The role of adenosine receptors A2A and A2B signaling in renal fibrosis

review

http://www.kidney-international.org & 2014 International Society of Nephrology

The role of adenosine receptors A2A and A2B signaling in renal fibrosis Veena S. Roberts1, Peter J. Cowan1, Stephen I. Alexander2, Simon C. Robson3 and Karen M. Dwyer1 1

Immunology Research Centre, St Vincent’s Hospital Melbourne and Department of Medicine, University of Melbourne, Melbourne, Australia; 2Centre for Kidney Research, Children’s Hospital at Westmead, Sydney, Australia and 3Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

Renal fibrosis, the key histopathological lesion in the development and progression of chronic kidney disease (CKD), has been the focus of much research in recent decades. The growing burden of CKD in both developed and developing nations highlights a need for novel therapies to halt the progression of renal disease. Insights into the pathogenesis of renal fibrosis and the key cellular and molecular mediators have been critical in the process of identifying potential targets of therapy. Adenosine signaling is an innate biological autocrine and paracrine cellular signaling pathway involving several key mediators: ectonucleotidases, adenosine, and adenosine receptors. Short-term activation of the adenosine A2A and A2B receptors decreases inflammation, which precedes renal fibrosis. However, in conditions of persistent, excessive adenosine exposure, such as in patients born with adenosine deaminase (ADA) deficiency, adenosine signaling via A2B receptor promotes renal fibrosis, as seen in chronic inflammation. This review will describe the increasingly recognized complex role of adenosine signaling in the development of renal fibrosis. We will speculate how the knowledge gained may be employed in the search for more effective therapies based on these complex signaling pathways.

Chronic kidney disease (CKD) is characterized by the progressive and irreversible loss of renal architecture and replacement with scar tissue following persistent or repetitive injury over a period of time. The histological hallmark and final common pathway of CKD is tubulointerstitial fibrosis irrespective of the initiating injury. Tubulointerstitial fibrosis correlates more strongly than glomerulosclerosis with reduced renal function in clinical and experimental CKD, and progression of tubulointerstitial fibrosis culminates in end-stage renal disease.1 Chronic hypoxia is reflected by capillary rarefaction in areas of tubulointerstitial fibrosis, which potentiate inflammation and fibrosis.2–4 Extracellular adenosine is a key signaling molecule induced under hypoxic conditions5–7 and is an endogenous regulator of acute and chronic inflammation in various tissues and organs.5,8,9 However, chronically elevated adenosine mediates fibrosis in skin,10 lung,11 liver,12 and potentially pancreas,13 although it is protective against cardiac fibrosis.14,15 Evidence for the role of adenosine signaling in the development and progression of renal fibrosis found in a variety of models is discussed in this review.

Kidney International (2014) 86, 685–692; doi:10.1038/ki.2014.244; published online 23 July 2014

Adenosine is normally present at low concentrations in the pericellular space in the kidney.16 The adenosine concentration increases significantly in states of inflammation and hypoxia, principally through the hydrolysis of adenosine triphosphate (ATP), which is released from injured/dying cells9 or in a more controlled manner from apoptotic and inflammatory cells.7 Extracellular ATP is sequentially hydrolyzed by the ecto-nucleoside triphosphate diphosphohydrolase (NTPDase-1/CD39) to adenosine diphosphate and adenosine monophosphate, which is then hydrolyzed by ecto-5’-nucleotidase (CD73) to adenosine (Figure 1). Whereas ATP promotes inflammation, adenosine is generally anti-inflammatory.17,18 Adenosine signals through four G-protein–coupled P1 receptors termed A1 receptor (A1R), A2A receptor (A2AR), A2B receptor (A2BR), and A3 receptor (A3R) (Figure 1). A1R and A3R are coupled to the G-inhibitory subunit, which leads to a reduction in intracellular cyclic AMP upon activation, whereas A2AR and A2BR are coupled to the G-stimulatory subunit resulting in an increase in

