BACKGROUND: Emerging evidence suggests that the renin-angiotensin system plays an important role in the pathogenesis of inflammatory bowel disease, but few studies have directly assessed the therapeutic effect of renin inhibitors on colitis development. METHOD: Experimental colitis was induced in wild-type C57BL/6 mice and renin transgenic (RenTg) mice by 2,4,6-trinitrobenzene sulfonic acid (TNBS). Following intrarectal TNBS instillation, the mice were treated with SPH3127 (sitokiren), a small-molecule renin inhibitor, twice a day by intraperitoneal injection or oral gavage. The therapeutic effect of SPH3127 was evaluated by assessing clinical symptoms, histological injuries, and colonic mucosal inflammatory parameters in these mice. RESULTS: SPH3127 treatment by either delivery route markedly attenuated body weight loss, reduced clinical severity, alleviated colon mucosal ulceration in both C57BL/6 and RenTg mice, and prevented animal death in the case of RenTg mice. SPH3127 treatment blocked the local induction of pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6, IFN-gamma, IL-17) and promoted the production of anti-inflammatory cytokine IL-10 in the colon. Fluorescence-activated cell sorting analysis revealed that SPH3127 substantially diminished the accumulation of TH1 and TH17 cells in the colonic mucosa and confirmed that SPH3127-induced IL-10 production from mucosal CD25+ T cells in the mice. CONCLUSIONS: These results demonstrate that SPH3127 is able to effectively block colitis development in mouse experimental colitis models. Its anti-colitogenic activity is achieved at least in part by suppressing mucosal TH1 and TH17 activation while promoting IL-10 production from mucosal CD25+ T cells, thus forming an anti-inflammatory environment in the colonic mucosa.