Division of Nephrology, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia 22908
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ABSTRACT |
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Present strategies in the treatment of inflammatory renal injury have focused on developing agents that specifically target individual mechanisms thought to contribute toward the pathogenesis of the disease. Such an approach is hindered by redundancies in the inflammatory cascade, rendering intervention suboptimal. The A2A adenosine receptor (A2A-AR) is a member of the family of guanine nucleotide binding proteins and has become a focus of major interest primarily because of its ability to broadly inactivate the inflammatory cascade. This review summarizes our present knowledge regarding the molecular biology and pharmacology of A2A-ARs as well as the physiological effects of activation of A2A-ARs in the kidney. We also review our recent experience in targeting this receptor subtype in abrogating the inflammatory cascade in ischemia-reperfusion injury.
inflammation; ATL-146e; ZM-243185; ischemia-reperfusion; acute renal failure
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INTRODUCTION |
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ADENOSINE, GENERATED LOCALLY in tissue by conditions that produce hypoxia, ischemia, or inflammation, mediates a variety of physiological functions. The renal effects mediated by adenosine are heterogeneous, due in part to activation of multiple adenosine receptor subtypes that are localized in different regions of the kidney. Traditionally, adenosine has been thought to play a critical role in the local regulation of blood flow, but, more recently, evidence has been accumulating that adenosine also has potent effects in modulating inflammatory processes. This review summarizes present knowledge on the characteristics of one subtype, the A2A adenosine receptor (A2A-AR) and its potential role in treating and preventing renal injury.
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PHARMACOLOGY AND MOLECULAR BIOLOGY OF A2A ADENOSINE RECEPTORS |
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Adenosine Receptor Subtypes
Adenosine and adenine nucleotides bind to P1 and P2 receptors, respectively (9). P2 receptors that bind adenine nucleotides, uracil nucleotides, and/or diadenine polyphosphates are composed of ligand-gated channels (P2X) and guanine nucleotide binding protein (G protein)-coupled receptors (P2Y) (43). Adenosine, on the other hand, binds to P1 purinergic receptors, which are members of the G protein-coupled receptor family. Four subtypes of adenosine receptors have been cloned: A1, A2A, A2B, and A3 (for a review, see Refs. 41 and 51). The four subtypes have the hallmark structural characteristics that are common to G protein-coupled receptors, including seven putative transmembrane-spanning domains, an extracellular NH2 terminus, cytoplasmic COOH terminus, and a third intracellular loop that is important in binding G proteins. The first adenosine receptors to be cloned, RDC7 (38) and RDC8 (39), were originally isolated as "orphan" cDNAs. On the basis of their binding properties to pharmacological agents and their effects on adenylyl cyclase, RDC7 and RDC8 were shown to encode canine A1- and A2A-ARs, respectively. Subsequently, adenosine receptor orthologs and homologs were identified in other species, including humans (40, 57, 66-68, 84). When the amino acid sequences of all four human adenosine receptor subtypes were compared, they were found to have an overall identity of 30% and a transmembrane domain identity of 45%. They were also found to have pharmacological properties distinct from those of other species. The human A1-, A2A-, A2B-, and A3-ARs are proteins comprising 326, 412, 332, and 318 amino acids, respectively (42). The receptors can be distinguished pharmacologically by their ability to bind selective ligands and their use of distinct signaling pathways (41, 51). Table 1 summarizes ligands and their affinities to adenosine receptor subtypes as well as major signaling pathways.