KEYWORDS: cell signaling; chronic renal disease; fibrosis; inflammation; renal fibrosis

Correspondence: Veena S. Roberts, Immunology Research Centre, St Vincent’s Hospital Melbourne and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, Melbourne 3065, Australia. E-mail: [email protected] Received 15 April 2013; revised 16 January 2014; accepted 24 January 2014; published online 23 July 2014 Kidney International (2014) 86, 685–692

ADENOSINE GENERATION AND SIGNALING DURING CELLULAR INJURY

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AMP Adenosine

ADP Extracellular

CD73

CD39

ATP

Inosine

ATP release

39

CD

AD

A

P1 (A1,A2A,A2B,A3)

ENT

P2X7 Intracellular

ATP

Figure 1 | Extracellular purinergic catabolic and signaling pathways.

intracellular cyclic AMP. In addition, A2BR couples to Gq proteins, which stimulate phospholipase C activity and intracellular calcium mobilization.19,20 A2BR has lower affinity for adenosine compared with the other receptors, and is principally activated in pathological states when the pericellular concentration of adenosine is significantly increased.19 Adenosine is removed from the extracellular space by adenosine deaminase (ADA) to form inosine, or transported into the cell by the equilibrative nucleoside transporters 1 and 2 (ENT1/2). EXPRESSION OF ECTONUCLEOTIDASES AND ADENOSINE RECEPTORS IN THE KIDNEY

Four subtypes of cell surface ectonucleotidases with specific substrate preferences have been identified. The ectoNTPDase-1/CD39 hydrolyzes ATP and adenosine diphosphate with equivalent activity, NTPDase 2 (CD39L1) preferentially hydrolyzes adenosine diphosphate, and NTPDase 3 and NTPDase 8 preferentially hydrolyze ATP.21 Within the murine renal cortex, CD39 and CD39L1 are predominantly expressed on interlobular arteries, glomerular arterioles, peritubular capillaries, and vascular smooth muscle cells; CD39L1 is also expressed in Bowman’s capsule and NTPDase 3 in the thick ascending limb, distal tubule, and collecting ducts.22,23 The localization of NTPDase 8 is not known.23 CD73 is predominantly expressed in the glomeruli and on peritubular fibroblasts.24 Although the localization of the adenosine receptors in normal human kidney has not been reported, all four receptors have been detected on the immortalized human proximal tubular cell line HK-2,25 and recently Zhang et al.26 demonstrated expression of A2BR in the glomeruli and tubules of patients with CKD. In the rodent kidney, A1R is expressed in the glomerulus, proximal tubule cells, and afferent arterioles, A2AR in the glomeruli, and A2BR on the vasculature.16 A3R has been identified in whole kidney, but its specific localization is unknown. 686

ADENOSINE SIGNALING ATTENUATES RENAL FIBROSIS BY CONTROLLING INFLAMMATION

Renal fibrosis is a complex and dynamic process involving both circulating and resident cells.27 Inflammation is part of the host’s defense against injury, but non-resolving inflammation drives the development of fibrosis via activation of fibroblasts.28 Several lines of evidence from rodent models suggest that the action of adenosine signaling in limiting inflammation helps prevent the development of renal fibrosis. The lack of CD73 potentiates renal inflammation and fibrosis

Mice lacking CD73 (CD73KO), which have an impaired ability to generate adenosine,29 spontaneously develop renal fibrosis by 6 months of age.30 The kidneys of these mice demonstrate glomerulitis, tubulitis, and tubulointerstitial fibrosis. Markers of inflammation include infiltration of pro-inflammatory macrophages (CD11b þ GR1 þ ) and CD8 þ T cells into the interstitium and increased serum levels of pro-inflammatory cytokines. The reduced generation of adenosine in these mice promotes a chronic pro-inflammatory environment with increased cellular infiltration and renal fibrosis. Macrophages are intrinsic to the development of renal fibrosis

