Renin–angiotensin system in intestinal inflammation—Angiotensin inhibitors to treat inflammatory bowel diseases?

Salmenkari, Hanne; Korpela, Riitta; Vapaatalo, Heikki

doi:10.1111/bcpt.13624

Cited by 12 publications

(12 citation statements)

References 63 publications

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“…11 The large intestine is able to locally synthetize corticosterone, a precursor of aldosterone, especially in an experimental model of colitis. 12–14 Thus, there are several lines of evidence to support our previous finding that the intestine is able to produce aldosterone in a parallel way as occurs for corticosterone.…”

Section: Introductionsupporting

confidence: 72%

Local aldosterone synthesis in the large intestine of mouse: An ex vivo incubation study

et al. 2022

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Objective To investigate the regulation of local aldosterone synthesis by physiological stimulants in the murine gut. Methods Male mice were fed for 14 days with normal, high (1.6%) or low (0.01%) sodium diets. Tissue liver receptor homolog-1 and aldosterone in the colon and caecum were detected using an enzyme-linked immunosorbent assay (ELISA). Released corticosterone and aldosterone in tissue incubation experiments after stimulation with angiotensin II (Ang II) and dibutyryl-cAMP (DBA; the second messenger of adrenocorticotropic hormone) were assayed using an ELISA. Tissue aldosterone synthase (CYP11B2) protein levels were measured using an ELISA and Western blots. Results In incubated colon tissues, aldosterone synthase levels were increased by a low-sodium diet; and by Ang II and DBA in the normal diet group. Release of aldosterone into the incubation buffer was increased from the colon by a low-sodium diet and decreased by a high-sodium diet in parallel with changes in aldosterone synthase levels. In mice fed a normal diet, colon incubation with both Ang II and DBA increased the release of aldosterone as well as its precursor corticosterone. Conclusion Local aldosterone synthesis in the large intestine is stimulated by a low-sodium diet, dibutyryl-cAMP and Ang II similar to the adrenal glands.

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Section: Introductionsupporting

confidence: 72%

Local aldosterone synthesis in the large intestine of mouse: An ex vivo incubation study

et al. 2022

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“…This observation indicates that the RAS, with its various components, could be involved in the pathogenesis of inflammation and fibrosis within the intestinal tissue of individuals with IBD. 36 Nevertheless, the role of specific medications like ACE inhibitors (such as enalapril) in this context is not fully understood. In several studies the likelihood of intestinal resection was significantly lower with the use of ACE inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Drug Repurposing in Crohn’s Disease Using Danish Real-World Data

Shakibfar,

Allin,

Jess

et al. 2024

POR

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Aim Drug repurposing, utilizing electronic healthcare records (EHRs), offers a promising alternative by repurposing existing drugs for new therapeutic indications, especially for patients lacking effective therapies. Intestinal fibrosis, a severe complication of Crohn’s disease (CD), poses significant challenges, increasing morbidity and mortality without available pharmacological treatments. This article focuses on identifying medications associated with an elevated or reduced risk of fibrosis in CD patients through a population-wide real-world data and artificial intelligence (AI) approach. Methods Patients aged 65 or older with a diagnosis of CD from 1996 to 2019 in the Danish EHRs were followed for up to 24 years. The primary outcome was the need of specific surgical procedures, namely proctocolectomy with ileostomy and ileocecal resection as proxies of intestinal fibrosis. The study explored drugs linked to an increased or reduced risk of the study outcome through machine-learning driven survival analysis. Results Among the 9179 CD patients, 1029 (11.2%) underwent surgery, primarily men (58.5%), with a mean age of 76 years, 10 drugs were linked to an elevated risk of surgery for proctocolectomy with ileostomy and ileocecal resection. In contrast, 10 drugs were associated with a reduced risk of undergoing surgery for these conditions. Conclusion This study focuses on repurposing existing drugs to prevent surgery related to intestinal fibrosis in CD patients, using Danish EHRs and advanced statistical methods. The findings offer valuable insights into potential treatments for this condition, addressing a critical unmet medical need. Further research and clinical trials are warranted to validate the effectiveness of these repurposed drugs in preventing surgery related to intestinal fibrosis in CD patients.

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“…Retrospective studies showed that IBD patients using RAS inhibitors had milder disease courses, fewer hospitalizations, and a less corticosteroid use compared with IBD patients not using these medications. However, prospective studies are recommended to assess the effectiveness of these RAS inhibitors in treatment of IBD (Salmenkari et al., 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Olmesartan medoxomil self-microemulsifying drug delivery system reverses apoptosis and improves cell adhesion in trinitrobenzene sulfonic acid-induced colitis in rats

et al. 2022

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Olmesartan medoxomil (OM) is an angiotensin receptor blocker. This study aimed to investigate the effects of OM self-microemulsifying drug delivery system (OMS) in trinitrobenzene sulfonic acid (TNBS)-induced acute colitis in rats. Besides two control groups, five TNBS-colitic-treated groups ( n = 8) were given orally sulfasalazine (100 mg/kg/day), low and high doses of OM (3.0 and 10.0 mg/kg/day) (OML and OMH) and of OMS (OMSL and OMSH) for seven days. A colitis activity score was calculated. The colon was examined macroscopically. Colonic levels of myeloperoxidase, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde, and reduced glutathione were measured. Plasma and colonic olmesartan levels were measured. Colonic sections were subjected to hematoxylin and eosin staining and immunohistochemical staining for E-cadherin, caspase-3, and matrix metalloproteinase-9 (MMP-9). Protein expression of E-cadherin, Bcl-2 associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2), and cleaved caspase-3 by Western blot was done. TNBS-colitic rats showed increased colonic myeloperoxidase, TNF-α, IL-6, and malondialdehyde, decreased colonic glutathione, histopathological, immunohistochemical, and protein expression alterations. OMS, compared with OM, dose-dependently achieved higher colonic free olmesartan concentration, showed better anti-inflammatory, antioxidant, and anti-apoptotic effects, improved intestinal barrier, and decreased mucolytic activity. OMS more effectively up-regulated the reduced Bcl-2, Bcl-2/Bax ratio, and E-cadherin expression, and down-regulated the overexpressed Bax, cleaved caspase-3, and MMP-9. OMSL exerted effects comparable to OMH. Sulfasalazine exerted maximal colonic protective effects and almost completely reversed colonic damage, and OMSH showed nearly similar effects with non-significant differences in-between or compared with the normal control group. In conclusion, OMS could be a potential additive treatment for Crohn's disease colitis.

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Renin–angiotensin system in intestinal inflammation—Angiotensin inhibitors to treat inflammatory bowel diseases?

Cited by 12 publications

References 63 publications

Local aldosterone synthesis in the large intestine of mouse: An ex vivo incubation study

Local aldosterone synthesis in the large intestine of mouse: An ex vivo incubation study

Drug Repurposing in Crohn’s Disease Using Danish Real-World Data

Olmesartan medoxomil self-microemulsifying drug delivery system reverses apoptosis and improves cell adhesion in trinitrobenzene sulfonic acid-induced colitis in rats

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