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

ObjectiveAngiotensin II (Ang II) is known to have proinflammatory actions, and Ang II type 1 (AT1) 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 AT1 receptor antagonist losartan, which is currently used for the treatment of cardiovascular disease.MethodsDose-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 10–6M) was further tested ex vivo in human inflammatory synovitis, using collagenase-digested synovium.ResultsWestern blot and immunohistochemical analyses both revealed a substantial increase in AT1 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).ConclusionTargeting the angiotensin pathway, particularly AT1 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.