Tissue macrophages have both pro- and anti-inflammatory roles in the kidney (reviewed by Anders and Cao31,32). M1 macrophages develop early after renal injury and propagate inflammation, whereas M2 macrophages appear later and support renal repair.33 In vitro studies indicate that ATP and adenosine influence the generation and activity of these subtypes. ATP, which is one of the best characterized damageassociated molecular pattern molecules,34 is released from lipopolysaccharide-treated macrophages by exocytosis and potentiates the development of M1 macrophages.35 However, the expression of CD39 and CD73 on M1 macrophages36 Kidney International (2014) 86, 685–692

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enables hydrolysis of ATP to adenosine, which signals via A2AR to suppress M1 activity and reduce the release of inflammatory cytokines.37–39 Furthermore, adenosine signaling via A2BR mediates a switch in phenotype from M1 to M2 macrophages, which generates an anti-inflammatory milieu by producing cytokines, including interleukin-10 and interleukin-4.40,41 It has also been proposed recently that A2AR signaling causes M1 macrophages to switch to another anti-inflammatory M2 subtype termed M2d.42 Thus, adenosine signaling acts as a regulatory ‘brake’ on macrophagemediated inflammation via A2AR and A2BR signaling (Figure 2). A2AR signaling reduces cellular infiltration and fibrosis

Macrophage infiltration of the renal parenchyma is inversely correlated with prognosis,43 and strategies to curb the inflammatory response therefore hold great therapeutic promise. Indeed, data from rodent models suggest that A2AR signaling on macrophages ameliorates renal fibrosis in vivo. In a rat model of glomerulonephritis-induced CKD, treatment with the A2AR agonist CGS21680 (see Table 1 for Ki values) significantly attenuated the development of tubulointerstitial fibrosis.44 Renal expression of collagen I and III, a-smooth muscle actin, and transforming growth factor-b (TGF-b) was reduced in agonist-treated rats. Consistent with this, more severe injury was observed in rats treated with the potent A2AR antagonist ZM-241385.44 In control rats, macrophages accumulated in the glomeruli and interstitium and were identified as predominantly M1 by their expression of CD169. Renal protection in the agonist-treated group was associated with a reduction in macrophage infiltration, whereas M1 macrophage accumulation in antagonist-treated rats was increased in both glomeruli and interstitium. Thus, A2AR activation reduced M1 macrophage infiltration into glomeruli and interstitium, leading to decreased expression of profibrotic factors such as TGF-b and less renal fibrosis.44 Similarly, in a rat model of diabetic nephropathy, treatment

CD39 ATP

with the A2AR agonist ATL-146e reduced macrophage infiltration in the kidney and urinary chemokine (C-C motif) ligand 2 (monocyte chemoattractant protein-1) levels, and attenuated the development of tubulointerstitial fibrosis and glomerulosclerosis.45 A2AR signaling promotes regulatory T-cell activity and reduces fibrosis

T cells precede the influx of macrophages and can independently promote renal fibrosis in the unilateral ureteric obstruction model of CKD.46 A2AR is expressed on CD4 þ T cells and is upregulated following stimulation.47 Signaling through A2AR inhibits T-cell proliferation. In the unilateral ureteric obstruction model, renal fibrosis was exacerbated in A2ARKO mice, particularly in the initial stages. A greater perivascular cellular infiltrate was evident in these mice at days 3, 7, and 14.48 Further studies on WT mice showed that renal levels of A2AR mRNA expression progressively increased in obstructed kidneys.49 Treatment with the A2AR agonist CGS21680 reduced the CD4 þ T-cell infiltrate and increased the ratio of regulatory to effector CD4 þ T cells, which was associated with decreased expression of profibrotic markers and attenuated fibrosis.49 Regulatory T cells also protect against Adriamycin nephropathy, an experimental model that mimics the human condition of focal glomerulosclerosis. Adriamycin is directly toxic to the glomeruli and leads to the development of Table 1 | Ki values of the adenosine receptor ligands53 Ki value (nmol/l) A2B

