Renin-angiotensin system in intestinal inflammation : experimental studies with therapeutic interventions

The intestine is a major site of immune activity, and disturbances in the balance of proinflammatory and anti-inflammatory signals can lead to difficult and chronic diseases, like inflammatory bowel diseases, manifesting in uncontrolled inflammation in intestine. Local intestinal renin-angiotensin system (RAS) and glucocorticoid synthesis are recently uncovered complex mechanisms participating in the pathophysiology of intestinal diseases. These systems can offer new therapy options, either by repurposing well-known drugs like angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers or by novel innovations like mesenchymal stromal cell therapy. The aim of this thesis was to investigate intestinal RAS and glucocorticoid production in intestinal inflammation and examine potential treatments with the focus on these two systems. RAS and glucocorticoid production and their possible interactions in intestine were characterized in a dextran sodium sulfate (DSS)-induced experimental colitis model using in vitro stimulations and inhibition of RAS in vivo. Glucocorticoid synthesis and ACE shedding were investigated as the release of corticosterone and ACE protein from live tissue to incubation media in vitro. The effects of ACE inhibitor, captopril, and ACE-inhibiting milk-derived bioactive tripeptide, Ile-Pro-Pro, were examined on intestinal RAS and glucocorticoid synthesis. ACE inhibitor, enalapril, and angiotensin II receptor blocker, losartan, were tested alone and in combination in alleviation of colitis. Finally, freshly cultivated and cryopreserved platelet-lysate expanded mesenchymal stromal cells were compared and their feasibility was examined in the treatment of colitis. Enalapril and losartan were effective at alleviating colitis and lessening inflammation on their own but were without synergistic effects, supporting their potential to be investigated in clinical trials. MSC treatments proved feasible and without adverse effects, and freshly cultivated MSC treatments had a modest anti-inflammatory effect reflected by reduction in proinflammatory cytokine levels. We found a specific induction of ACE ectodomain shedding in distal colon, the most affected region in DSS-induced colitis, and in proximal colon following a high DSS dose. ACE shedding could be downregulated by cryopreserved MSCs and an ACE-inhibiting tripeptide Ile-Pro-Pro treatment in vivo. These data imply that cell-surface ACE levels are actively regulated in intestinal inflammation, which could be a feedback mechanism to reduce the proinflammatory angiotensin II (Ang II) signaling. Ang II induced glucocorticoid production in small intestine incubations in vitro, thus implying of an anti-inflammatory property in Ang II signaling. We suggest that Ang II enhances the TNFα-mediated induction of glucocorticoid production during intestinal inflammation. In vitro or in vivo inhibition of Ang II production or signaling did not modulate intestinal glucocorticoid production, although captopril abolished the gene expression of the rate-limiting enzyme of glucocorticoid synthesis, Cyp11b1, in vivo.

Grantor dc:publisher

Helsingin yliopisto

Year dc:date.issued

2019

Author dc:creator

• Salmenkari, Hanne

• Biolääketiede
• farmakologia
• lääketieteellinen ravitsemusfysiologia

Statement dc:rights

• Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.
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Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/10138/306844

OAI record oai:identifier

https://helda.helsinki.fi/server/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Ahelda.helsinki.fi%3A10138%2F306844