The Non-Peptide MAS-R Agonist AVE0991 Alleviates Colitis Severity in Mice and Exhibits an Additive Effect with Azathioprine

A growing body of evidence suggests the potent anti-inflammatory properties of the newly discovered arm of the renin-angiotensin-aldosterone system, ACE2/Ang-(1-7)/MasR, in various disease conditions. Our group was the first to report the anti-inflammatory properties of the Ang-(1-7) polypeptide in the murine dextran sulfate sodium (DSS) colitis model. Both its short half-life and high degradation rate limit the clinical use of Ang-(1-7). One way to compensate for these limitations is through the use of the non-peptide MasR agonist AVE0991. Herein, we aimed to study the anti-inflammatory effects of AVE0991 using the DSS model and the possible synergistic effects with other clinically available medications. Colitis severity was determined using both prophylactic and treatment approaches by gross anatomical and histological assessments and daily weight changes. The colonic expression level/activity of various pro-inflammatory and adhesion molecules was determined by western blotting, immunofluorescence, and proteomic profiling. We showed that AVE0991 treatment significantly reduced colitis severity more effectively with the prophylactic than the treatment approach. An additive anti-inflammatory effect was observed in the combination regimen with AVE0991 plus azathioprine, which was mediated through an increased colonic expression level of mucins and focal adhesion kinase, decreased colonic activity of p38 MAPK and Akt, and decreased colonic expression level of various pro-inflammatory mediators. In conclusion, these data suggest a promising potential for the non-peptide MasR agonist AVE0991 in the treatment of inflammatory bowel disease.