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Abstract
Objective We evaluated the influence of the renin–angiotensin system (RAS) on intestinal inflammation and fibrosis.
Design Cultured human colonic myofibroblast proliferation and collagen secretion were assessed following treatment with angiotensin (Ang) II and Ang (1–7), their receptor antagonists candesartan and A779, and the ACE inhibitor captopril. Circulating and intestinal RAS components were evaluated in patients with and without IBD. Disease outcomes in patients with IBD treated with ACE inhibitors and angiotensin receptor blockers (ARBs) were assessed in retrospective studies.
Results Human colonic myofibroblast proliferation was reduced by Ang (1–7) in a dose-dependent manner (p<0.05). Ang II marginally but not significantly increased proliferation, an effect reversed by candesartan (p<0.001). Colonic myofibroblast collagen secretion was reduced by Ang (1–7) (p<0.05) and captopril (p<0.001), and was increased by Ang II (p<0.001). Patients with IBD had higher circulating renin (mean 25.4 vs 18.6 mIU/L, p=0.026) and ACE2:ACE ratio (mean 0.92 vs 0.69, p=0.015) than controls without IBD. RAS gene transcripts and peptides were identified in healthy and diseased bowels. Colonic mucosal Masson’s trichrome staining correlated with Ang II (r=0.346, p=0.010) and inversely with ACE2 activity (r=−0.373, p=0.006). Patients with IBD who required surgery (1/37 vs 12/75, p=0.034) and hospitalisation (0/34 vs 8/68, p=0.049) over 2 years were less often treated with ACE inhibitors and ARBs than patients not requiring surgery or hospitalisation.
Conclusions The RAS mediates fibrosis in human cell cultures, is expressed in the intestine and perturbed in intestinal inflammation, and agents targeting this system are associated with improved disease outcomes.
- Renin-angiotensin system
- inflammatory bowel disease
- fibrosis
- myofibroblasts
- angiotensin (1-7)
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Footnotes
Correction notice This article has been corrected since it published Online First. The title has been amended.
Contributors All authors approved the final version. Each author’s contribution is as follows:
MG conceived and designed the studies; performed specimen and data collection and experiments including PCR, immunohistochemistry, serum ACE2 activity analyses; analysed and interpreted the data; and wrote the manuscript.
SGR designed and performed immunohistochemistry studies and cell culture studies, analysed and interpreted the data, critically appraised the manuscript and approved the final version.
CT designed and performed PCR and tissue ACE2 activity studies, analysed and interpreted the data, critically appraised the manuscript and approved the final version.
CS performed PCR studies, critically appraised the manuscript and approved the final version.
DB performed tissue ACE2 activity assays, critically appraised the manuscript and approved the final version.
EV performed plasma ACE2 activity assays, critically appraised the manuscript and approved the final version.
LMB designed and supervised plasma ACE2 activity assays, critically appraised the manuscript and approved the final version.
LB collected patient data for retrospective cohort and case–control studies and approved the final version.
AJ collected patient data for retrospective cohort and case–control studies and approved the final version.
KB collected patient data for retrospective cohort and case–control studies, and approved the final version.
ML collected patient data for retrospective cohort and case–control studies and approved the final version.
PS performed and assisted with the PCR studies, critically appraised the manuscript and approved the final version.
HW performed and assisted with the PCR studies, critically appraised the manuscript and approved the final version.
YH isolated colonic tissue for cell culture studies, critically appraised the manuscript and approved the final version.
CWT isolated colonic tissue for cell culture studies, critically appraised the manuscript and approved the final version.
MF isolated colonic tissue for cell culture studies, critically appraised the manuscript and approved the final version.
AWB designed and supervised colonic tissue isolation for cell culture studies, critically appraised the manuscript and approved the final version.
PH analysed the histological activity of colonic biopsies, critically appraised the manuscript and approved the final version.
SM analysed the histological activity of colonic biopsies, critically appraised the manuscript and approved the final version.
MT supervised PCR and tissue ACE2 activity studies, critically appraised the manuscript and approved the final version.
PRG conceived, designed and supervised the studies, critically appraised the manuscript and approved the final version.
JL conceived, designed and supervised the studies, analysed and interpreted the data, critically appraised the manuscript and approved the final version.
Funding statement This work was supported by the Gastroenterological Society of Australia Scholarship awarded to MG and a Broad Medical Research Program Grant awarded to JL.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval Written informed consent was obtained from all participants for the prospective studies where patient information and samples were collected. No informed consent was required from the patients who were part of retrospective cohort and case–control studies, in which anonymised patient data were collected. The protocols for these studies were approved by the Eastern Health Department of Research and Ethics (E03-1112 and LR93-1112).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement The authors declare that most of the data supporting the findings of this study are available within the paper and its supplementary information files. All other data are available from the corresponding author upon reasonable request.