Angiotensin II (Ang II) is well-considered to be the principal effector of the renin–angiotensin system (RAS), which binds with strong affinity to the angiotensin II type 1 (AT1R) and type 2 (AT2R) receptor subtype. However, activation of both receptors is likely to stimulate different signalling mechanisms/pathways and produce distinct biological responses. The haemodynamic and non-haemodynamic effects of Ang II, including its ability to regulate blood pressure, maintain water–electrolyte balance and promote vasoconstriction and cellular growth are well-documented to be mediated primarily by the AT1R. However, its biological and functional effects mediated through the AT2R subtype are still poorly understood. Recent studies have emphasized that activation of the AT2R regulates tissue and organ development and provides in certain context a potential counter-regulatory mechanism against AT1R-mediated actions. Thus, this review will focus on providing insights into the biological role of the AT2R, in particular its actions within the renal and cardiovascular system.

INTRODUCTION

The biological actions of the renin–angiotensin system (RAS) are regarded to be primarily mediated by the octapeptide, angiotensin II (Ang II). Originally thought to be a circulating endocrine hormone that acts locally in the circulation, it is now well-documented that Ang II can act in both a paracrine and autocrine fashion [1]. The RAS is often activated in response to low blood pressure or injury. Indeed, the increase in local Ang II production during wound healing and tissue repair is considered to be part of this repair [2]. Ang II production can be mediated via an angiotensin converting enzyme (ACE)-dependent or independent pathway [35]. Figure 1 provides a schematic illustration on the formation of Ang II and its metabolite peptides. The effect of Ang II and its metabolite peptides have been shown to be mediated via activation of different angiotensin receptors, such as the angiotensin II type 1 receptor (AT1R), angiotensin II type 2 receptor (AT2R), angiotensin II type 4 receptor (AT4R) and Mas receptors, to produce their distinct biological actions. In most cases, these peptides have been shown to evoke renal and cardiovascular effects that are opposite to the classical effects of Ang II [69]. To date, studies have demonstrated that the AT1R and AT2R are the cognate receptors for Ang II, to which the peptide binds with high and equal affinity to both receptors. On the other hand, the effects of Ang (1–7) and Ang IV are primarily mediated by their native receptors, the Mas receptor and AT4R respectively [10,11]. Interestingly, beside their cognate receptor, numerous studies have demonstrated that endogenous angiotensin peptides can also interact with other angiotensin receptors. Indeed, the effects of Ang (1–7) and Ang IV have been shown to be mediated by the AT2R [1216] and there is growing evidence that Ang III is the endogenous AT2R agonist in the kidney [17,18] and coronary vessels [19]. Although Ang (1–7), Ang IV and Ang III have limited affinity for the AT1R, these angiotensin peptides exhibit modest affinity for the AT2R in comparison with Ang II [20], with the endogenous angiotensin peptides rank order of affinity at the AT2R found to be as follows: Ang II ≥ Ang III> Ang IV > Ang (1–7).

Illustration of the enzymatic events involved in the formation of Ang II and its peptides, and their receptors

Despite belonging to the same family of G-protein coupled receptors (GPCRs), there is only approximately 34% sequence homology between the AT1R and AT2R subtypes [21]. Therefore, it appears that activation of the AT1R and AT2R is likely to stimulate different signalling mechanisms/pathways and produce distinct biological responses (Figure 2). Although the AT1R has been shown to be primarily involved in mediating the biological functions of Ang II, including its ability to maintain fluid-electrolyte balance, regulate blood pressure and promote sympathetic transmission and cellular proliferation [22], much remains to be learnt about the AT2R. The discovery of a non-peptide AT2R agonist, compound 21 (C21), has greatly facilitated research into elucidating the role of the AT2R. This present review will provide insights into the renal and cardiovascular function of the AT2R. In addition, the cellular signalling pathways and therapeutic potential of targeting the AT2R will also be discussed.

The biological role of Ang II through its cognate receptors, the AT1R and AT2R

Figure 2
The biological role of Ang II through its cognate receptors, the AT1R and AT2R

Ang II-mediated activity has been shown to be dependent on the type of receptors it activates. Activation of the AT1R is well-implicated to be involved in mediating both the classical and deleterious actions of Ang II. On the other hand, stimulation of the AT2R is recognized to counteract the adverse effects mediated through the AT1R and confer organ protection. However, to date, the exact role of the AT2R still remains unclear, and its activity may vary in different tissue/cell-type.

Figure 2
The biological role of Ang II through its cognate receptors, the AT1R and AT2R

Ang II-mediated activity has been shown to be dependent on the type of receptors it activates. Activation of the AT1R is well-implicated to be involved in mediating both the classical and deleterious actions of Ang II. On the other hand, stimulation of the AT2R is recognized to counteract the adverse effects mediated through the AT1R and confer organ protection. However, to date, the exact role of the AT2R still remains unclear, and its activity may vary in different tissue/cell-type.

ANGIOTENSIN TYPE 2 RECEPTOR

Properties

The AT2R belongs to the rhodopsin subclass of GPCRs and comprises 363 amino acids [21,23,24]. With the AT2R gene located on the X-chromosome as a single copy and containing no introns in its coding region, this excludes the possibility of the receptor being encoded by homologous genes or alternative splicing [25]. To date, no AT2R subtypes or splice variants have been identified [26]. Structural analyses by protein purification and cloning have identified several key characteristic features of the AT2R. These include an extracellular N-terminal region, three extra- and intra-cellular loops and an intracellular C-terminal domain. Mutation within the intracellular third loop completely abolishes AT2R-mediated functions, whereas deletion of the N- and C-terminal residues has no effect in modulating the receptor activity [27].

The AT2R has been increasingly suggested to play a critical role in regulating cellular differentiation and organ development due to its high abundance in fetal mesenchymal tissues [28,29]. Although AT2R expression has reportedly been shown to rapidly decline to an undetectable level in numerous tissues after birth, the receptor is constantly present in low abundance in adult tissues including the heart, adrenal gland, kidney, brain and reproductive tissues [3032]. Furthermore, there is growing evidence to indicate that AT2R exhibits pleiotropic actions in the setting of a wide tissue distribution of this receptor subtype. Up-regulation in AT2R levels during certain disease states has strongly implicated its importance in wound healing, tissue remodelling and inflammation [23,33,34]. Activation of the AT2R has been demonstrated to produce anti-inflammatory, anti-proliferative, anti-hypertrophic, anti-fibrotic, pro-apoptotic and vasodilatory responses [3538]. These effects of AT2R have been shown to be essential to counterbalance the detrimental effects mediated by the AT1R subtype and protect against the progression of organ damage/failure as a result of excessive action of Ang II.

