Imbalance of the renin-angiotensin system may contribute to inflammation and fibrosis in IBD

Novel therapeutic target?

Mayur Garg, Simon G. Royce, Chris Tikellis, Claire Shallue, Duygu Batu, Elena Velkoska, Louise M. Burrell, Sheila K. Patel, Lauren Beswick, Anvesh Jackson, Kaushali Britto, Matthew Lukies, Pavel Sluka, Hady Wardan, Yumiko Hirokawa, Chin Wee Tan, Maree Faux, Antony W. Burgess, Patrick Hosking, Shaun Monagle & 3 others Merlin Thomas, Peter R. Gibson, John Lubel

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Number of pages11
JournalGut
DOIs
Publication statusAccepted/In press - 13 Aug 2019

Keywords

  • angiotensin (1-7)
  • fibrosis
  • inflammatory bowel disease
  • myofibroblasts
  • Renin-angiotensin system

Cite this

Garg, Mayur ; Royce, Simon G. ; Tikellis, Chris ; Shallue, Claire ; Batu, Duygu ; Velkoska, Elena ; Burrell, Louise M. ; Patel, Sheila K. ; Beswick, Lauren ; Jackson, Anvesh ; Britto, Kaushali ; Lukies, Matthew ; Sluka, Pavel ; Wardan, Hady ; Hirokawa, Yumiko ; Tan, Chin Wee ; Faux, Maree ; Burgess, Antony W. ; Hosking, Patrick ; Monagle, Shaun ; Thomas, Merlin ; Gibson, Peter R. ; Lubel, John. / Imbalance of the renin-angiotensin system may contribute to inflammation and fibrosis in IBD : Novel therapeutic target?. In: Gut. 2019.
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title = "Imbalance of the renin-angiotensin system may contribute to inflammation and fibrosis in IBD: Novel therapeutic target?",
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.",
keywords = "angiotensin (1-7), fibrosis, inflammatory bowel disease, myofibroblasts, Renin-angiotensin system",
author = "Mayur Garg and Royce, {Simon G.} and Chris Tikellis and Claire Shallue and Duygu Batu and Elena Velkoska and Burrell, {Louise M.} and Patel, {Sheila K.} and Lauren Beswick and Anvesh Jackson and Kaushali Britto and Matthew Lukies and Pavel Sluka and Hady Wardan and Yumiko Hirokawa and Tan, {Chin Wee} and Maree Faux and Burgess, {Antony W.} and Patrick Hosking and Shaun Monagle and Merlin Thomas and Gibson, {Peter R.} and John Lubel",
year = "2019",
month = "8",
day = "13",
doi = "10.1136/gutjnl-2019-318512",
language = "English",
journal = "Gut",
issn = "0017-5749",
publisher = "BMJ Publishing Group",

}

Garg, M, Royce, SG, Tikellis, C, Shallue, C, Batu, D, Velkoska, E, Burrell, LM, Patel, SK, Beswick, L, Jackson, A, Britto, K, Lukies, M, Sluka, P, Wardan, H, Hirokawa, Y, Tan, CW, Faux, M, Burgess, AW, Hosking, P, Monagle, S, Thomas, M, Gibson, PR & Lubel, J 2019, 'Imbalance of the renin-angiotensin system may contribute to inflammation and fibrosis in IBD: Novel therapeutic target?', Gut. https://doi.org/10.1136/gutjnl-2019-318512

Imbalance of the renin-angiotensin system may contribute to inflammation and fibrosis in IBD : Novel therapeutic target? / Garg, Mayur; Royce, Simon G.; Tikellis, Chris; Shallue, Claire; Batu, Duygu; Velkoska, Elena; Burrell, Louise M.; Patel, Sheila K.; Beswick, Lauren; Jackson, Anvesh; Britto, Kaushali; Lukies, Matthew; Sluka, Pavel; Wardan, Hady; Hirokawa, Yumiko; Tan, Chin Wee; Faux, Maree; Burgess, Antony W.; Hosking, Patrick; Monagle, Shaun; Thomas, Merlin; Gibson, Peter R.; Lubel, John.

In: Gut, 13.08.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Imbalance of the renin-angiotensin system may contribute to inflammation and fibrosis in IBD

T2 - Novel therapeutic target?

AU - Garg, Mayur

AU - Royce, Simon G.

AU - Tikellis, Chris

AU - Shallue, Claire

AU - Batu, Duygu

AU - Velkoska, Elena

AU - Burrell, Louise M.

AU - Patel, Sheila K.

AU - Beswick, Lauren

AU - Jackson, Anvesh

AU - Britto, Kaushali

AU - Lukies, Matthew

AU - Sluka, Pavel

AU - Wardan, Hady

AU - Hirokawa, Yumiko

AU - Tan, Chin Wee

AU - Faux, Maree

AU - Burgess, Antony W.

AU - Hosking, Patrick

AU - Monagle, Shaun

AU - Thomas, Merlin

AU - Gibson, Peter R.

AU - Lubel, John

PY - 2019/8/13

Y1 - 2019/8/13

N2 - 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.

AB - 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.

KW - angiotensin (1-7)

KW - fibrosis

KW - inflammatory bowel disease

KW - myofibroblasts

KW - Renin-angiotensin system

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U2 - 10.1136/gutjnl-2019-318512

DO - 10.1136/gutjnl-2019-318512

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JO - Gut

JF - Gut

SN - 0017-5749

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