AUTNEU-01758; No of Pages 6 Autonomic Neuroscience: Basic and Clinical xxx (2015) xxx–xxx
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Vascular and inflammatory actions of P2X receptors in renal injury Amelia R. Howarth, Bryan R. Conway, Matthew A. Bailey ⁎ British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, United Kingdom
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Available online xxxx Keywords: P2 receptors Renal inflammation Hypertension Pressure natriuresis Macrophage
a b s t r a c t P2 purinergic receptors are activated by extracellular ATP and subserve a plethora of roles in the body, including metabolism, inflammation and neuronal signalling. This review focuses on renal purinergic receptors and how different roles that they play may contribute to renal dysfunction and the progression of chronic kidney disease. Numerous studies have linked P2 receptors, particularly the P2X4R and P2X7R subtypes, to kidney injury and damage. However, the mechanisms underlying this association are not fully defined. Several studies show that activation of P2X4R and particularly P2X7R can have a pro-inflammatory effect, causing or exacerbating damage to renal tissue. However, clinical trials aiming to utilise P2X7R antagonists to treat inflammatory disease have been unsuccessful, and it is possible that other mechanisms besides inflammation tie P2X7R activation to disease progression. In this context, purinergic signalling is also involved in the control of vascular tone and our recent studies suggest that activation of P2X4R/P2X7R causes renal vascular dysfunction and contributes to chronic kidney disease. This brief review aims to summarise the complementary inflammatory and vascular roles of P2X receptors in the kidney, with emphasis on the subtypes P2X4R and P27XR, and how each contributes to and presents therapeutic targets in the progression of chronic kidney disease. © 2015 Elsevier B.V. All rights reserved.
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . . . . 1.1. Chronic kidney disease: hypoxia and inflammation 1.2. P2X receptors and renal disease . . . . . . . . . 2. P2X receptors and inflammation in kidney disease . . . . 3. P2X receptors and vascular dysfunction . . . . . . . . . 4. Clinical applications of P2X receptor antagonists . . . . . 5. Concluding remarks . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction In the forty years since their discovery, purinergic receptors have evolved from a contentious biological concept (Burnstock, 1972) to druggable targets for a number of diseases (Arulkumaran et al., 2011). In this brief review, we discuss the role of purinergic signalling within the kidney and briefly explore the role of P2X receptors (P2XR) in the progression of chronic kidney disease (CKD) via vascular and inflammatory pathways. (See Fig. 1.) ⁎ Corresponding author at: BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, EH16 4TJ, United Kingdom. Tel.: +44 131 242 9233. E-mail address: [email protected] (M.A. Bailey).
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Two categories of purinergic receptor are defined; P1, which bind adenosine and P2, which can be activated by purine or pyrimidine nucleotides. P2R are further subdivided: P2Y are G-protein coupled receptors and the 8 subtypes have differential selectivity for ATP, ADP, UTP and UDP; P2XR are ligand-gated ion channels (International Union of Basic and Clinical Pharmacology database: http://www. iuphar-db.org/) activated by ATP. Most P2R subtypes are expressed in the kidney and purinergic signalling exerts marked physiological effects on renal blood flow and epithelial transport properties, as reviewed in detail elsewhere (Burnstock et al., 2014; Shirley et al., 2013). It is increasingly recognised that ATP signalling via P2R contributes to a variety of pathophysiological conditions, ranging from hypertension (Menzies et al., 2015) to transplant rejection and polycystic kidney disease (Solini et al., 2013).
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Please cite this article as: Howarth, A.R., et al., Vascular and inflammatory actions of P2X receptors in renal injury, Auton. Neurosci. (2015), http:// dx.doi.org/10.1016/j.autneu.2015.05.001
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Fig. 1. Vascular and inflammatory pathways of establishing renal injury and the role that P2X4 receptors (R) and P2X7R may play in each. Expression of P2X4R and P2X7R on renal vascular may mediate vascular tone and hence renal blood flow and pressure. Increased expression of P2XR may lead to abnormal regulation of these functions and thus loss of microvasculature, hypoxia and renal injury. Expression of P2X4R and P2X7R on immune cells contributes to release and modulation of cytokines, such as interleukin (IL)-1β, IL-18 and tumour necrosis factor α (TNFα). Upregulation of these P2XR may lead to increased inflammation, which results in renal injury. SMC, smooth muscle cell.
