Activation of the Renin-Angiotensin System Promotes Colitis Development.
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.
Department of Pediatrics, Shengjing Hospital, China Medical University, Shenyang, Liaoning, 110004, China.|Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA.
Yongyan
Y
Shi
Department of Pediatrics, Shengjing Hospital, China Medical University, Shenyang, Liaoning, 110004, China.|Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA.
Tianjing
T
Liu
Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA.
Lei
L
He
Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA.
Urszula
U
Dougherty
Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA.|Department of Endocrinology, Shengjing Hospital, China Medical University, Shenyang, Liaoning, 110004, China.
Li
L
Chen
Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA.
Sarbani
S
Adhikari
Department of Pathology, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA.
Lindsay
L
Alpert
Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA.
Guolin
G
Zhou
Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA.
Weicheng
W
Liu
Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA.|Department of Cardiology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, 110001, China.
Jiaolong
J
Wang
Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA.
Dilip K
DK
Deb
Department of Pathology, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA.
John
J
Hart
Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA.
Shu Q
SQ
Liu
Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA.
John
J
Kwon
Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA.
Joel
J
Pekow
Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA.
David T
DT
Rubin
Department of Pediatrics, Shengjing Hospital, China Medical University, Shenyang, Liaoning, 110004, China.
Qun
Q
Zhao
Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA.
Marc
M
Bissonnette
Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA.
Yan Chun
YC
Li
D000577:Amides / Q000008:administration & dosage; D000804:Angiotensin II / Q000235:genetics; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D003092:Colitis / Q000235:genetics* / Q000503:physiopathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005650:Fumarates / Q000008:administration & dosage; D006801:Humans; D006830:Hydralazine / Q000008:administration & dosage; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019808:Losartan / Q000008:administration & dosage; D051379:Mice; D008822:Mice, Transgenic; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D012083:Renin / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000235:genetics*; D058504:Th17 Cells / Q000187:drug effects
D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers; D005650:Fumarates; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D006830:Hydralazine; C446481:aliskiren; D012083:Renin; D019808:Losartan