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A2A Adenosine Receptors
The A2A-AR cDNA, which has been cloned from several species including humans (53), encodes a protein of ~45 kDa, larger than the molecular masses of the other subtypes. This is primarily due to the additional 80-90 amino acids of the COOH-terminal tail. The overall amino acid identity is >90% among species, with most of the differences occurring in the second extracellular loop and the long COOH-terminal domain. The COOH-terminal domain has several serine and threonine residues that are potential phosphorylation sites. It is well known the A2A-ARs undergo rapid agonist-induced desensitization associated with phosphorylation of the receptor (55). A2A-ARs stimulate adenylyl cyclase and increase the production of cAMP by coupling to stimulatory G proteins (Gs) or to Golf in certain tissues in which Golf is expressed as the primary stimulatory G protein (29). In addition to the cAMP-protein kinase A (PKA) pathway, recent studies indicate that serine/threonine protein phosphatase (61), mitogen-activated protein kinase (MAP kinase) (71, 72), PKC (56), and phospholipase D (83) may participate in mediating the effects of A2A-AR activation. ![]() |
LOCALIZATION AND FUNCTIONAL EFFECTS OF A2A ADENOSINE RECEPTORS IN THE KIDNEY |
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Determining the adenosine receptor subtypes that mediate specific effects of adenosine in the kidney has been difficult for several reasons. First, the low abundance of multiple subtypes in many tissues, including kidney, hinders detection by standard methods. Second, specific pharmacological reagents for the characterization of adenosine receptor subtypes have been largely unavailable. For example, selective reagents for A2B and A3 receptors have yet to be developed, and only recently have selective antagonists for A2A-AR been developed (53). The cloning of adenosine receptor subtypes enabled the development of highly specific reagents for receptor localization, using in situ hybridization, ligand binding autoradiography, RT-PCR of microdissected nephron segments, and immunohistochemistry. Although these techniques have been useful for the localization of adenosine receptors in other tissue, such as brain, very little information exists regarding the precise localization within kidney tissue. Weaver and Reppert (87) used radiolabeled probes to determine the localization of A1- and A2A-ARs in the kidney. A1-AR mRNA was expressed in collecting ducts of the inner medulla and cells of the juxtaglomerular apparatus. A2A-AR mRNA was expressed in the renal papilla. Kreisberg et al. (35) demonstrated that A2A-AR mRNA was present in the outer medullary descending vasa recta (OMDVR). Antibodies have been used successfully to localize A2A-ARs in the brain (64). More recently, a peptide antibody was developed that identified A1-ARs in afferent arterioles, mesangial cells, proximal convoluted tubules, medullary collecting ducts, and papillary surface epithelium of the kidney (75).
The functional effects of adenosine on renal hemodynamics have been reviewed recently (45). Drury and Szent-Gyorgi (19) reported in 1929 that adenosine produced a marked reduction in renal blood and urine flow. Early studies demonstrated biphasic effects of adenosine with an initial transient vasoconstriction followed by vasodilation, effects mediated by A1- and A2-ARs, respectively (45). Defining the functional effects of the A2A-AR subtype has become possible with the availability of selective A2A agonists. Infusion of CGS-21680, a selective A2A agonist, produced an increase in renal blood flow and glomerular filtration rate (37). With the use of a laser Doppler probe, CGS-21680 was found to increase medullary blood flow to 184% of control without a change in cortical blood flow (37). Because all blood flow to the renal medulla must pass through the OMDVR, Silldorff et al. (73) isolated OMDVR from rats, perfused them in vitro, and examined the vasoactive properties of CGS-21680. They found that the vasoconstrictive effects of angiotensin II were inhibited in the presence of CGS-21680 but that CGS-21680 had no effect when applied to vessels alone in the absence of angiotensin II. These results indicate that A2A-ARs are expressed in the OMDVR and mediate vasodilation in constricted vessels. Recently, Nishiyama et al. (46) examined afferent and efferent arteriolar response to adenosine in an in vitro blood-perfused juxtamedullary nephron preparation. They found that afferent and efferent vasodilatory responses to adenosine are blocked by KF-17837, a novel A2A antagonist, suggesting the presence of A2A-ARs in both afferent and efferent arterioles. These results indicate the important renal hemodynamic effects are mediated by A2A-ARs. Moreover, the expression of A2A-ARs in afferent and efferent arterioles, which permits critical control of glomerular filtration, could serve as a potential target for therapeutic intervention.
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A2A ADENOSINE RECEPTORS IN INFLAMMATION |
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A2A Adenosine Receptor Expression on Hematopoietic Cells
In addition to the renal vascular and hemodynamic effects of adenosine, studies over the last 10 years have indicated that adenosine has a direct effect on hematopoietic and endothelial cells to reduce inflammation (for a review, see Ref. 42). Given the fact that A2A-ARs are expressed in a variety of hematopoietic cell types, i.e., monocytes, lymphocytes, neutrophils, basophils, and mast cells, all of which share a common stem cell source in the bone marrow (23), this receptor subtype is ideally suited to modulate inflammatory processes. Evidence for an anti-inflammatory role of A2A-AR activation comes from a variety of studies both in vivo and in vitro.A large body of evidence suggests that the major signaling pathway that
links A2A-receptor activation and reduction of inflammation is the cAMP-PKA pathway (23, 78). A2A agonists
increase cAMP in a dose-dependent manner, an effect that is enhanced in
the presence of a phosphodiesterase (PDE) inhibitor (29).