A3

Function

CGS21680 ATL-146e ZM-241385 PSB-1115 MRS1754

A2AR agonist 289 27 410,000 67 77 0.5 Not available 45 A2AR agonist 774 1.6 75 743 A2AR antagonist 53.4 410,000 A2BR antagonist 410,000 410,000 403 503 1.97 570 A2BR antagonist

CD39 ADP

A1

A2A

Ligand

CD73 AMP

ADO

CD39 M1

M2

A2AR; A2BR

CD73 ADO

A2AR

Pro-inflammatory factors • TNFα • IL-1 • IL-12

Anti-inflammatory factors • IL-10 • IL-4

Figure 2 | Adenosine inhibits the expression of pro-inflammatory cytokines by M1 macrophages via A2AR signaling, and promotes a shift to the anti-inflammatory M2 phenotype via A2BR signaling. Kidney International (2014) 86, 685–692

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glomerulosclerosis, interstitial fibrosis, and proteinuria by 6 weeks. Severe Adriamycin nephropathy is induced in immunodeficient mice, and cell therapy with regulatory T cells is protective.50 A direct pro-apoptotic effect of ATP on renal tubular cells has recently been demonstrated, implicating a role for extracellular nucleotides in the pathogenesis of Adriamycin-induced kidney injury.51 This innate injury is mitigated in mice that overexpress CD39 in the renal parenchyma51: urinary protein and serum creatinine were decreased and there was significantly less renal injury compared with WT mice. In cell adoptive transfer studies, regulatory T cells from mice overexpressing CD39 offered greater protection against Adriamycin nephropathy than regulatory T cells from WT mice,51 suggesting an additional independent effect of CD39 within the kidney. The mechanisms underlying this observation are yet to be defined, but likely involve adenosine signaling pathways within the renal parenchyma (discussed below). Collectively, these data provide evidence for a protective role of adenosine signaling, mediated principally via the A2AR, during the inflammatory phase of renal fibrosis. Immune cells often co-express A2A and A2B receptors.52 Activation of A2AR is likely to predominate on these cells as it has a 50-fold higher affinity for adenosine compared with A2BR,53 although receptor density may also have a role. The potential impact of purinergic catabolism and adenosine signaling on inflammation and the development of renal fibrosis is summarized in Figure 3.

actin and are a major source of ECM consisting of collagen I, III, and fibronectin,55 are not present in the normal tubulointerstitium. In addition to secreting ECM, myofibroblasts have contractile properties, which contribute to wound closure, the initiation of revascularization,56 and stabilization of injured organs.57 In the glomerulus, myofibroblasts arise from mesangial cells and respond to TGF-b, plateletderived growth factor, and CTGF,58 and mesangial hypercellularity precedes glomerulosclerosis.59 Within the interstitium the origin of myofibroblasts is not defined, and potential sources include quiescent fibroblasts60,61 and circulating bone marrow–derived fibrocytes,62 which under the influence of TGF-b expand, proliferate, and express a-smooth muscle actin. The process of epithelial or endothelial to mesenchymal transition as a source of myofibroblasts has been difficult to prove in vivo,63 and more recently pericytes have emerged as a potential source of ECMproducing cells.55,64 Pericytes express CD73 and plateletderived growth factor receptor and are closely associated with renal capillaries, providing support and stability.65 During injury and in response to platelet-derived growth factor and other profibrotic growth factors, these cells detach from capillaries and are modified into myofibroblasts promoting expression of a-smooth muscle actin and loss of expression of CD73. A2BR is the predominant adenosine receptor expressed on isolated renal fibroblasts and is upregulated in fibrosis,66 suggesting a role in ECM expansion and collagen deposition. In keeping with this, antagonism of A2BR on kidney fibroblasts limited pro-collagen mRNA expression.66