Regulation and signalling transduction pathways

Although sharing similar structural characteristics to a GPCR, the signalling pathway mediated by the AT2R is still not fully elucidated. For most GPCRs, studies have shown that in response to prolonged agonist exposure, activated GPCRs undergo desensitization, whereby activated receptors are phosphorylated by second messenger-dependent kinases in the absence of receptor sequestration to prevent sustained signalling and response [39,40], and/or undergo internalization that results in a down-regulation of receptor number that contributes to a decrease in cellular responses [41,42]. The latter process is often mediated by GPCR kinases, which phosphorylate activated GPCRs to prevent their coupling to G-proteins and recruiting β-arrestins to the phospholipids to interact with the receptor [39,41,42]. However, unlike typical GPCRs, recent studies have shown that AT2Rs do not undergo desensitization and degradation [43,44] and are likely to mediate a prolonged signalling response upon activation. This is largely attributed to their inability to interact with and/or recruit β-arrestins (the key adaptor proteins required for GPCR internalization) to the cell membrane. Of importance, the AT2R may possess constitutive activity and exert cellular effects independent of ligand binding, undergo dimerization with other GPCRs, or interact with distinct receptor binding proteins to mediate its activity [6,45]. Previous studies have demonstrated that the AT2R can exist either as a homo- or hetero-dimer receptor complex on the plasma membrane.

Formation of the AT2R/AT2R homodimer has been shown to enhance the biological effects of the receptor [46] and is predominantly formed in the endoplasmic reticulum before being translocated to the cell membrane [47]. This implies that AT2R exists as a constitutive functional dimer once it reaches the cell surface. This has suggested that the cellular expression of the AT2R is highly regulated by a number of factors during receptor synthesis and maturation, to ensure the smooth trafficking of the receptor complex to the plasma membrane for normal receptor functioning and signalling. To date, several studies have reported that AT2R translocation to the plasma membrane is highly critical to ensure the normal functional role of the receptor in particular in regulating renal homoeostasis. Indeed, studies by Padia et al. [48] have demonstrated that the AT2R is required to be translocated to the apical membrane of the proximal tubule cells to mediate a natriuretic response. Moreover, subsequent studies by Gildea et al. [49] have shown that the presence of the AT2R on the plasma membrane promotes its dimerization with the dopamine D1-like receptor to stimulate the internalization of sodium-potassium ATPase and inhibit sodium transport. In line with these observations, a separate study by Kemp et al. [50] has reported that the presence of the AT2R on the cell surface is crucial in driving the internalization of two major sodium transporters, the Na+/H+ exchanger 3 (NHE-3) and Na+/K+ ATPase (NKA) to mediate its natriuretic effect. Taken together, these studies have suggested that AT2R translocation to the cell surface is obligatory for the receptor to mediate its biological responses. Indeed, impairment in AT2R translocation to the plasma membrane was found to drive the development of hypertension and excessive sodium retention in spontaneously hypertensive rats (SHR) [48]. In that study, the authors have reported that AT2R was predominantly localized in the intracellular compartment and was not translocated to the apical plasma membrane of the proximal tubule cells in hypertensive rats. Recent studies by Jang et al. [51] have implicated the presence of intracellular reactive oxygen species, in particular nitric oxide (NO), as the key mechanism in driving the translocation and activation of the AT2R in cardiac myocytes. Nonetheless, the precise mechanism involved in regulating the normal trafficking of the AT2R is still yet to be fully elucidated.

On the other hand, AT2R heterodimer receptor complexes are generally formed when AT2R interacts with other GPCRs that are co-expressed within the plasma membrane. Interestingly, studies by Zhang et al. [47] have shown that heterodimerization of the AT2R can also occur in the endoplasmic reticulum and that this process is mediated by a Rab1 GTPase-dependent pathway. Although the precise mechanism whereby the AT2R dimerizes with other GPCRs still remains elusive, AT2R has consistently been demonstrated to form a heterodimer with the AT1R, with both receptors widely co-expressed in several cell populations [26,52]. Studies have described the ability of the AT2R to form a heterodimer complex with the AT1R (AT2R/AT1R) [43,53] as one of the ways the receptor inhibits and counterbalances the adverse effects mediated by the AT1R. In support of this notion, activation of the AT2R has been shown to reduce AT1R expression [54]. Taken together, this suggests that the AT2R is likely to activate a diverse range of signalling pathways in order to mediate its effects.

Moreover, several studies have demonstrated a close interaction between the AT2R and the Mas receptor [10]. Indeed, recent studies have demonstrated the ability of the AT2R to form an oligomerized complex with the Mas receptor [55] and that Mas-mediated protective effects can be blocked by an AT2R antagonist. This observation has been shown in numerous experimental models, including models of atherosclerosis [16], ischaemic stroke [56], hypertension [57] and salt-induced endothelial dysfunction [58,59]. Interestingly, similar to the AT2R, the Mas receptor has reportedly been shown to dimerize with the AT1R as a means to antagonize AT1R-mediated signalling and functions [60]. With both receptors shown to mediate similar tissue protective and regenerative actions in various pre-clinical models including cardiovascular and renal diseases [6,8,61], this could mean that both receptors are acting through similar downstream signalling pathways and that some compensatory mechanisms are activated when either receptor is inhibited. It is proposed that the signalling pathway(s) activated by the AT2R is dependent on its specific actions utilized and/or the cell-type involved. Of interest to this review, the signalling pathway(s) involved in the AT2R-mediated renal and cardiac effects but not other receptors involved in the RAS will specifically be discussed.

Renal signalling of the AT2R

AT2R activation has been shown to be capable of either activating or inhibiting phosphatases to modulate the mitogen-activated protein kinase (MAPK) pathway, in particular the extracellular signal-regulated kinase (ERK)1/2-dependent pathway [62,63]. In renal fibroblasts and proximal tubular cells, AT2R activation has been shown to promote ERK1/2 phosphorylation (pERK1/2) and signals through a NO-cyclic guanosine monophosphate (cGMP)-dependent pathway to promote vasodilation and inhibit fibrogenesis [35,64]. The importance of NO in mediating AT2R-effects has been demonstrated in previous studies in a sodium-depletion rat model of renal injury where activation of the AT2R signals through a neuronal nitric oxide synthase (nNOS)-NO-cGMP pathway to exert its reno-protective effects and stimulate the release of bradykinins [65,66]. Of importance, nNOS activation has been shown to be a key regulator of renal haemodynamics by maintaining fluid and sodium reabsorption via stimulation of the Na+/H+ exchanger [67]. A close relation between the AT2R and the bradykinin receptor (BR) has recently been documented, with both AT2R and BR forming a functional heterodimer to increase NO production and promote vasodilation [6870]. In addition, studies conducted by Bergaya et al. [71] have shown that the AT2R is essential for the vasodilatory action of the kallikrein–kinin system [71]. However, it is important to note that the AT2R can directly activate NO-cGMP production independent of bradykinins [72]. Although these studies have demonstrated a positive correlation between an increased level of cGMP and the natriuretic effect of AT2R, recent studies by Sabuhi et al. [73] have reportedly shown that AT2R promotes natriuresis via inhibition of NADPH oxidase activity, therefore suggesting the involvement of an additional signalling pathway of the AT2R in the kidney.

Nonetheless, a recent study by Chow et al. [35] has further demonstrated the central role of the pERK1/2-nNOS-NO-cGMP pathway in mediating the anti-fibrotic activity of the AT2R in the kidney. Of importance, other potential pathways that have been implicated in mediating the renal effects of the AT2R which include activation of the phospholipase A2, arachidonic acid and its cytochrome P450-dependent metabolites [74]. Although the exact signalling pathway in which AT2R mediates its renal actions remains unclear, it is well documented that the anti-fibrotic effect of the AT2R involves the dysregulation of matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitor of matrix metalloproteinases (TIMPs) [35,7577].

