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

Mol Biol Rep. 2021 Sep;48(9):6619-6629. doi: 10.1007/s11033-021-06672-8. Epub 2021 Aug 20.

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.

Keywords: Angiogenesis; Angiotensin receptor blockers; Osteoarticular disease; Osteopenia; Renin angiotensin system; Rheumatoid arthritis.

Publication types

  • Review

MeSH terms

  • Adrenal Cortex Hormones / therapeutic use
  • Angiotensin I / metabolism
  • Angiotensin II / metabolism
  • Angiotensin Receptor Antagonists / therapeutic use
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Animals
  • Antirheumatic Agents / therapeutic use
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / metabolism*
  • Arthritis, Rheumatoid / physiopathology*
  • Humans
  • Osteoarthritis / drug therapy
  • Osteoarthritis / metabolism*
  • Osteoarthritis / physiopathology*
  • Peptide Fragments / metabolism
  • Peptidyl-Dipeptidase A / metabolism
  • Proto-Oncogene Mas / metabolism
  • Receptor, Angiotensin, Type 1 / metabolism
  • Renin-Angiotensin System* / drug effects
  • Signal Transduction / drug effects
  • Treatment Outcome

Substances

  • AGTR1 protein, human
  • Adrenal Cortex Hormones
  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors
  • Antirheumatic Agents
  • MAS1 protein, human
  • Peptide Fragments
  • Proto-Oncogene Mas
  • Receptor, Angiotensin, Type 1
  • Angiotensin II
  • Angiotensin I
  • ACE protein, human
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • angiotensin I (1-7)