Fibroblast activation results in renal fibrosis

Extracellular matrix (ECM) expansion and renal parenchymal loss correlate with decline in renal function and progression of CKD.54 Myofibroblasts, which express a-smooth muscle

A2BR SIGNALING PROMOTES RENAL FIBROSIS

Although A2AR signaling can reduce inflammation-mediated renal fibrosis, data from several mouse models suggest that

Renal injury Macrophage and T-cell infiltration

CD39, CD73

ATP release

Adenosine

CD39 CD73

CD39 CD73

ENT

T effector

ENT

M1

T reg

M2 A2BR

M1

ENT

T effector ENT Inflammation

Fibrosis

A2AR Reduced inflammation

Reduced fibrosis

Figure 3 | Adenosine signaling via A2AR and A2BR reduces inflammation. (Left panel) Renal injury promotes macrophage and T effector cell infiltration that is associated with increased inflammation and renal fibrosis. Cellular damage releases adenosine triphosphate (ATP), which is hydrolyzed to adenosine by extracellular CD39 and CD73. Equilibrative nucleoside transporter (ENT) removes adenosine from the extracellular space into the intracellular space and is distributed on the blood vessels and tubular cells. (Right panel) Adenosine signaling via A2AR and A2BR reduces infiltration of T-effector and M1 macrophages and promotes generation of regulatory T cells and M2 macrophages, which are associated with reduced inflammation and less fibrosis. 688

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chronic A2BR signaling may actually promote fibrosis. Mice deficient in adenosine deaminase (ADA  /  ) exhibit chronically elevated adenosine levels and develop glomerulosclerosis, interstitial fibrosis, and collagen deposition in renal tissue.66 This phenotype was associated with increased A2BR expression in the kidney and was attenuated by treatment with pegylated ADA or the selective A2BR inhibitor PSB-1115.66 A2BR expression in fibroblasts isolated from WT mouse kidneys was significantly upregulated by treatment with NECA, a potent nonselective adenosine receptor agonist. NECA also induced expression of interleukin-6 and secretion of collagen by the fibroblasts, an effect abolished by treatment with the A2BR inhibitor PSB-1115,66 and parallels changes observed in the lung.67 In the unilateral ureteric obstruction model, A2BR mRNA expression was upregulated in WT mice, and injury was attenuated in A2BRKO mice.66 Although interleukin-6 was implicated in A2BR-driven fibrosis in unilateral ureteric obstruction, others have shown that interleukin-6-deficient mice are not protected from fibrosis in this model.68 These conflicting data may reflect the role of other downstream pathways activated by A2BR, such as the potent vasoconstrictor endothelin-1 (see below). A2BR signaling also appears to have a role in the development of tubulointerstitial fibrosis in angiotensin IItreated mice. Angiotensin II infusion upregulates CD73 expression and reduces ADA activity, increasing the adenosine content within the kidney.26 The precise mechanism of CD73 upregulation by angiotensin II is not known, although it may involve the canonical pro-fibrotic factor TGF-b, which is induced by angiotensin II and increases CD73 expression and activity on tubular cells.69 The increased levels of adenosine in the angiotensin II infusion model are paralleled by an increase in A2BR mRNA expression and correlated with greater collagen deposition and proteinuria.26,66 Tubulointerstitial fibrosis was attenuated in CD73KO and A2BRKO mice, either by removal of adenosine through treatment with pegylated ADA or by inhibition of A2BR.26,66 One downstream effect of A2BR activation is an increase in the potent vasoconstrictor endothelin-1, which accumulates in the microvascular endothelium and potentiates renal fibrosis.26,70 Hypoxia secondary to vasoconstriction activates hypoxiainducible factor, which upregulates A2BR expression, creating a cycle of hypoxia and A2BR-mediated fibrosis. Indeed renal biopsy samples from patients with CKD demonstrate elevated levels of CD73 and A2BR mRNA expression compared with patients without CKD,26 implicating a pathogenic role for A2BR signaling in the progression of renal fibrosis. Diabetes is another experimental setting in which A2BR signaling has been implicated in the development of renal fibrosis. Increased glomerular injury and proteinuria is a stimulus for tubular injury and finally tubulointerstitial fibrosis with reduced renal function.71 Rat podocytes cultured in high glucose produce 10-fold higher extracellular adenosine,72 and adenosine levels in rat glomeruli are 6-fold higher in hyperglycemia compared with those in Kidney International (2014) 86, 685–692

