Activation of the Renin-Angiotensin System Promotes Colitis Development.

Area of Science:

• Gastroenterology
• Cardiovascular Biology
• Immunology

Background:

• The renin-angiotensin system (RAS) is implicated in renal and cardiovascular diseases.
• Its role in colitis, a form of inflammatory bowel disease, remains largely uncharacterized.

Purpose of the Study:

• To investigate the involvement of the RAS in the pathogenesis of colitis.
• To determine if RAS activation exacerbates colitis independently of blood pressure changes.

Main Methods:

• Utilized transgenic mice overexpressing active renin (RenTgMK) to model RAS activation.
• Administered renin inhibitor (aliskiren), smooth muscle relaxant (hydralazine), angiotensin II, and angiotensin type 1 receptor blocker (ARB, losartan).
• Assessed colitis severity, immune responses (TH17, TH1/TH17), epithelial cell apoptosis, and inflammatory cytokine levels in mouse models and human biopsies.

Main Results:

• RenTgMK mice exhibited more severe colitis, higher mortality, increased mucosal TH17 responses, and greater epithelial cell apoptosis than wild-type controls.
• Aliskiren ameliorated colitis in RenTgMK mice, while hydralazine did not, despite both normalizing blood pressure.
• Angiotensin II infusion mimicked severe colitis in wild-type mice, and losartan treatment improved colitis, confirming a colitogenic role for RAS.
• Human inflammatory bowel disease patients on ARB therapy showed suppressed pro-inflammatory cytokines.

Conclusions:

• RAS activation promotes colitis in a blood pressure-independent manner.
• Angiotensin II drives colonic inflammation by increasing epithelial cell apoptosis and TH17 responses.
• Targeting the RAS may offer a therapeutic strategy for colitis.