Activation of the Renin-Angiotensin System Promotes Colitis Development.

Yongyan Shi,David T Rubin,Sarbani Adhikari,Urszula Dougherty,Joel Pekow,Marc Bissonnette,Yan Chun Li,Jiaolong Wang,Qun Zhao,Weicheng Liu,Shu Q Liu,Li Chen,Lindsay Alpert,Dilip K Deb,John Kwon,John Hart,Tianjing Liu,Lei He,Guolin Zhou

doi:10.1038/srep27552

Abstract

The renin-angiotensin system (RAS) plays pathogenic roles in renal and cardiovascular disorders, but whether it is involved in colitis is unclear. Here we show that RenTgMK mice that overexpress active renin from the liver developed more severe colitis than wild-type controls. More than 50% RenTgMK mice died whereas all wild-type mice recovered. RenTgMK mice exhibited more robust mucosal TH17 and TH1/TH17 responses and more profound colonic epithelial cell apoptosis compared to wild-type controls. Treatment with aliskiren (a renin inhibitor), but not hydralazine (a smooth muscle relaxant), ameliorated colitis in RenTgMK mice, although both drugs normalized blood pressure. Chronic infusion of angiotensin II into wild-type mice mimicked the severe colitic phenotype of RenTgMK mice, and treatment with losartan [an angiotensin type 1 receptor blocker (ARB)] ameliorated colitis in wild-type mice, confirming a colitogenic role for the endogenous RAS. In human biopsies, pro-inflammatory cytokines were suppressed in patients with inflammatory bowel disease who were on ARB therapy compared to patients not receiving ARB therapy. These observations demonstrate that activation of the RAS promotes colitis in a blood pressure independent manner. Angiotensin II appears to drive colonic mucosal inflammation by promoting intestinal epithelial cell apoptosis and mucosal TH17 responses in colitis development.

Highlights

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are complex disorders
Our study demonstrates that the renin-Ang II cascade promotes colitis by stimulating apoptosis of intestinal epithelial cells (IEC) and mucosal TH17 responses, and this effect is independent of blood pressure changes
Much higher levels of mucosal pro-inflammatory cytokines and chemokines (TNF-α, IL-1β, IL-6, INF-γ, MCP-1, IL-23p19 and IL-17) were produced in the RenTg colons compared to WT controls (Fig. 1E), consistent with the higher histological and clinical inflammation scores seen in the RenTg colons

Summary

Introduction

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are complex disorders Their exact etiologies remain incompletely understood, it is believed that these disorders are caused and/or perpetuated by inappropriate and ongoing activation of the mucosal immune system driven by the presence of commensal bacteria. This aberrant response is facilitated by defects in mucosal barrier functions of the intestine and/or derangements in the mucosal immune system[1]. Our study demonstrates that the renin-Ang II cascade promotes colitis by stimulating apoptosis of IECs and mucosal TH17 responses, and this effect is independent of blood pressure changes

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Results

Conclusion