Vascular signalling of the AT2R

Similar to that of the kidney, the vasodilatory response of the AT2R in the coronary circulation has been shown to be mediated by a NO-dependent pathway. Previous studies conducted by Zhang et al. [78] have demonstrated that the presence of a NO synthase inhibitor abolishes the AT2R-mediated vasodilatory response. Conversely, AT2R activation has been shown to inhibit pERK1/2 in both vascular smooth muscle cells and cardiomyocytes, via stimulating a variety of phosphatases [including MAPK phosphatase (MKP-1) and protein phosphatase 2 (PP2A)] to exert its growth-inhibitory and pro-apoptotic actions [23,79,80]. These effects have been documented to be mediated either by a G-protein dependent and/or independent pathway [81], with the latter appearing to involve the activation of Src homology 2 domain phosphatase-1 (SHP-1). In addition, activation of the SHP-1 has also been shown to be involved in AT2R-mediated antioxidant effects by inhibiting NADPH oxidase activity [23,80]. Of importance, additional signalling cascades have also been implicated in mediating the growth-inhibitory effect of the AT2R. Previous studies conducted by Nouet et al. [82] have identified a close interaction between the AT2R and its interacting protein, ATIP1, which binds specifically to the C-terminus of the AT2R but not to other GPCRs. Often co-expressed with the AT2R in numerous tissues including the heart and blood vessels, ATIP1 was found to interact with the AT2R in its constitutive (inactivated) form to mediate the pro-apoptotic effect of the receptor. This is mediated by the ability of ATIP1 to cooperate with the AT2R to trans-inactivate receptor tyrosine kinases. Interestingly, subsequent studies have reportedly demonstrated that the anti-proliferative effect of the AT2R is dependent on the presence of the ATBP50 (AT2R binding protein of 50 kDa), which regulates the transportation of the AT2R to the plasma membrane [83]. A down-regulation of ATBP50 was found to reduce AT2R cellular expression and results in a reduction in the AT2R-mediated anti-proliferative response. Moreover, findings from recent studies have postulated a possible interaction between ATIP1 and peroxisome proliferator-activated receptor (PPAR)-γ in mediating the vascular protective effects of the AT2R, in particular its ability to ameliorate vascular intimal proliferation [84].

Nonetheless, with accumulating evidence suggesting a pro-fibrotic effect of the AT2R in the cardiovascular system, this implies that the receptor is likely to activate other distinct signalling pathways to mediate this detrimental effect. The interaction between the AT2R and promyelocytic zinc finger protein (PLZF) has been implicated in promoting a cardiac hypertrophic response, with recent in vivo studies confirming the ability of PLZF to bind on to the AT2R, and that Ang II-induced cardiac hypertrophy and fibrosis is completely abolished in PLZF knockout mice [85]. Upon activation, AT2R binds to PLZF and undergoes endocytosis. During this process, AT2R remains in the perinuclear region whereas PLZF translocates to the nucleus and binds to the promoter region of the regulatory subunit p85α of phosphatidylinositol-3 kinase (PI3K). This in turn promotes PI3K-p85 transcription, which is associated with cardiac hypertrophy [26,86]. Interestingly, additional studies have now highlighted that the actions mediated by PLZF are highly dependent on the cellular conditions when it is activated, suggesting that AT2R itself does not induce cardiac hypertrophy. Under appropriate cellular conditions, the recruitment of PLZF to the AT2R switches the receptor-mediated cardiac actions from an anti-hypertrophic to a hypertrophic response [87,88].

To date, it still remains unclear as to whether the AT2R activates the above signalling pathways either as a homo- or hetero-dimer receptor complex (with AT1R and/or other GPCRs). It needs to be considered that (i) the interaction between GPCRs is complex, (ii) a particular GPCR can only dimerize with other GPCRs which share similar structural features, and (iii) receptor heterodimerization is likely to affect the signalling and function of the individual receptor, which in turn is likely to influence the normal regulation and cellular functions mediated by that particular receptor. Thus, future research into extensively elucidating the signalling mechanistic pathway of the AT2R is highly warranted. Figure 3 provides a schematic illustration of the possible signalling cascade involved in AT2R-mediated biological actions. Moreover, with the limitations of the currently used AT2R agonists and antagonists, with some of the key reagents such as CGP42112 being partial agonists, it is evident that the use of transgenic animal models to specifically elucidate the functional role of the AT2R in both physiological and pathological states is needed. Although modern technology has allowed researchers to manipulate the level of the AT2R in various animal models using molecular approaches to either increase or suppress/knockout the AT2R, these methodologies have generally involved global strategies resulting in ubiquitous expression of the receptor with numerous biological effects. This global approach has not allowed researchers to explore the specific renal and/or vascular effect of the AT2R. To solve this problem, identifying and developing cell- and/or tissue-specific AT2R promoters are highly crucial in selectively targeting the expression of the AT2R to a specific site that is particularly relevant to a certain organ. The increased use of cell specific transgenic and knockout mice will improve our understanding of the pathophysiological role of the AT2R and its mode of action, as well as hopefully facilitating the identification of novel targets that may be utilized to enhance the therapeutic potential of the AT2R.

A schematic illustration of the key signalling pathways of the AT2R

Figure 3
A schematic illustration of the key signalling pathways of the AT2R

The AT2R has been shown to activate several pathways which are dependent on its specific action. AT2R-mediated natriuresis, vasodilation and anti-fibrotic effects involve the activation of a NO-cGMP-dependent pathway, which is likely mediated by the release of BK and an increased NOS activity, whereas its mediated antioxidant, anti-inflammatory and growth inhibition involve the interaction with its interacting protein, ATIP1 and activation of several phosphatases (MKP-1, PP2A, SHP-1) to interfere with ERK1/2 and other kinases' phosphorylation. On the other hand, the interaction with PLZF is involved in its mediated hypertrophic effect, primarily in cardiac tissues.

Figure 3
A schematic illustration of the key signalling pathways of the AT2R

The AT2R has been shown to activate several pathways which are dependent on its specific action. AT2R-mediated natriuresis, vasodilation and anti-fibrotic effects involve the activation of a NO-cGMP-dependent pathway, which is likely mediated by the release of BK and an increased NOS activity, whereas its mediated antioxidant, anti-inflammatory and growth inhibition involve the interaction with its interacting protein, ATIP1 and activation of several phosphatases (MKP-1, PP2A, SHP-1) to interfere with ERK1/2 and other kinases' phosphorylation. On the other hand, the interaction with PLZF is involved in its mediated hypertrophic effect, primarily in cardiac tissues.