Furthermore, several studies indicate that inhibitors of PKA block the
anti-inflammatory action of A2A agonists (44, 49,
79). In tumor necrosis factor (TNF)--activated human
neutrophils, ATL-146 ester (e) in the presence of rolipram, a PDE type
IV (PDE 4) inhibitor, increased cAMP and decreased human neutrophil
oxidative activity. These results suggest that the decrease in
neutrophil oxidative activity produced by the selective activation of
A2A-ARs expressed on neutrophils may be due to increased
cAMP and activation of PKA.
Effect of A2A Activation on Reactive Oxygen Species
For the past decade, adenosine has been known as a molecule that mediates an anti-inflammatory effect through the activation of A2A-ARs (13, 70, 77). This physiological role of endogenous adenosine became apparent after the demonstration that activated neutrophils or endothelial cells release and respond to adenosine (5, 14, 15, 25). Neutrophils play a critical role in the inflammatory process. They are the most abundant leukocyte in blood and the first to arrive at a site of injury. Several groups of investigators have demonstrated that adenosine, largely through A2A-ARs, acts on activated neutrophils (17, 23) to reduce oxygen metabolites such as superoxide anion or hydrogen peroxide (14, 17, 63, 69, 70, 79). These data provide compelling evidence that selective activation of A2A-ARs decreases neutrophil oxidative activity. Tissue damage is induced, in part, by the migration of neutrophils into damaged tissue and the release of these reactive oxygen species. Adenosine's effect through A2A-ARs is thought to limit tissue damage (12).Effect of A2A Activation on Neutrophil Adherence
Adenosine also reduces neutrophil adherence to endothelial cells through an effect attributed to A2A-ARs (8, 16, 22, 89). Adhesion of neutrophils to endothelial cells occurs through a complex series of events that may involve several classes of adhesion molecules, including selectins, mucin, and other selectin ligands, integrins, and the immunoglobulin superfamily (24, 33, 58, 59). In particular, the role of intercellular adhesion molecule (ICAM)-1 has been well studied. ICAM-1 (CD-54) is expressed on endothelial cells and binds to counterreceptors on neutrophils, lymphocyte function antigen (LFA-1; CD11There is accumulating evidence that adenosine regulates adhesion molecule expression. Using monoclonal antibodies and flow cytometry, N-formylmethionylleucylphenlyalanine-induced expression of neutrophil Mac-1 was inhibited by a selective A2A agonist (88). More recently, in vivo studies using a selective A2A agonist, ATL-146e, reduced the heightened expression of renal endothelial cell expression of ICAM-1 and P-selectin induced by ischemia-reperfusion injury (48). On the other hand, adenosine paradoxically mediates neutrophil chemotaxis via A1-ARs (13, 63). Such a dual effect might protect endothelial cells from the deleterious effects of activated neutrophils yet allow chemotaxis to the site of infection (13). These data from the use of selective agonists of A1 and A2A-ARs suggest a complex interaction between adenosine receptor subtypes and neutrophil adhesion. Adenosine, acting on A2A-ARs, may reduce inflammation by inhibiting adhesion molecule expression and subsequent neutrophil adherence to endothelial cells. The precise signaling pathways whereby adenosine reduces neutrophil adherence are not known.
A2A Activation and Cytokines
Monocytes accumulate more slowly at sites of inflammation than neutrophils and contribute to the inflammatory process by producing and releasing cytokines. The results of several studies indicate that the proinflammatory cytokine TNF-A2A Adenosine Receptors Activation Reduces Tissue Injury
On the basis of the evidence that activation of A2A-ARs regulates factors that attenuate inflammation, studies have been performed using selective A2A agonists in nonrenal tissue to determine whether activation of A2A-ARs confers tissue protection. In many of these studies, the observation that A2A agonist-induced tissue protection was associated with a reduction of factors associated with inflammation suggested that A2A agonists contribute to tissue protection by attenuating inflammation. Although a direct causal relationship between tissue protection and attenuation of inflammation by A2A agonists has not been proven, the abundant data suggest this direct link. In dog heart, CGS-21680, a highly selective A2A agonist, reduced myocardial tissue injury, an effect associated with a decrease in neutrophil accumulation, superoxide generation, and neutrophil adherence to endothelium (31). Recently, using a lung transplantation model, ATL-146e, an agonist that is 50 times more potent than CGS-21680 (62), reduced neutrophil sequestration and microvascular permeability in parallel with a reduction in tissue injury (65). The role of A2A-ARs in neuroprotection appears to be more complex due to the role of A2A-ARs in neural function. Both by immunohistochemistry using a selective A2A-AR monoclonal antibody and by in situ hybridization, A2A-ARs have been localized to the striatum, nucleus accumbens, and globus pallidus (53, 86). A2A agonists lead to the release of neurotoxic chemical mediators such as glutamate which may augment cerebral ischemia-reperfusion. In contrast, A2A antagonists, when given before ischemia-reperfusion, can lead to a decrease in the release neurotoxic chemicals, leading to a reduction of cerebral damage (86). This finding is in sharp contrast to what is known about the effects of A2A agonists on neutrophil function and reperfusion injury in other tissues (31, 48). Because leukocyte accumulation occurs after the ischemic period and during reperfusion, cerebral tissue protection achieved by A2A agonists (52) is typically optimal when given during the reperfusion period and not before the ischemic period (86). ![]() |
