Emerging Role of Angiotensin AT2 Receptor in Anti-Inflammation: An Update

Abstract

The hyperactive RAS and inflammation are closely associated. The angiotensin-II/AT1R axis of the RAS has been explored extensively for its role in inflammation and a plethora of pathological conditions. Understanding the role of AT2R in inflammation is an emerging area of research. The AT2R is expressed on a variety of immune and non-immune cells, which upon activation triggers the release of a host of cytokines and has multiple effects that coalesce to anti-inflammation and prevents maladaptive repair. The anti-inflammatory outcomes of AT2R activation are linked to its well-established signaling pathways involving formation of nitric oxide and activation of phosphatases. Collectively, these effects promote cell survival and tissue function. The consideration of AT2R as a therapeutic target requires further investigations.

Correcting the imbalanced protective RAS in COVID-19 with angiotensin AT2-receptor agonists

“…It is well-known that AT 2 R agonists exert powerful anti-inflammatory actions [72][73][74][75]; thus, they may be prime candidates to compensate for the loss of ACE2/Ang-(1-7) protective mechanisms and help offset the large pro-inflammatory response in COVID-19 patients with severe disease (Figure 2). Based on the literature available, the anti-inflammatory effects associated with AT 2 R may result from direct effects on immune system cells, as well as effects on non-immune cells.…”

“…In general, initial COVID-19 infection will result in activation of the innate immune system, including monocytes, macrophages, dendritic cells and the complement system [50,51,53]. Human monocytes, macrophages and dendritic cells contain AT 2 R [75][76][77] and a number of studies indicate that activation of this angiotensin receptor subtype interferes with certain aspects of the innate immune system response. For example, in vitro studies have demonstrated that the AT 2 R agonist CGP42112 inhibits the IL-1β induced activation of monocytes [78].…”

“…There is a host of data indicating powerful anti-inflammatory actions of AT 2 R within the parenchymal tissues of multiple organ systems throughout the body [73,75]. This includes the lungs [26,82,83,97], heart [85,92,98,99], kidney [100][101][102][103], vasculature [72,73,102,[104][105][106][107][108] and the central nervous system (CNS) [109][110][111][112][113][114][115][116].…”

“…This includes the lungs [26,82,83,97], heart [85,92,98,99], kidney [100][101][102][103], vasculature [72,73,102,[104][105][106][107][108] and the central nervous system (CNS) [109][110][111][112][113][114][115][116]. These anti-inflammatory actions of AT 2 R activation at non-immune tissues and cells largely involve interruption of intracellular signalling pathways that lead to production of pro-inflammatory cytokines, and also through induction of pathways that elicit production of anti-inflammatory cytokines such as IL-10 [73,75,116]. The cellular and intracellular actions of AT 2 R have been recently reviewed in detail elsewhere [75,117], and the objective of the current article is not to re-review them here.…”

Novel anti-thrombotic mechanisms mediated by Mas receptor as result of balanced activities between the kallikrein/kinin and the renin-angiotensin systems

“…Ang II also binds to another receptor, angiotensin II receptor type 2 (AT2R) with equal affinity to AT1R. If the AT2R is expressed in larger amounts than the AT1R, signals from Ang II binding to the AT2R are amplified leading to NO and PGI 2 production [ 38 ] to reduce thrombosis risk. Additionally, the receptor for Ang-(1−7) is Mas, whose activation also stimulates NO and PGI 2 production to inhibit thrombus formation [ 39 ].…”