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normoglycemia, mediated by an increase in the expression of CD73.73 CD73 expression and adenosine are also elevated in diabetic mice.74 Expression and activity of the equilibrative nucleoside transporters ENT-1 and -2 are reduced in diabetic rats,75 indicating a tendency for extracellular adenosine accumulation in hyperglycemia. Concurrently, hyperglycemia upregulates expression of hypoxia-inducible factor1a,76 which in turn upregulates expression of A2BR77 on mesangial cells and podocytes.73 Increased expression of A2BR, TGF-b,73 and vascular endothelial growth factor78 in rat glomeruli was associated with the development of glomerulosclerosis. Mesangial cells are transformed by TGFb to acquire the myofibroblast phenotype, characterized by a-smooth muscle actin expression and secretion of fibronectin (reviewed in Barnes and Gorin79). Inhibition of A2BR with the antagonist MRS1754 reduced the expression of TGF-b and vascular endothelial growth factor and inhibited the development of glomerulosclerosis.73,80 Cardenas et al 80 further demonstrated that A2BR signals through the downstream ERK and PKC pathway to increase the vascular endothelial growth factor expression. However, it has been reported recently that the absence of endothelial A2BR is associated with increased vascular endothelial growth factor levels and more severe diabetic nephropathy in a model of streptozotocin-induced diabetes.74 This highlights the complexity in understanding the variable effects of different cells that express the A2BR in diabetes. Of interest, Tak et al. 74 further demonstrated that infusion of BAY 60-6583 (previously recognized as an agonist of the A2BR) in a mouse model of streptozotocin-induced diabetes and in genetically diabetic Akita (Ins2 þ /  ) mice reduced the development of diabetic nephropathy. Recent studies from Mu¨ller’s laboratory in Germany81 have demonstrated that, in the presence of high levels of adenosine, BAY 60-6583 acts as an antagonist of the A2BR. So perhaps, in the diabetic mouse models above74 in which adenosine levels are inherently high, infusion of BAY 60-6583 may have led to the inhibition of the A2BR and subsequent protection from diabetic nephropathy. In humans, plasma adenosine levels were also higher in patients with diabetic nephropathy compared with that in patients with diabetes, but without renal involvement.82 Interestingly, CD39 polymorphisms have been shown to influence the susceptibility to diabetic nephropathy in African Americans with Type 2 diabetes.83 Two common polymorphisms (rs12763743 and rs3897983) were identified, which when used together specifically showed a strong association with the presence of diabetic nephropathy in this population. Cell lines derived from individuals homozygous for both polymorphisms expressed more CD39 mRNA,83 likely contributing to an increased generation of adenosine. Curiously, in mice null for Cd39 (NTPDase1), the absence of NTPDase1 removed an important protective mechanism relevant to diabetic nephropathy that modulates glomerular inflammation and thromboregulation.84 Understanding the role of adenosine in the progression of diabetic nephropathy may enable the development of new 689

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Metabolic injury (Hyperglycemia, angiotensin II) Increased adenosine A2BR

A2BR antagonist

Fibroblasts

Mesangial cells

ET-1 mediated vasoconstriction

Fibrosis Chronic hypoxia

A2BR

Figure 4 | Experimental models of hypertension and diabetes reveal increased adenosine generation and A2BR expression. A2BR activation on fibroblasts and mesangial cells promotes extracellular matrix deposition driving the development of renal fibrosis. Vasoconstriction mediated by endothelin-1 promotes hypoxia which is perpetuated by renal fibrosis. Chronic hypoxia further drives adenosine generation and A2BR activity, creating a vicious cycle of chronic hypoxia and renal fibrosis.

