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

J Crohns Colitis. 2025 Jun 4;19(6):jjaf083. doi: 10.1093/ecco-jcc/jjaf083.

Abstract

Background and aims: The renin-angiotensin system (RAS) 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 preclinical models of Crohn's-like disease.

Methods: Effector molecules of the RAS were mined in a large publicly available RNA-Seq dataset of intestinal biopsies from Crohn's patients and healthy individuals, and the presence of associated proteins was confirmed by immunohistochemistry in full-thickness intestinal tissues. Losartan's efficacy in altering mediators of the RAS 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 (SAMP) 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 RAS, 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 the expression of molecules related to fibrosis, fibroblast-to-myofibroblast differentiation, collagen deposition, and cytoskeletal alterations. In vivo, losartan decreases both inflammation and fibrosis in SAMP mice with established disease, and prevents the reoccurrence of fibrosis following a novel relapse protocol.

Conclusions: Losartan, and other drugs targeting the RAS, 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.

Keywords: SAMP1/YitFc mouse model of Crohn’s disease-like ileitis; angiotensin receptor blockers; intestinal fibrosis.

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers* / pharmacology
  • Angiotensin II Type 1 Receptor Blockers* / therapeutic use
  • Angiotensin Receptor Antagonists* / pharmacology
  • Animals
  • Crohn Disease* / complications
  • Crohn Disease* / drug therapy
  • Crohn Disease* / pathology
  • Disease Models, Animal
  • Female
  • Fibrosis / prevention & control
  • Humans
  • Ileitis* / drug therapy
  • Ileitis* / pathology
  • Ileum / pathology
  • Inflammation / drug therapy
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / pathology
  • Losartan* / pharmacology
  • Losartan* / therapeutic use
  • Male
  • Mice
  • Remission Induction
  • Renin-Angiotensin System / drug effects

Substances

  • Losartan
  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensin Receptor Antagonists