Renal role

Although AT2R expression has been shown to decrease significantly after birth, with the AT1R predominantly expressed in the adult kidney [89,90], pharmacological and gene targeting studies have clearly shown that the AT2R plays a central role in maintaining renal homoeostasis in both the neonatal and adult kidney. With the receptor highly expressed in fetal and neonatal kidneys, accumulating studies have now illustrated a profound role for the AT2R in the development of renal vascular and tubular structures, including the morphogenesis of the urogenital system [91] and fetal vasculogenesis and vascular differentiation [90,92]. AT2R-mutant mice were found to develop ectopic ureteral budding and double collecting duct systems [93], suggesting that the presence of the AT2R is essential for normal kidney formation and function. These observed effects are likely to be attributed at least in part to a reduced rate of apoptosis of mesenchymal cells surrounding the nascent ureteral bud, a process driven by AT2R activation [93]. In support of this notion, further studies have demonstrated that AT2Rs are highly expressed during mouse nephrogenesis [94] and inhibition of AT2R activity was found to hinder ureteral bud cellular proliferation at both the in vitro and in vivo level [95]. Of importance, these urinary tract anomalies in the rodent kidney were found to be similar to that observed in humans.

Interestingly, recent studies have also revealed that AT2R has an integral role in facilitating postnatal maturation of the kidney. Findings from Brown et al. [90] have demonstrated that the AT2R confers reno-protection by blunting the AT1R-induced vasoconstriction response in the postnatal kidneys, resulting in a rise in renal blood flow to levels similar to that observed in adults [96,97]. With this in mind, renal blood flow is maintained and is initially low in infants due to a high renal vascular resistance, with the latter markedly reduced during the postnatal period and in the adult kidney. It has now been validated that this developmental change mediated by the AT2R is crucial for the growth, development and function of the normal kidney [96,98]. Indeed, previous studies exploiting genetic deletion and pharmacological inhibition of the AT2R had delineated the importance of the receptor in regulating normal tubular function and maintaining constant renal blood flow through vasodilation [99,100].

In the adult kidney, AT2Rs have constantly been detected in low abundance, where they are mainly localized in the glomerular mesangial cells, the adventitia of the preglomerular arteries, proximal tubules and the tubulo-interstitium [24,101]. Accumulating evidence has now demonstrated that AT2Rs are highly expressed in the adult proximal tubule [102,103] with the receptor playing a key role in mediating natriuresis [17,18,104106]. AT2R knockout mice were found to have an exaggerated anti-natriuretic response to systemically infused Ang II when compared with their wild-type counterparts, and that the pressure-natriuresis mechanisms in these mice were markedly impaired [66,107]. Absence of the AT2R also resulted in sustained renal hypersensitivity to Ang II, including elevated blood pressure and reduced urinary sodium excretion. In recent years, the natriuretic role of the AT2R in maintaining sodium homoeostasis has been further supported by previous studies involving direct renal interstitial microinfusion of pharmacological agents. Selective activation of the AT2R with agonists such as C21 markedly promoted natriuresis [50,108] whereas selective inhibition of the AT1R in rats was found to induce a natriuretic response that was abolished with intrarenal co-administration of the AT2R specific antagonist, PD123319 [18]. Moreover in that study, the authors have reported that in the presence of systemic AT1R blockade, intrarenal administration of Ang II was unable to induce natriuresis, whereas Ang III infusion significantly induced a marked increase in renal sodium excretion which was subsequently abolished by the presence of PD123319. These observations were subsequently found to be associated with the importance of Ang II converting to Ang III to interact with the AT2R; thereby implicating Ang III as the preferred AT2R agonist in the regulation of renal sodium excretion [17]. Indeed, when Ang III degradation is inhibited, this effect was found to be enhanced both in the presence [104] and absence of systemic AT1R blockade [109]. Of interest, in addition to the kidney, two cardiovascular hormonal systems have also implicated Ang III as the preferred agonist for the AT2R. This angiotensin peptide was found to be the preferred ligand to induce Ang II-mediated vasodilation and aldosterone secretion in the coronary vascular bed [19] and adrenal cortex [110] respectively. Nevertheless, further molecular conformation studies are still required to elucidate how Ang III binds to the AT2R. Interestingly, the natriuretic effect of AT2R was found to be absent from SHR [48] and Dahl salt-sensitive rats [111], with studies implying a link between AT2R cellular expression on the plasma membrane and its effect on natriuresis [4850] (as discussed above, in the regulation and signalling transduction pathways section).

Despite being expressed in low abundance in healthy tissues, AT2R was found to be markedly up-regulated in patients with kidney disease [112]. Accumulating evidence has now implicated the AT2R as a reno-protective target that protects the aging and injured kidneys from the progression of fibrosis (tissue scarring). Fibrosis is often regarded as a hallmark of all forms of renal disease regardless of the underlying aetiology, and its inevitable consequence is the progression to end-stage kidney failure [113,114]. Inhibition of the AT2R by genetic deletion or pharmacological approaches has been shown to aggravate renal injury and reduce survival in mice with chronic kidney disease [35,115117]. In these studies, increased macrophage infiltration and an expanded interstitium were also observed. In line with these observations, previous studies by Hashimtoto et al. [118] have demonstrated that over-expression of the AT2R in a mouse remnant kidney model markedly ameliorated glomerular injury, reduced the expression/activity of pro-fibrotic cytokines and improved renal function. These protective effects are thought to be mediated by an inhibition of renin biosynthesis and the subsequent production of Ang II [119]. The effect of AT2R deficiency in the kidney has been summarized in Table 1. Nonetheless, limited studies have been conducted to elucidate the role of the AT2R in the context of diabetes. In a recent study conducted by Chang et al. [120] in an experimental model of type 1 diabetes in mice, deficiency of the AT2R rapidly accelerated the progression of diabetic nephropathy by promoting oxidative stress and disrupting the ACE/ACE2 ratio balance. Indeed, an increase in the ACE/ACE2 ratio was linked to cause an aggravation in renal injury in association with diabetes. Interestingly, AT2R activation has also been implicated in attenuating the adverse effect associated with the receptor for advanced glycation end-products (RAGE)-driven type 1 diabetic nephropathy [121] and the progression of nephropathy in an insulin-deficient model [36,122]. The reno-protective role of the AT2R has been further extended to numerous diabetes settings. Studies by Hakam and Hussain [106] in an experimental model of type 2 diabetes have reportedly demonstrated that AT2R activation protected obese Zucker diabetic rats against an increase in blood pressure associated with sodium and water retention. Similar findings were also observed in an insulin-deficient model of diabetes [105]. Since the kidney is a major cardiovascular organ with immense influence on sodium and water balance, as well as blood pressure maintenance, the pro-natriuretic effect of the AT2R observed in these studies have identified the AT2R as a therapeutic target that can be utilized to maintain renal and cardiovascular homoeostasis in pathological conditions. Taken together, these studies suggest that activation of the AT2R is likely to provide beneficial effects in the pathogenesis and progression of kidney disease regardless of the aetiology.

Over the past decades, the availability of genetic experimental models and pharmacological agents has strongly facilitated the research on elucidating the renal role of the AT2R. Nonetheless, these studies were mainly conducted (1) in animal models either over-expressing or lacking the AT2R and/or (2) by pharmacological activation or blockade of the AT2R by the peptide agonist (CGP42112) or antagonist (PD123319). However, several issues have been raised with regard to the specificity of these compounds that has led to conflicting data. Accumulating studies have suggested a possible antagonistic effect of CGP42112 and agonist-mediated activation by PD123319 [123,124]. As a result it was not feasible to draw a clear conclusion that AT2R is reno-protective. Previous studies have reportedly shown that blockade of the AT2R by PD123319 markedly reduced macrophage infiltration and the expression/activity of inflammatory markers [125]. In line with these observations, studies by Esteban et al. [126] in a mouse model of unilateral ureteral obstruction (UUO)-induced tubulointerstitial fibrosis have also reportedly shown that administration of PD123319 significantly inhibited the infiltration of inflammatory cells.

