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 Qian Liu, John Kwon, Joel Pekow, David T. Rubin, Qun Zhao*, Marc Bissonnette, Yan Chun Li

*Corresponding author for this work

Research output: Contribution to journalArticle

14 Citations (Scopus)

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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Colitis
Renin-Angiotensin System
Angiotensin II Type 1 Receptor Blockers
Renin
Angiotensin II
Epithelial Cells
Apoptosis
Blood Pressure
Hydralazine
Losartan
Therapeutics
Inflammatory Bowel Diseases
Smooth Muscle
Cytokines
Inflammation
Phenotype
Kidney
Biopsy
Liver
Pharmaceutical Preparations

ASJC Scopus subject areas

  • General

Cite this

Shi, Y., Liu, T., He, L., Dougherty, U., Chen, L., Adhikari, S., ... Li, Y. C. (2016). Activation of the Renin-Angiotensin System Promotes Colitis Development. Scientific reports, 6, [27552]. https://doi.org/10.1038/srep27552
Shi, Yongyan ; Liu, Tianjing ; He, Lei ; Dougherty, Urszula ; Chen, Li ; Adhikari, Sarbani ; Alpert, Lindsay ; Zhou, Guolin ; Liu, Weicheng ; Wang, Jiaolong ; Deb, Dilip K. ; Hart, John ; Liu, Shu Qian ; Kwon, John ; Pekow, Joel ; Rubin, David T. ; Zhao, Qun ; Bissonnette, Marc ; Li, Yan Chun. / Activation of the Renin-Angiotensin System Promotes Colitis Development. In: Scientific reports. 2016 ; Vol. 6.
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title = "Activation of the Renin-Angiotensin System Promotes Colitis Development",
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.",
author = "Yongyan Shi and Tianjing Liu and Lei He and Urszula Dougherty and Li Chen and Sarbani Adhikari and Lindsay Alpert and Guolin Zhou and Weicheng Liu and Jiaolong Wang and Deb, {Dilip K.} and John Hart and Liu, {Shu Qian} and John Kwon and Joel Pekow and Rubin, {David T.} and Qun Zhao and Marc Bissonnette and Li, {Yan Chun}",
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language = "English (US)",
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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, DK, Hart, J, Liu, SQ, Kwon, J, Pekow, J, Rubin, DT, Zhao, Q, Bissonnette, M & Li, YC 2016, 'Activation of the Renin-Angiotensin System Promotes Colitis Development', Scientific reports, vol. 6, 27552. https://doi.org/10.1038/srep27552

Activation of the Renin-Angiotensin System Promotes Colitis Development. / Shi, Yongyan; Liu, Tianjing; He, Lei; Dougherty, Urszula; Chen, Li; Adhikari, Sarbani; Alpert, Lindsay; Zhou, Guolin; Liu, Weicheng; Wang, Jiaolong; Deb, Dilip K.; Hart, John; Liu, Shu Qian; Kwon, John; Pekow, Joel; Rubin, David T.; Zhao, Qun; Bissonnette, Marc; Li, Yan Chun.

In: Scientific reports, Vol. 6, 27552, 08.06.2016.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Activation of the Renin-Angiotensin System Promotes Colitis Development

AU - Shi, Yongyan

AU - Liu, Tianjing

AU - He, Lei

AU - Dougherty, Urszula

AU - Chen, Li

AU - Adhikari, Sarbani

AU - Alpert, Lindsay

AU - Zhou, Guolin

AU - Liu, Weicheng

AU - Wang, Jiaolong

AU - Deb, Dilip K.

AU - Hart, John

AU - Liu, Shu Qian

AU - Kwon, John

AU - Pekow, Joel

AU - Rubin, David T.

AU - Zhao, Qun

AU - Bissonnette, Marc

AU - Li, Yan Chun

PY - 2016/6/8

Y1 - 2016/6/8

N2 - 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.

AB - 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.

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Shi Y, Liu T, He L, Dougherty U, Chen L, Adhikari S et al. Activation of the Renin-Angiotensin System Promotes Colitis Development. Scientific reports. 2016 Jun 8;6. 27552. https://doi.org/10.1038/srep27552