A2A ADENOSINE RECEPTORS IN RENAL DISEASE |
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Given the possibility of multiple functional consequences by nonspecific activation of adenosine receptors, agents that are targeted to specific A2A-AR subtypes are potentially important novel therapeutic agents. The foregoing discussion demonstrating the protective effect of A2A activation in other tissues strongly suggests that selective A2A agonists could provide a means of reducing tissue injury in kidney. One such compound is ATL-146e, which has been developed and extensively characterized (62, 79) by chemically modifying the structure of adenosine. The high selectivity of ATL-146e for A2A-ARs is due to substitutions at the C2 and 5' positions. Radioligand binding studies indicate that ATL-146e has a higher affinity for A2A-ARs than the acid form (ATL-146 acid) and a higher affinity and selectivity for A2A-ARs than the commercially available CGS-21680, a highly selective A2A agonist (Table 1, Ref. 30).
Acute Ischemic Renal Failure
We tested the potential role of A2A-AR activation in reducing renal injury in a model of acute ischemic renal failure (48-50). This model was chosen because of the well-characterized effects of reperfusion on the inflammatory cascade associated with renal ischemia-reperfusion injury (36, 76, 82). Although the pathogenic role of neutrophils in ischemia-reperfusion injury of the kidney has been controversial, many studies have clearly shown that neutrophils and other inflammatory cells accumulate in kidneys subjected to ischemia-reperfusion (10, 54, 80). We studied both rats and mice and found that ATL-146e, when administered before ischemia and during the period of reperfusion, produced a 70% reduction in the elevation of plasma creatinine produced by ischemia-reperfusion (49). Significant protection was also observed when ATL-146e administration was delayed and begun immediately at the onset of reperfusion (50). ATL-146e-induced preservation of renal function was associated with pronounced histological preservation as well (50). Figure 1 shows the dose-dependent reduction in plasma creatinine by ATL-146e in mice subjected to 32 min of ischemia followed by 24 h of reperfusion (49). Maximal protection was observed with doses of ATL-146e between 1 and 10 ng · kg
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Additional studies have been performed to elucidate the mechanism of
protection by ATL-146e. These studies demonstrate that A2A
activation reduces neutrophil accumulation, a result that may be due to
a decrease in P-selectin and ICAM-1 expression (48). Furthermore, studies in neutrophils indicate that ATL-146e decreased neutrophil oxidative activity and neutrophil adherence factors (48). Figure 2 summarizes
potential targets for A2A agonists in reducing renal
injury. Evidence from in vitro and in vivo studies suggest that
A2A receptor activation regulates tissue-specific function.
Activation of A2A-ARs on leukocytes could attenuate inflammation by reducing the release of leukocyte free radicals and
hydrogen peroxide (14, 17, 63, 69, 70, 79), the releasing
of various leukocyte proteases, and reducing the expression of adhesion
molecules such as Mac-1 (88). Characterization of A2A-AR expression by microvascular endothelial cells is
lacking; however, certain microvascular endothelial cell adhesion
molecules may be directly or indirectly regulated by A2A
agonists (48). There is evidence that reduction of
cytokine release by activation of A2A-ARs on other
inflammatory cells such as monocyte/macrophages may potentially reduce
renal injury (27, 44). Although there are several targets
for A2A agonists in mediating tissue protection, not all
necessarily participate in the protection observed in ischemia-reperfusion injury of the kidney. Differentiating
effects on inflammatory cells and endothelial/smooth muscle cells could lead to a further understanding of the mechanism of action of A2A agonists as well as of the pathogenesis of
ischemia-reperfusion injury. The generation of chimeric mice in
which the bone marrow of wild-type mice is ablated and repopulated with
stem cells from A2A-knockout mice could address this issue.
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The cellular mechanism by which A2A-ARs produce these
effects is likely through an increase in intracellular cAMP and PKA activation, as the effects of A2A activation on neutrophil
oxidative activity were blocked by a PKA inhibitor (48).
