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The role of renin angiotensin system in the pathophysiology of rheumatoid arthritis

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Abstract

Background

In rheumatoid arthritis (RA) and osteoarthritis (OA), chronic inflammatory processes lead to progresive joint destruction. The renin-angiotensin system (RAS) is involved in the pathogenesis of RA and OA. The aim of this mini-review article is to summarize evidence on the role of RAS in RA and OA.

Methods

A non-systematic search in Pubmed included terms as “rheumatoid arthritis”, “renin angiotensin system”, “osteopenia”, “RANKL”, “DKK-1”, “MMP”, “inflammation”, “angiogenesis”, “local renin-angiotensin system”, “angiotensin converting enzyme”, “AT2 receptor”, “Ang-(1-7)”, “VEGF”, “angiotensine receptor blocker”, “angiotensin converting enzyme inhibitors”, “renin inhibitors”.

Results

Both RAS axes, the classical one, formed by angiotensin converting enzyme (ACE), angiotensin (Ang) II and AT1 receptor (AT1R) and the counter-regulatory one, composed by ACE2, Ang-(1-7) and the Mas receptor, modulate inflammation and tissue damage. Ang II activates pro-inflammatory mediators and oxidative stress. Conversely, Ang-(1-7) exerts anti-inflammatory actions, decreasing cytokine release, leukocyte attraction, density of vessels, tissue damage and fibrosis. Angiogenesis facilitates inflammatory cells invasion, while osteopenia causes joint dysfunction. Up-regulated osteoclastogenisis and down-regulated osteoblastogeneses were associaed with the activation of the classical RAS axis. Three different pathways, RANKL, DKK-1 and MMPs are enhanced by classical RAS activation. The treatment of RA included methotrexate and corticosteroids, which can cause side effects. Studies with angiotensin receptor blockers (ARBs), angiotensin converting enzyme inhibitors (ACEi) and renin inhibitors have been conducted in experimental and clinical RA with promising results.

Conclusion

The classical RAS activation is an important mechanism in RA pathogenesis and the benefit of ARB and ACEi administration should be further investigated.

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Funding

This work was partially supported by Brazilian National Council of Research Development (CNPq—Grant # 302153/2019-5), Coordination of High Education Level Personnel (CAPES) and Foundation of Research of Minas Gerais (FAPEMIG).

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FRCM, TAO, NER and MADA searched the literature, extracted data and wrote the first draft of the manuscript; MADA helped in data organization and revised the manuscript; ACSS conceived the study, made general supervision, revised and submitted the final version of the manuscript, which is approved by all authors.

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Correspondence to Ana Cristina Simões e Silva.

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Moreira, F.R.C., de Oliveira, T.A., Ramos, N.E. et al. The role of renin angiotensin system in the pathophysiology of rheumatoid arthritis. Mol Biol Rep 48, 6619–6629 (2021). https://doi.org/10.1007/s11033-021-06672-8

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