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

Abstract

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. 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. 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 (> or =50%; P < 0.0001). Losartan also suppressed tumor necrosis factor alpha generation from inflamed human synovium in a dose-dependent manner (P < 0.05). 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.