Table 1
Effect of AT2R deficiency in the kidney
Species Effect of AT2R deficiency Reference 
Mouse Anomalies of the urinary tract similar to that of humans with congenital renal and urinary tract anomalies, and developed hypertension in adulthood [93,226,227
 Decreased cellular proliferation and apoptosis during ureter development [93,95,227
 Increased renal AT1R level [107,228
 Reduced pressure natriuresis [107,228
 Sustained hypersensitivity to Ang II, and reduced Ang II-induced urinary sodium excretion and flow rate [66,229
 Blunted vasodilator response after dietary sodium restriction or Ang II infusion [66,229
 Accelerated fibrosis and collagen deposition in a model of obstructive nephropathy [35,116
 Exacerbated renal injury and reduced survival rate in a renal ablation model of renal injury [115
 Enhanced oxidative stress and accelerated development of type 1 diabetic nephropathy [120
Species Effect of AT2R deficiency Reference 
Mouse Anomalies of the urinary tract similar to that of humans with congenital renal and urinary tract anomalies, and developed hypertension in adulthood [93,226,227
 Decreased cellular proliferation and apoptosis during ureter development [93,95,227
 Increased renal AT1R level [107,228
 Reduced pressure natriuresis [107,228
 Sustained hypersensitivity to Ang II, and reduced Ang II-induced urinary sodium excretion and flow rate [66,229
 Blunted vasodilator response after dietary sodium restriction or Ang II infusion [66,229
 Accelerated fibrosis and collagen deposition in a model of obstructive nephropathy [35,116
 Exacerbated renal injury and reduced survival rate in a renal ablation model of renal injury [115
 Enhanced oxidative stress and accelerated development of type 1 diabetic nephropathy [120

These conflicting results have been found to be highly dependent on the duration of the disease and concentration at which the agonist/antagonist is administrated. However, the discovery of the novel non-peptide agonist, C21, has strongly facilitated our research into the AT2R. C21 is increasingly recognized as a potential therapeutic agent due to its (i) ideal route of administration, where it can be given both orally and intravenously and (ii) its specificity in stimulating the AT2R at both the in vitro and in vivo level, without influencing the AT1R. [127]. Studies conducted to date have consistently demonstrated that C21-mediated AT2R activation confers reno-protection in all experimental models of renal disease regardless of the aetiology and species tested to date (Table 2). Of importance, C21 has recently been shown to be protective against type 1 [36] and type 2 [128] models of diabetic nephropathy via its ability to inhibit inflammation, oxidative stress and fibrosis. Accumulating evidence has suggested that the effectiveness of the angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitor (ACEi) in lowering blood pressure [129,130] and ameliorating the pathology of renal diseases [131,132] is mediated by the AT2R. Indeed, animals pre-treated with ARBs were found to have elevated levels of the AT2R [106] and the protective effects of ARB and ACEi were found to be completely abolished by blockade of the AT2R [129,133,134]. Taken together, these findings have highlighted that a future drug class of AT2R agonists may represent the next generation of therapeutic approaches for the treatment of certain renal diseases.

Table 2
Effect of C21-mediated AT2R activation in experimental models of renal disease
Species Model of renal disease used Effect of C21 treatment Reference 
Rat Streptozotocin-induced type 1 diabetic nephropathy Improved diabetic albuminuria [122,230
  Improved glucose tolerance  
  Decreased inflammation  
  Decreased oxidative stress  
  Decreased apoptosis  
 2-Kidney, 1-clipped Goldblatt- induced renovascular hypertension Decreased inflammation [231
 Age-related progressive renal disease Increased renal blood flow [50,208
  Increased sodium and water excretion  
  Promoted vasodilation and natriuresis  
  Decreased glomerular filtration rate  
 Obesity-induced renal disease Promoted natriuresis [108,232
  Improved mesangial matrix expansion  
  Decreased pro-inflammatory molecules  
  Decreased macrophage infiltration  
 Spontaneous hypertensive-induced renal disease Improved survival rate [188,189
  Decreased inflammatory cell infiltration  
  Decreased collagen accumulation  
  Reduced plasma renin activity  
 High-sodium diet-induced hypertension in obese rats Improved glomerular filtration rate [233
 Non-insulin dependent (type 2) induced diabetic nephropathy Improved diabetic albuminuria [128
  Reduced glomerular, tubulointerstitial and perivascular fibrosis  
  Reduced macrophage infiltration  
 Doxorubicin-induced nephrotoxicity Reduced oxidative stress [234
  Reduced glomerular density  
Mouse Streptozotocin-induced type 1 diabetic nephropathy Improved diabetic albuminuria [36
  Decreased inflammation  
  Decreased oxidative stress  
  Decreased collagen accumulation  
Species Model of renal disease used Effect of C21 treatment Reference 
Rat Streptozotocin-induced type 1 diabetic nephropathy Improved diabetic albuminuria [122,230
  Improved glucose tolerance  
  Decreased inflammation  
  Decreased oxidative stress  
  Decreased apoptosis  
 2-Kidney, 1-clipped Goldblatt- induced renovascular hypertension Decreased inflammation [231
 Age-related progressive renal disease Increased renal blood flow [50,208
  Increased sodium and water excretion  
  Promoted vasodilation and natriuresis  
  Decreased glomerular filtration rate  
 Obesity-induced renal disease Promoted natriuresis [108,232
  Improved mesangial matrix expansion  
  Decreased pro-inflammatory molecules  
  Decreased macrophage infiltration  
 Spontaneous hypertensive-induced renal disease Improved survival rate [188,189
  Decreased inflammatory cell infiltration  
  Decreased collagen accumulation  
  Reduced plasma renin activity  
 High-sodium diet-induced hypertension in obese rats Improved glomerular filtration rate [233
 Non-insulin dependent (type 2) induced diabetic nephropathy Improved diabetic albuminuria [128
  Reduced glomerular, tubulointerstitial and perivascular fibrosis  
  Reduced macrophage infiltration  
 Doxorubicin-induced nephrotoxicity Reduced oxidative stress [234
  Reduced glomerular density  
Mouse Streptozotocin-induced type 1 diabetic nephropathy Improved diabetic albuminuria [36
  Decreased inflammation  
  Decreased oxidative stress  
  Decreased collagen accumulation  

Cardiovascular role

Similar to that of the renal system, the AT2R has been shown to be constitutively expressed at a low level in the physiological state, but is markedly up-regulated in certain cardiovascular disorders, including hypertension, atherosclerosis, myocardial infarction and heart failure [63,135]. In addition, the AT2R has been shown to be up-regulated in hypertensive diabetic patients [112]. Interestingly, a recent study by Banos et al. [136] has demonstrated that the AT2R was significantly down-regulated in aortic tissues in patients with coronary artery disease. Thus, these findings indicate a complex local regulation of the AT2R expression in particular within the cardiovascular system, which may likely contribute to a differential effect mediated by the AT2R. Of importance, it still remains unclear as to whether activation of the AT2R leads to a protective or detrimental response.

