Angiotensin II type 1 receptor as a novel therapeutic target in rheumatoid arthritis: In vivo analyses in rodent models of arthritis and ex vivo analyses in human inflammatory synovitis
✍ Scribed by A. Price; J. C. Lockhart; W. R. Ferrell; W. Gsell; S. McLean; R. D. Sturrock
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 170 KB
- Volume
- 56
- Category
- Article
- ISSN
- 0004-3591
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✦ Synopsis
Abstract
Objective
Angiotensin II (Ang II) is known to have proinflammatory actions, and Ang II type 1 (AT~1~) receptors are up‐regulated in the rheumatoid synovium, suggesting that this receptor could be a therapeutic target. The purpose of this study was to investigate the antiinflammatory potential of the selective AT~1~ receptor antagonist losartan, which is currently used for the treatment of cardiovascular disease.
Methods
Dose‐ranging studies of losartan (1–50 mg/kg) were initially conducted in a rat model of acute (carrageenan/kaolin) arthritis, with subsequent evaluation in a rat model of adjuvant‐induced arthritis (Freund's complete adjuvant). Losartan (10^–10^ to 10^–6^M) was further tested ex vivo in human inflammatory synovitis, using collagenase‐digested synovium.
Results
Western blot and immunohistochemical analyses both revealed a substantial increase in AT~1~ receptor protein content in synovium from acutely and chronically inflamed rat knee joints. Similarly, synovial Ang I/II protein content was elevated during inflammation. Losartan inhibited acute joint inflammation in a dose‐dependent manner, with 15 mg/kg being the optimal dose (and used in subsequent studies). Both prophylactic and therapeutic administration of 15 mg/kg of losartan substantially reduced knee joint swelling in rats with adjuvant monarthritis (≥50%; P < 0.0001). Losartan also suppressed tumor necrosis factor α generation from inflamed human synovium in a dose‐dependent manner (P < 0.05).
Conclusion
Targeting the angiotensin pathway, particularly AT~1~ receptors, could have significant therapeutic potential. Randomized placebo‐controlled trials are now warranted to establish the extent to which angiotensin receptor blockers may provide antiinflammatory benefits.