The angiotensin receptor blocker, losartan, reduces inflammation and fibrosis, and prevents relapse of fibrosis after steroid-induced remission, in mice prone to Crohn’s disease-like ileitis

Abstract Background and Aims The renin-angiotensin system is known to modulate fibrosis, which is a common complication of ileal Crohn’s disease. We tested the efficacy of losartan, an angiotensin receptor blocker, to treat intestinal fibrosis in relevant pre-clinical models of Crohn’s-like disease. Methods Effector molecules of the renin-angiotensin system were mined in a large publicly-available RNA-Seq dataset of intestinal biopsies from Crohn’s patients and healthy individuals, and presence of associated proteins confirmed by immunohistochemistry in full-thickness intestinal tissues. Losartan’s efficacy in altering mediators of the renin-angiotensin system and of fibrosis was tested in vitro using activated CCD-18Co fibroblasts, while its in vivo effects were investigated by administering losartan to SAMP1/YitFc mice, a well-described model of Crohn’s-like disease that progressively develops both ileal-specific inflammation and fibrosis, using either therapeutic or maintenance of remission (treatment after dexamethasone) approaches. Results Angiotensinogen, an upstream regulator of the renin-angiotensin system, and the downstream effector, angiotensin II receptor type 1, expressed on target cells, are both increased in involved vs. non-involved gut mucosa from Crohn’s patients compared to healthy controls. In vitro, losartan suppresses expression of molecules related to fibrosis, fibroblast-to-myofibroblast differentiation, collagen deposition, and cytoskeletal alterations. In vivo, losartan decreases both inflammation and fibrosis in SAMP1/YitFc mice with established disease, and prevents reoccurrence of fibrosis following a novel relapse protocol. Conclusions Losartan, and other drugs targeting the renin-angiotensin system, may serve as an effective treatment to successfully dampen intestinal fibrosis during active inflammation, as well as prevent its progression after corticosteroid-induced remission in Crohn’s patients.