Over the years, it has been well-established that AT2R activation opposed AT1R-mediated vasoconstriction. This vasodilatory effect of the AT2R has been demonstrated in small resistance arteries of the adrenal, coronary and peripheral circulations [112,137,138], as well as in large capacitance vessels including the aorta [138,139]. Moreover, in a recent study by Chai et al. [140], activation of the AT2R was found to improve skeletal muscle blood flow, by stimulating capillary arterioles and glucose uptake in the skeletal muscle.

The availability of AT2R-deficient rodents has strongly facilitated researchers in elucidating the functional role of the receptor in the cardiovascular system. AT2R knockout mice were found to exhibit higher basal blood pressure and sensitivity to Ang II, in comparison with their wild-type counterparts [141144]. Importantly, these haemodynamic responses were not observed in mice over-expressing the AT2R. Haemodynamic responses to Ang II infusion, including increased blood pressure, heart rate and myocardial fibrosis were significantly blunted in over-expressing AT2R transgenic mice [145147]. These haemodynamic findings demonstrate the importance of the AT2R in opposing the effect mediated through the Ang II–AT1R-axis, and the ability of this receptor subtype to mediate a vasodepressor effect. This negative chronotropic effect of the AT2R was thought to be mediated by its ability to inhibit the release of catecholamines, which in turn decrease the sensitivity of pacemaker cells to Ang II [148].

Accumulating evidence has now demonstrated a crucial role for the AT2R in mediating the vasodilator response of the ARB in both animal models and in human resistance vessels. For example, chronic AT1R blockade attenuates Ang II-induced vasoconstriction via an AT2R-NO dependent pathway [149]. Moreover, in the presence of losartan, Ang II was found to activate the unopposed AT2R which led to a vasodilatory response in resistant arteries of rat mesentery [150]. These beneficial haemodynamic effects were subsequently found to be inhibited in the presence of the AT2R antagonist, PD123319. In addition, studies by Moltzer et al. [151] have shown that PD123319 potentiates the coronary constrictor effects of Ang II in the Wistar rat. Surprisingly, PD123319 did not alter the Ang II-induced response in SHR. Furthermore, AT2R-mediated vaso-relaxation was not detected in iliac arteries and abdominal aortas. The constricting effect of Ang II in SHR in the absence of PD123319 was found to be similar to that observed in the Wistar rats treated with the AT2R antagonist. In fact, these observations have been attributed to the lack of counter-regulatory AT2R-mediated coronary vasodilation and/or a change in the AT2R phenotype from a relaxant to a constrictor. Studies by You et al. [152] have demonstrated that in resistance arteries of SHR, AT2R expression is down-regulated in the presence of hypertension and that AT2R activation causes vasoconstriction. Interestingly, anti-hypertensive treatment for 4 weeks was found to restore AT2R expression, as well as mediating its vasodilatory actions. Indeed, several studies in human coronary microarteries [137] and resistance vessels of diabetic hypertensive patients [112] have also reported a functional vasodilatory role for the AT2R.

Nevertheless, there is accumulating evidence to suggest that the cardiovascular role of the AT2R is very complex. Activation of the AT2R appears to have dual effects in response to cardiac injury, either acting in a protective or injurious manner. These conflicting reports on the role of the AT2R suggest that its actions are dependent on the aetiology [153] and severity [154] of the disease, the absence or presence of hyperglycaemia [146,155] and the particular animal strain examined in the study [31].

Numerous studies have demonstrated that AT2R deficiency in mice exacerbated myocardial infarction [154,156] by increasing heart-to-body weight ratios and expanding myocardial cross-sectional areas. AT2R deficiency has also been shown to aggravate heart failure and reduce the survival rate in mice after acute myocardial infarction [157]. Conversely, in a model of myocardial infarction induced by coronary artery ligation, moderate over-expression of the AT2R was found to protect against ischaemic injury and maintain cardiac function via attenuating cardiac hypertrophy. The up-regulation of the RAS including AT1R expression after myocardial infarction was markedly attenuated by the over-expression of the AT2R [158]. Similarly, in a separate study by Yang et al. [159], cardiac-selective over-expression of the AT2R was found to significantly improve left ventricular function after myocardial infarction in mice. In that study, the authors had demonstrated that the beneficial effect of AT2R over-expression on left ventricular remodelling and function occurred in the absence of any changes in heart rate, stroke volume and left ventricular mass. In addition, in accordance with previous studies that AT2R activation exhibits a protective role in atherosclerosis, over-expression of the AT2R markedly reduced atherogenesis by inhibiting aberrant collagen accumulation, oxidative stress and inflammation [160,161]. In contrast, AT2R knockout mice were found to develop accelerated cardiac fibrogenesis and dysfunction [162] and atherosclerosis [163166].

Interestingly, contradictory results have also been reported in numerous studies. AT2R has been documented to exert a stimulatory effect in driving the progression of ventricular hypertrophy and cardiac fibrosis in an experimental model of Ang II- and pressure overload-induced cardiac hypertrophy [167,168]. Mice over-expressing the AT2R were found to significantly develop severe cardiac fibrosis and heart failure [169], and intrinsic myocyte contractile dysfunction [170]. In support of this notion, studies conducted by Yvan-Charvet et al. [171] have implicated the AT2R in driving Ang II-mediated glucose intolerance and adipose cell mass, and thus contributing to the deleterious effects of high fat diet. Moreover, D'Amore et al. [172] have demonstrated that Ang II-mediated hypertrophy was amplified with increasing expression of the AT2R. Similar findings were also observed in the context of diabetes. Both genetic deletion and pharmacological blockade of the AT2R were found to markedly attenuate the development of atherosclerosis [155] and reverse the morphological and endothelial changes caused by type 1 diabetes [173]. Moreover, a recent study by Matsushita et al. [174] also implied a detrimental role of the AT2R, whereby AT2R blockade markedly inhibited vascular calcification. Strikingly, findings from Daugherty et al. demonstrated that genetic deletion or pharmacological inhibition of the AT2R had no effect in modulating hypercholesterolaemia- [175] and Ang II- [176] induced atherosclerosis. Taken together, it seems plausible that the differential effects mediated by the AT2R may be dependent on the receptor density (relative ratio of AT2R/AT1R), the cellular signalling pathways activated and/or the aetiology of the disease including the absence or presence of hyperglycaemia.

A close correlation has been shown between the AT2R level and the severity of cardiovascular disease. However, conflicting findings have been reported, with no clear conclusion being made as to whether over-expression of the AT2R is beneficial or detrimental. Nonetheless, the response mediated by the AT2R seems to be largely dependent on its expression level. In studies showing that activation of the AT2R is beneficial in cardiovascular disease, AT2R levels were approximately 20–35% relative to that of the AT1R [145,148]. Conversely, AT2R levels were found to be similar or higher than AT1R in studies which demonstrated a detrimental effect of the AT2R [169,172,177].