An intriguing observation with potential therapeutic implications is
the observation that the effects of A2A activation on
neutrophil oxidative activity and adherence were potentiated in the
presence of a PDE 4 inhibitor. Both A2A agonists and PDE
inhibitors act along different pathways to increase intracellular cAMP
accumulation. We evaluated the effects of combination therapy and found
that treatment with both compounds in combination has a greater effect
in reducing renal injury and neutrophil accumulation than the use of
either compound alone (49). Combination therapy using low
doses of each agent might be a useful strategy for providing maximal
tissue protection by blocking the inflammatory cascade while minimizing
the risk of side effects (Fig. 3). These
studies indicate a novel approach to reducing renal injury that takes
advantage of the ability of a single receptor to broadly abrogate the
inflammatory cascade.
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A2A Adenosine Receptors in Other Renal Diseases
Recent evidence also suggests the potential utility of A2A agonists in renal transplantation. All renal allografts encounter substantial injury due to the transplant process, which may enhance the antigenicity of the transplanted organ and initiate rejection (18). Reducing reperfusion injury by A2A-AR activation may enhance allograft survival. Independent of the effects of A2A-agonists on reperfusion injury, we have recently shown that activation of A2A-ARs reduces human leukocyte antigen class I and II expression on human lymphocytes (47). Direct effects on human leukocyte antigen expression by A2A agonists may reduce the antigenicity of allografts and provide an additional mechanism for enhanced graft survival.Additional potential therapeutic applications of A2A agonists include reducing renal injury associated with nephrotoxins. Contrast-induced acute renal failure is thought to be due in part to renal vasoconstriction (1) and to oxidant injury (3). The latter mechanism forms the basis for the use of N-acetylcysteine in the prevention of acute renal failure from contrast agents (81), whereas adenosine agonists could be protective by intervention of either mechanism. Experimental studies point to adenosine as a candidate in mediating renal vasoconstriction (1), a hypothesis supported by the finding that theophylline, a nonselective adenosine receptor antagonist, prevents the reduction of glomerular filtration rate associated with contrast agents (1, 21). A2A-ARs are expressed in afferent and efferent arterioles and induce vasodilation when activated (46); thus selective A2A-agonists could potentially prevent a contrast-induced decrease in glomerular filtration rate. Furthermore, because of the known effects of adenosine in reducing oxidative injury, A2A agonists could mediate renal protection by reducing the oxidant damage produced by contrast agents.
Cisplatin is an anticancer therapeutic agent that is associated with significant nephrotoxicity due to hemodynamic changes and oxidant injury (4). Antagonizing A1-ARs with a selective antagonist, 8-cyclopentyl-1,3-dipropylxanthine, has been shown to decrease renal injury associated with cisplatin (34). Thus the potential exists for using selective A2A agonists to counteract oxidant injury and renal vasoconstriction in reducing cisplatin-induced nephrotoxicity.
The known anti-inflammatory effects of A2A agonists on both neutrophils and mononuclear cells may permit wide-ranging effects on other types of acute inflammatory renal injury. Among these, the involvement of the inflammatory cascade in glomerulonephritis may be a likely target for similar anti-inflammatory strategies with A2A-AR agonists. Previous studies have demonstrated the potential role of PDE inhibition in suppressing the injury associated with mesangial proliferative glomerulonephritis (85). This finding along with the foregoing discussion establish the potential for the use of A2A agonists in glomerulonephritis. The expression of A2A-ARs on key structures involved in the regulation of glomerular filtration such as afferent and efferent arterioles and mesangial cells could provide the foundation for studies examining chronic models of glomerular disease.
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CONCLUSION |
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Although various strategies have been employed to abrogate the inflammatory cascade of renal injury, activation of A2A-ARs has emerged as a novel therapeutic approach. Newer agents have been synthesized that are potent and selective for this receptor subtype. Their further development awaits their use in human clinical trials.
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ACKNOWLEDGEMENTS |
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The author is grateful to Dr. Diane Rosin (Dept. of Pharmacology, Univ. of Virginia) for a careful reading of the manuscript and helpful discussions and to Dr. Joel Linden and Gail Sullivan (Dept. of Medicine, Univ. of Virginia) for invaluable advice.
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FOOTNOTES |
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This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grants NIH RO1-DK-56223 and 1R41-DK-58413.
Address for reprint requests and other correspondence: M. D. Okusa, Div. of Nephrology, Box 133, Univ. of Virginia Health System, Charlottesville, VA 22908 (E-mail: mdo7y{at}virginia.edu).
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