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

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 ␣ generation from inflamed human synovium in a dosedependent 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.

Anti-Inflammatory Effects of the Activation of the Angiotensin-(1–7) Receptor, Mas, in Experimental Models of Arthritis

“…2 for review). Consistent with the latter finding, blockade of AT 1 , the major receptor mediating the inflammatory actions of Ang II, reduces neutrophil recruitment and cytokine release in models of inflammation (12,37,38). However, to our knowledge, the expression of Mas receptor in periarticular tissues was demonstrated for the first time in the present study.…”

“…Hence, blockade of Ang II may be useful in the context of inflammatory diseases, such as RA, in which a complex array of cytokines and leukocytes are involved (9). In this regard, few clinical studies have shown that Ang-converting enzyme (ACE) inhibitor (captopril) or AT 1 receptor antagonist (losartan) may be useful in the treatment of RA (10)(11)(12).…”

Anti-inflammatory effect of angiotensin type 1 receptor antagonist on endotoxin-induced uveitis in rats

“…AT1 receptor antagonists have been developed as drugs that selectively and markedly blocked the RAS at the receptor level, differently from ACE inhibitors [46]. Indeed, it has been reported that the AT1 receptor antagonist effectively attenuates various inflammatory processes [11,16,33,35]. One of the AT1 receptor blockers, telmisartan, showed a neuroprotective effect via modulating AT1 receptor and AT2 receptor signaling in retinal inflammation in a mouse EIU model [26].…”

“…Recent studies have collectively demonstrated the protective effect of RAS antagonism against immunemediated inflammatory diseases such as myocarditis, chronic allograft rejection, antiglomerular basement membrane nephritis, colitis, and arthritis [1,2,6,14,15,20,22,35,38,43]. However, no report has clearly demonstrated beneficial contribution of the RAS antagonism in ocular inflammatory conditions.…”

Studies of the T-Cell Angiotensin Receptor Using Cre-Lox Technology

“…6 Similarly, the AT 1 R is upregulated in the synovium of humans with rheumatoid arthritis, another T-cell-mediated disease, and angiotensin II receptor blockade improves parameters of collagen-induced arthritis in rats and mice. 7,8 In mice with collagen-induced arthritis, angiotensin receptor blocker administration also reduces T-cell proliferation and T H 1 cytokine production. 8 An obvious question is, what does the T-cell angiotensin II receptor have to do with the disease most commonly implicated as a target of the renin angiotensin aldosterone system, ie, hypertension?…”