Activation of the Renin-Angiotensin System Promotes Colitis Development

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

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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 TH 17 and TH 1/TH 17 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 TH 17 responses in colitis development.

Original languageEnglish (US)
Article number27552
JournalScientific Reports
Volume6
DOIs
StatePublished - Jun 8 2016

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    Shi, Y., Liu, T., He, L., Dougherty, U., Chen, L., Adhikari, S., Alpert, L., Zhou, G., Liu, W., Wang, J., Deb, D. K., Hart, J., Liu, S. Q., Kwon, J., Pekow, J., Rubin, D. T., Zhao, Q., Bissonnette, M., & Li, Y. C. (2016). Activation of the Renin-Angiotensin System Promotes Colitis Development. Scientific Reports, 6, [27552]. https://doi.org/10.1038/srep27552