Table 2 | The impact of adenosine signaling on the development of renal fibrosis in animal models of kidney injury Outcome Rodent models of kidney injury

Intervention/genetic modification

Diabetic nephropathy

A2AR agonist A2BR antagonist CD39 KO mice Vascular endothelial deletion of A2BR A2AR agonist

Anti-glomerular basement membrane-induced glomerulonephritis Unilateral ureteric obstruction

A2AR KO mice

A2AR agonist A2BR KO mice Adriamycin nephropathy CD39 over-expression Angiotensin II–induced A2BR inhibitor/PEG-ADA hypertensive nephrosclerosis treatment/CD73KO mice Severe combined immune PEG-ADA treatment/A2BR deficient (SCID) mice inhibitor (ADA  /  )

Mechanism of action

Tubular injury

Reduced macrophage infiltration Reduced VEGF expression Reduced thromboregulation Increased VEGF

Reduced tubulointerstitial fibrosis Reduced glomerulitis Not examined Reduced glomerular sclerosis Not examined Increased glomerular sclerosis Not examined Increased glomerular sclerosis

45 80 84 74

Reduced macrophage infiltration

Reduced tubulointerstitial fibrosis Reduced glomerular sclerosis

44

Increased cellular infiltrate

Increased tubulointerstitial fibrosis No significant impact

48

Reduced CD4 þ cellular infiltrate Reduced IL-6 mediated injury Increased regulatory T-cell activity Reduced ET-1-mediated kidney injury Inhibition of fibroblast and tissue activity of A2BR

Reduced Reduced Reduced Reduced

No significant impact No significant impact Reduced glomerular sclerosis Reduced glomerular sclerosis

49 66 51 26

Reduced tubulointerstitial fibrosis Reduced glomerular sclerosis

66

tubulointerstitial tubulointerstitial tubulointerstitial tubulointerstitial

Glomerular injury

fibrosis fibrosis fibrosis fibrosis

Ref

Abbreviations: ADA, adenosine deaminase; ET-1, endothelin-1; IL-6, interleukin-6; PEG-ADA, pegylated ADA; VEGF, vascular endothelial growth factor.

therapies to prevent progression of glomerulosclerosis and tubulointerstitial fibrosis. Figure 4 depicts the putative pathway for A2BR-mediated renal fibrosis. THE YIN AND YANG OF ADENOSINE SIGNALING IN RENAL FIBROSIS

Tubulointerstitial fibrosis within the renal parenchyma leads to progressive CKD irrespective of the etiology of the fibrosis. Animal models have provided valuable insight into the varied role of adenosine signaling in the development of renal 690

fibrosis (summarized in Table 2). Signaling via A2AR mitigates inflammation, reducing renal tubulointerstitial fibrosis in inflammatory models of kidney injury (Figure 3). However, the accumulation of adenosine in certain conditions including hyperglycemia and increased angiotensin II can promote fibrosis via activation of A2BR on mesangial cells and fibroblasts in the kidney. A2BR activation also increases endothelin-1 expression and promotes vasoconstriction resulting in chronic hypoxia, which perpetuates fibrogenesis (Figure 4). Recognition of the dynamic and progressive Kidney International (2014) 86, 685–692

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nature of CKD may allow for therapeutic intervention. Targeting inflammation with A2AR agonists or targeting chronic hypoxia–induced fibrosis with A2BR antagonists may prove to be of clinical benefit. The challenge remains to identify such stages, given the clinically silent nature of progressive CKD, for the timely initiation of such agents. DISCLOSURE

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All the authors declared no competing interests.

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Kidney International (2014) 86, 685–692