In addition, accumulating studies have now provided further evidence that the genetic background of the AT2R-deficient mice exploited in the studies could play a key role in contributing to the conflicting findings with respect to the role of the AT2R in cardiovascular disease. Genetic deletion of the AT2R in the FVB/N mice strain was found to rapidly accelerate the progression of cardiac and vascular hypertrophy [145,154,178], enhance coronary arterial thickening and perivascular fibrosis [179] and increase arterial neointima formation [180]. Moreover, studies have reportedly demonstrated that AT2R-deficient mice on the FVB/N background had greater left ventricular dilation and reduced survival rate after myocardial infarction compared with their wild-type counterparts [154,157,169]. Strikingly, opposite findings were demonstrated in AT2R knockout mice on the C57BL/6 background strain. Deletion of the AT2R in C57BL/6 mice was found to abolish the development of cardiac hypertrophy and fibrosis in pressure overload- [167] and Ang II- [168] induced hypertension.

Thus, based on these conflicting experimental findings obtained from AT2R-deficient mice and issues that arise as a result of the specificity of its agonist (CGP42112) or antagonist (PD123319), it has been difficult to provide a definitive conclusion on the cardiovascular role of the AT2R. However, the emergence of the newer agonist, C21 has clearly improved our understanding of the cardiovascular effects of the AT2R.

Studies conducted by Kaschina et al. [181] have reportedly shown that C21 significantly improved post-myocardial infarct cardiac function and reduced scar formation via its ability to inhibit inflammation and apoptosis. In addition, C21 has been shown to reduce arterial stiffness and collagen deposition, a key pathological mechanism that contributes to the development of organ dysfunction [182]. Direct stimulation of the AT2R with C21 was found to promote vasodilation [183] and reduce vascular injury and myocardial fibrosis in an experimental model of SHR via its ability to inhibit aortic oxidative stress, macrophage infiltration and collagen deposition [182,184]. Vasodilation in response to C21 has been demonstrated in coronary, iliac and mesenteric arteries of rats and mice [185]. Interestingly, the vasodilatory role of C21 appears to be concentration dependent. Indeed, the vasodilatory response to high concentrations of C21 was found to be followed by a brief vasoconstriction due to the activation of the AT1R, an effect which could be inhibited by AT1R blockade [185]. In addition, findings from that study have suggested that C21 induces vasodilation primarily by blocking cellular calcium transport rather than having a direct effect on the AT2R. Preliminary data by Steckelings et al. [186] have demonstrated that C21 could promote vasodilation either by a direct and/or indirect effect via the AT2R, the different results dependent on species, vascular bed and the specific contractile stimulus. In that study, the authors demonstrated that C21 antagonizes the thromboxane receptor (TxR) by acting as a low affinity TxR antagonist. Nevertheless, further studies are still required to confirm if this is a direct effect of C21 or involves an indirect action via the AT2R. Moreover, it remains crucial to determine if there is any potential protective/detrimental effect associated with each of the mechanisms discussed above.

Nonetheless, numerous studies have reportedly demonstrated that the beneficial effects mediated by C21 were found to be independent of blood pressure, suggesting that activation of the AT2R is likely to have a limited systemic haemodynamic action. This observation has been demonstrated in lean- and obese-normotensive animals [108,181] as well as in numerous hypertensive animal models, particularly models such as SHR [187,188] and stroke-prone SHR [184,189]. Moreover, other non-genetic models of hypertension such as induction of increased blood pressure via inhibition of NO production [182] have consistently demonstrated that C21 had no anti-hypertensive effect. However, it still remains controversial as to whether AT2R activation has any influence on blood pressure. Previous studies had demonstrated a blood pressure lowering effect of C21 in SHR [127] and in conscious rats [190]. Nonetheless, it is important to note that as these experiments were performed on anaesthetized animals which causes profound RAS activation, this could explain why these animals may have been more sensitive to pharmacological RAS modulation. Moreover, the different concentrations of C21 in the various studies may explain the observed differences in blood pressure responses. Studies by Bosnyak et al. [183] have previously demonstrated that C21 at a very high concentration causes AT1R activation and results in an increase in blood pressure. This could represent an effect of C21 on other receptors when given at a very high dose (greater than 1 μM). Although AT2R agonist appears to have a limited effect in regulating blood pressure when given as a mono-therapy, an anti-hypertensive response was observed when co-administrated with an ARB [183]. It is therefore envisaged that an improved understanding of the mechanisms associated with the AT2R, in particular why and how the phenotype of AT2R changes under pathological conditions, is likely to be helpful in trying to enhance its therapeutic potential.

C21-mediated AT2R activation has been shown to possess potent anti-fibrotic properties in numerous studies, which demonstrate a complex interaction between collagen-degrading, MMPs and transforming growth factor (TGF)-β1. Activation of both the RAS and TGF-β1 has been shown to contribute to the pathogenesis of several renal and cardiovascular diseases, and the pro-fibrotic actions of Ang II (through its AT1R) are mainly mediated by the pro-sclerotic growth factor, TGF-β1 [191,192]. Studies by Lauer et al. [76] have demonstrated that C21-mediated AT2R activation markedly reduced TGF-β1 pro-fibrotic activity and MMP-9-induced proteolysis, which in turn limits the influence of TGF-β1 on stimulating collagen production. These effects of C21 were subsequently found to be associated with improved endothelial function and vascular mechanics. Of importance, C21 has consistently been shown to relax pre-constricted vessels in all species tested to date [185]. Direct stimulation of the AT2R by C21 markedly attenuated tumour necrosis factor (TNF)-α and high-fat diet-induced leukocyte adhesion and plaque formation [193]. Importantly, these effects were completely abolished by the presence of the AT2R antagonist, PD123319, confirming that the observed effects of C21 are mediated through the AT2R. Furthermore, C21 was also found to confer cardio-protection in a more chronic experimental model of myocardial infarction [76]. Similar to its reno-protective effect, C21 has also been shown to be protective in numerous experimental models of cardiac diseases, regardless of their genetic strain and the aetiology of the underlying disease (Table 3).

Table 3
Effect of C21-mediated AT2R activation in experimental models of cardiovascular disease
Species Model of cardiovascular disease used Effect of C21 treatment Reference 
Rat Myocardial infarction Improved systolic and diastolic ventricular function [76,181
  Improved survival rate  
  Decreased inflammation  
  Reduced collagen content  
 Spontaneous hypertensive-induced vascular disease Promoted vasodilation [183,187
 Ang II-induced hypertension Decreased blood pressure [50
 Stroke-prone spontaneous hypertensive-induced vascular disease Decreased vascular stiffness [184
  Decreased myocardial interstitial collagen content  
  Decreased aortic fibronectin content  
  Decreased inflammation  
 Coronary ligation-induced heart failure Improved aortic baroreflex sensitivity [235
  Decreased AT1R expression  
  Suppressed sympathetic outflow  
 Monocrotaline-induced pulmonary hypertension Improved cardiac function [236
  Decreased vessel wall thickness  
  Decreased inflammation  
Mouse Polyethylene-cuff-induced vascular injury Decreased neointimal formation [237
  Decreased cellular proliferation  
  Decreased inflammation  
 High-fat diet-induced vascular injury Improved plaque size and stability [193
  Decreased lipid size  
  Decreased inflammation  
Species Model of cardiovascular disease used Effect of C21 treatment Reference 
Rat Myocardial infarction Improved systolic and diastolic ventricular function [76,181
  Improved survival rate  
  Decreased inflammation  
  Reduced collagen content  
 Spontaneous hypertensive-induced vascular disease Promoted vasodilation [183,187
 Ang II-induced hypertension Decreased blood pressure [50
 Stroke-prone spontaneous hypertensive-induced vascular disease Decreased vascular stiffness [184
  Decreased myocardial interstitial collagen content  
  Decreased aortic fibronectin content  
  Decreased inflammation  
 Coronary ligation-induced heart failure Improved aortic baroreflex sensitivity [235
  Decreased AT1R expression  
  Suppressed sympathetic outflow  
 Monocrotaline-induced pulmonary hypertension Improved cardiac function [236
  Decreased vessel wall thickness  
  Decreased inflammation  
Mouse Polyethylene-cuff-induced vascular injury Decreased neointimal formation [237
  Decreased cellular proliferation  
  Decreased inflammation  
 High-fat diet-induced vascular injury Improved plaque size and stability [193
  Decreased lipid size  
  Decreased inflammation  

