rats (Al-Maghrebi et al, 2009). The protective effects of ANG 1-7 were further substantiated by decreased neutrophil accumulation and inflammatory cytokine release in experimental models of arthritis (da Silveira et al, 2010). Interestingly, we could observe increased protein levels of CD68, iNOS, NF-kB and mRNA expressions of IL-1β, IFN-γ and MCP-1 in rats with DCM, and these changes were significantly decreased by telmisartan treatment (Figs.…”

Effect of Angiotensin-(1-7) on Aortic Response, TNF-α, IL-1β and Receptor for Advanced Glycation Endproduct in Rat's Adjuvant-Induced Arthritis

“…However, the present results showed that although the effect of Ang-1-7 on blood pressure and paw edema appeared after administration, a greater effect was that exerted on blood pressure and reached a significant level after 10 days, whereas a significant effect on paw edema was obtained after 14 days. This result could be due to the more direct vascular effect of Ang-1-7 by direct inhibition of leukocyte-endothelial cell interaction [21] and downregulation of AT1 receptors on vascular cells [31] , whereas in case of paw edema, a time lag is necessary for downregulating the already upregulated RAS components in the inflammatory cells infiltrating synovium [32] . Moreover, inhibiting cytokines production is consequent to activation of MasR [21] , and since MasR are Gprotein coupled, it is plausible to suggest that the antiinflammatory (decreasing cellular infiltration and edema) effect of Ang-(1-7) is observed after an adequate latency.…”

“…The present results showed that Ang-(1-7) reduced TNF-α (but not IL-1β) and paw volume. Accordingly, it is plausible to suggest that the effect of Ang-(1-7) involves reduction of TNF-α displayed systemically, as in this study, and/or within the joint TNF-α [21] .…”

“…This result is in line with the key role played by TNF-α in the pathogenesis of RA [19] , especially in the local inflammatory reaction in the ipsilateral paw [20] . It has been reported that MasR agonists exert anti-inflammatory actions in animal models of arthritis [21] . Ang-(1-7) reduces inflammation induced by lipopolysaccharide [22] and atherosclerosis [23] .…”

Endotoxin-induced skeletal muscle wasting is prevented by angiotensin-(1–7) through a p38 MAPK-dependent mechanism

“…The main peptide of the classical RAS pathway is AngII (angiotensin II) which is associated with a deleterious effect in skeletal muscle [26][27][28][29][30]. The main peptide of the non-classical axis is Ang-(1-7) [angiotensin-(1-7)], which produces its cellular effects through the G-protein-coupled receptor Mas [31][32][33][34]. The Mas receptor is expressed in several tissues, including skeletal muscle [35,36].…”