Reduced Severity of a Mouse Colitis Model with Angiotensin Converting Enzyme Inhibition

Spencer, Ariel U.; Yang, Hua; Haxhija, Emir Q.; Wildhaber, Barbara E.; Greenson, Joel K.; Teitelbaum, Daniel H.

doi:10.1007/s10620-006-9124-2

Cited by 63 publications

(62 citation statements)

References 61 publications

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“…When wild-type mice were treated with losartan, which blocks AT1 receptor signaling, colonic inflammation was attenuated and colitis ameliorated. This is consistent with a few early studies that reported that an ACE inhibitor ameliorated colonic damage in experimental colitis models2829. Therefore, the endogenous RAS does play a key role in the development of colitis.…”

Section: Discussionsupporting

confidence: 92%

“…Inconsistently, another study showed that serum ACE concentration was reduced in CD and UC patient population27. There are a few reports that show blockade of the RAS with an ACE inhibitor ameliorates colonic damage or colonic fibrosis in experimental colitis models2829, and genetic deletion of AT1 receptor or angiotensinogen gene reduces the severity of colitis in mice212223. Although these studies suggest a role for the RAS in colitogenesis, the underlying mechanism is unclear.…”

Section: Discussionmentioning

confidence: 99%

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Activation of the Renin-Angiotensin System Promotes Colitis Development

Shi

Liu

et al. 2016

Sci Rep

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Activation of the Renin-Angiotensin System Promotes Colitis Development

Shi

Liu

et al. 2016

Sci Rep

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“…Although angiotensin converting enzymes (ACE) are commonly thought to control blood pressure, the expression of ACE and its associated receptors have been identified within the gastrointestinal mucosa [3], and their abundance has been shown to increase in states of intestinal injury and colitis in both animal models and humans [4–6]. Thus, ACE may be associated with the pathogenesis of IBD.…”

Section: Introductionmentioning

confidence: 99%

Angiotensin Converting Enzyme-Inhibitor Reduces Colitis Severity in an IL-10 Knockout Model

et al. 2013

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Background We previously demonstrated angiotensin converting enzymes (ACE) over-expression in a dextransodium sulfate colitis model; ACE inhibitor (ACE-I) treatment reduced colitis severity in this model. However, ACE-I has not been tested in more immunologically relevant colitis models. Aim We hypothesized that ACE-I would decrease disease severity in an IL-10 knockout (−/−) colitis model. Methods Colitis was induced by giving 10-week old IL-10−/− mice piroxicam (P.O.) for 14 days. The ACE-I enalaprilat was given transanally at a dose of 6.25 mg/kg for 21 days. Prednisolone (PSL) with or without enalaprilat were used as therapeutic, comparative groups. All groups were compared to a placebo treated group. Outcome measures were clinical course, histology, abundance of pro-inflammatory cytokines/chemokines, and epithelial barrier function. Results Enalaprilat exhibited better survival (91 %) versus other treatment groups (PSL: 85.7 %, PSL + ACE-I: 71.4 %, placebo: 66.6 %). The ACE-I and PSL + ACE-I groups showed significantly better histological scores versus placebo mice. ACE-I and the PSL groups significantly reduced several pro-inflammatory cytokines versus placebo mice. FITC-dextran permeability was reduced in the ACE-I and PSL + ACE-I groups. Blood pressure was not affected in ACE-I treated mice compared to placebo mice. Conclusions ACE-I was effective in reducing severity of colitis in an IL-10−/− model. The addition of prednisolone minimally augmented this effect. The findings suggest that appropriately dosed ACE-I with or without steroids may be a new therapeutic agent for colitis.

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“…OCT preserved sections were snap-frozen in liquid nitrogen and later used for immunofluorescence staining (see PCNA below). The remaining segment was immediately processed for mucosal cell isolation, and RT-PCR as described previously (26). Whole isolated segments were also used for vascularity evaluation.…”

Section: Collection Of Tissuementioning

confidence: 99%

“…cDNA was purified and processed as previously described (26). All primers for selected gene sequences were selected by Primer-BLAST software http://blast.ncbi.nlm.nih.gov/Blast.cgi.…”

Section: Realtime Pcr (Rt-pcr)mentioning

confidence: 99%