Gender-specific effects

There is an increasing body of data to suggest that gender differences with respect to RAS could potentially explain the lower rates of progression in renal and cardiovascular disease in females compared with males [194,195]. There is evidence that the decrease in rate of progression of renal disease is linked to oestrogen levels based on data from women during menopause [196], during the various phases of the menstrual cycle [197] and finally in studies comparing users versus non-users of oral contraceptive medications [198,199].

Indeed, several findings have shown that both oestrogen and ARB could act in synergy to down-regulate AT1R-mediated adverse effects. Co-administration of oestrogen and olmersartan was found to significantly inhibit neointimal formation and thickening in ovariectomized mice [200,201]. Interestingly, these gender-specific findings have been extended to humans. For example, studies by Miller et al. [202] have shown that normotensive healthy males and females responded differently to ARB at both the peripheral vascular and at the renal microvascular level. In that study, the authors have shown that a higher dosage of ARB is required in men compared with women, and this is likely to account for the observed difference in sensitivity to RAS modulation and rate of disease progression in both genders. Strikingly, similar findings were also observed in patients receiving ACEi treatment [203205].

Recent studies have suggested that sex specific differences also exist in response to RAS activation through its receptors. Since the AT2R gene is located on the X-chromosome, various studies have suggested that AT2R expression and its mediated actions may be gender-specific. Accumulating evidence has now implied a gender-specific role for the AT2R, with its activity highly enhanced in females. AT2R expression was found to be highly expressed in the vasculature and kidney in both female rats and mice [89,206208], when compared with their male counterparts. In addition, females were found to exhibit a higher AT2R/AT1R ratio. It is therefore proposed that this observed sex difference could influence the regulation of blood pressure and renal function mediated by the AT2R.

Studies by Okumura et al. [209] have shown that AT2Rs were significantly up-regulated following cuff injury in female mice, and this was associated with a marked reduction in neointimal formation, inflammation and oxidative stress. Moreover, an age-related gender difference was observed in mice subjected to cuff-induced vascular injury in the femoral artery [210]. In that study, the authors have reported that the absence of the AT2R resulted in a significant increase in neointimal formation in the aged female mice group, and that the protective effect of oestrogen-treatment in attenuating vascular remodelling was also abolished. Given that a close correlation exists between the AT2R and oestrogen, it seems plausible that the female hormone plays a key role in contributing to the gender-specific role of the AT2R, with females likely to greatly benefit from AT2R-mediated effects. Previous studies have demonstrated that AT2R expression was markedly up-regulated in the presence of oestrogen [206,207,211,212] and chronic infusion of Ang II decreases arterial pressure in female rats, at a concentration that cause an increase in arterial pressure in male rats [213]. These effects were subsequently found to be mediated through an AT2R-mediated oestrogen dependent mechanism [214]. Conversely, similar findings were also observed in AT2R knockout mice. Although the chronic pressor response to Ang II was markedly inhibited in female AT2R wild-type mice, this effect was not observed in their male wild-type counterparts or in female AT2R deficient mice [215]. Taken together, these findings have strongly demonstrated that there is an enhanced role for the AT2R in regulating arterial pressure in females [216]. Moreover, sex differences were also found to play a role in the regulation of renal function. Although AT2R modulates pressure-natriuresis in both genders, activation of the AT2R was found to confer an additional protective role in the female renal vasculature. Previous studies that measured renal function have demonstrated that AT2R blockade markedly enhanced the Ang II-induced renal vasoconstriction response and greatly reduced renal blood flow and glomerular filtration rate in female, but not in male rats [208,217,218]. Moreover, the sensitivity of the tubulo-glomerular feedback mechanism to Ang II was also reduced in female rats [217]. In support of this notion, previous clinical studies involving type 1 diabetic patients have also reportedly demonstrated a gender-specific role of the AT2R in kidney function and pulse pressure [219]. Taken together, it is evident that AT2R exhibits a gender-specific effect on both the kidney and vasculature. Of importance, activation of the AT2R provides auto-regulation of renal blood flow and vasodilation in both male and female kidney. Therefore, an agent that specifically stimulates the AT2R may represent a therapeutic target for the treatment of both renal and cardiovascular disease in both genders. In line with this, administration of the AT2R agonist, C21, has been shown to promote vasodilation and natriuresis in both male and female normotensive rats [208].

In conclusion, the protective RAS which composed of the AT2R is now well-regarded as a new therapeutic platform for the treatment of several underlying diseases [220–225]. The availability of the AT2R agonists have provided insights to understanding the pathophysiological and repair mechanisms of the AT2R in diseased state, and could represent the next generation of therapeutic approaches.

We thank Dr Audrey Kokita (BakerIDI Heart and Diabetes Institute, Australia) for her comments on the earlier draft of the manuscript.

FUNDING

This work was supported by the Juvenile Diabetes Research Foundation postdoctoral fellowship (to B.S.M.C.).

Abbreviations

     
  • ACEi

    angiotensin converting enzyme inhibitor

  •  
  • Ang II

    angiotensin II

  •  
  • ARB

    angiotensin receptor blocker

  •  
  • AT1R

    angiotensin II type 1 receptor

  •  
  • AT2R

    angiotensin II type 2 receptor

  •  
  • BR

    bradykinin receptor

  •  
  • C21

    compound 21

  •  
  • cGMP

    cyclic guanosine monophosphate

  •  
  • ERK1/2

    extracellular signal-regulated kinase 1/2

  •  
  • GPCR

    G-protein coupled receptor

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MKP

    MAPK phosphatase

  •  
  • MMP

    matrix metalloproteinase

  •  
  • nNOS

    neuronal nitric oxide synthase

  •  
  • NO

    nitric oxide

  •  
  • pERK1/2

    ERK1/2 phosphorylation

  •  
  • PI3K

    phosphatidylinositol-3 kinase

  •  
  • PLZF

    promyelocytic zinc finger protein

  •  
  • PP2A

    protein phosphatase 2

  •  
  • PPAR

    peroxisome proliferator-activated receptor

  •  
  • RAS

    renin–angiotensin system

  •  
  • SHP-1

    Src homology 2 domain phosphatase-1

  •  
  • SHR

    spontaneously hypertensive rats

  •  
  • TGF

    transforming growth factor

  •  
  • TxR

    thromboxane receptor

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