In this review we focus on the role of P2XR in the onset and progression of CKD. CKD is a global disease affecting 10% of the population and its patients are one of the most ‘at-risk’ groups for the progression of cardiovascular diseases (Eckardt et al., 2013; Gansevoort et al., 2013). Diabetes and hypertension are leading risk factors for CKD, but this is a complex condition with many contributors to its progression, including hypoxia, inflammation and vascular dysfunction (Nakayama et al., 2011). Despite high socio-economic burden and widespread prevalence, treatment options for CKD are limited and hypertension remains the major modifiable risk factor for the disease. There is therefore an unmet need to identify new druggable targets to expand CKD treatment options (Remuzzi et al., 2013). P2XR may offer new avenues for treatment. P2X7R in particular has strong therapeutic potential: this receptor is expressed in cells of the immune system and plays a key role in the normal immune response (Lister et al., 2007). Aberrant P2X7R activation is linked to a number of inflammatory conditions and, as we discuss, CKD has a strong inflammatory component. 1.1. Chronic kidney disease: hypoxia and inflammation An extensive literature places sustained tubulointerstitial inflammation at the heart of CKD. Such inflammation primes the kidney for a cycle of injury and fibrosis and can impair the acute pressure natriuresis response (PN), the physiological processes through which the kidney regulates long-term blood pressure (BP) (Franco et al., 2013). Under normal circumstances, an increase in BP leads to increased renal arterial perfusion, which stimulates the kidney to excrete sodium, reducing
extracellular fluid volume and intravascular vascular volume and hence normalizing BP. If the PN response becomes impaired, long term BP control is lost, leading to hypertension. This is one way in which hypertension can be established and, under these circumstances, barotrauma of the renal microvasculature can provoke a further cycle of injury and inflammation (Ivy and Bailey, 2014). Subclinical inflammation and its effect on PN may therefore be a common early event on the pathway to renal injury. However, the process that initiates inflammation remains unclear. In 1998, one hypothesis was proposed that suggested CKD has causation at the vasculature. Fine and colleagues suggested that primary glomerular diseases, such as hypertension, lead to alterations in microvasculature which compromises renal blood supply, generating a local hypoxic environment at the tubule-interstitium. Hypoxia encourages production of hypoxia-inducible factor-1α, which acts as a transcription factor for a multitude of pro-fibrotic factors that act to build the extracellular matrix, induce fibrosis and promote further loss of vasculature and decline of renal blood flow (Norman and Fine, 2006). Thus, the ‘chronic hypoxia hypothesis’ posits that renal microvascular dysfunction and/or rarefaction creates a hostile, pro-inflammatory environment in the renal medulla and locks the kidney in a cycle of declining renal function (Fine et al., 1998). Whether or not this cycle of progressive renal disease has a single point of entry is not established but it is likely that interstitial inflammation is an important early event underlying vascular dysfunction (Johnson et al., 2005; Rodríguez-Iturbe et al., 2014). Anti-inflammatory strategies can restore the acute PN response and improve blood pressure
Please cite this article as: Howarth, A.R., et al., Vascular and inflammatory actions of P2X receptors in renal injury, Auton. Neurosci. (2015), http:// dx.doi.org/10.1016/j.autneu.2015.05.001
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control in hypertensive rodents (Franco et al., 2013; Ji et al., 2012a, 2012b). In the rest of this review we discuss how P2R signalling contributes to these events and highlight pathways linking P2XR activation to kidney disease. 1.2. P2X receptors and renal disease Purinergic receptors are present in both renal vascular tissue and immune cells and the role of P2XR in both locations has been explored (Lewis and Evans, 2001; Menzies et al., 2013; North, 2002). Increased P2X4R and P2X7R activation in particular are strongly associated with kidney disease and elevated expression of these receptors in the “normal” state increases the susceptibility to hypertensive renal vascular injury (Menzies et al., 2013). P2X7R expression is also upregulated in rodent models of type 1 diabetes and hypertension, as well as in human and experimental glomerulonephritis (Taylor et al., 2009; Turner et al., 2007; Vonend et al., 2004). Human studies are limited, but genetic association studies in human populations have uncovered significant association between a singular P2X7 single nuclear polymorphism and increased blood pressure (Palomino-Doza et al., 2008). This research points towards the idea that it may be hypertension that builds a ‘bridge’ between upregulated P2XR expression, particularly P2X7R, and development of CKD. Many theories have been proposed to explain the progression of CKD and the role of hypertension within that progression. In this review we discuss the “vascular” and the “inflammatory”, which are predicated on either vascular physiological dysfunction or localised tissue inflammation as the initial disease mechanism. Both possibilities are discussed, with emphasis on P2XR as the mediators of these effects. It is likely however, that there is considerable interaction between vascular and inflammatory events. 2. P2X receptors and inflammation in kidney disease Enhanced P2XR signalling has long been thought to be contributory in chronic inflammatory disease (Turner et al., 2009). P2X7R is expressed on many immune cells, including macrophages and other antigen-presenting cells (Surprenant et al., 1996). Activation of P2X7R on such cells via ATP leads to release of interleukin-1β (IL-1β), interleukin-18 (IL-18) and tumour necrosis factor α which generate a pro-inflammatory environment conducive to kidney tissue degeneration, injury and cell death (Fadok et al., 1998; Gonçalves et al., 2006; Le Feuvre et al., 2002; Pelegrin and Surprenant, 2006). This effect is mediated through activation of the NLPR3 inflammasome, potentially by a P2X7R/P2X4R/pannexin-1 complex that initiates pore formation, priming the cell for apoptosis (Hung et al., 2013; Pelegrin and Surprenant, 2006; Solini et al., 2013). P2X7R blockade actually protects against renal nephrotoxic injury by reducing inflammatory response, reducing apoptosis and the NLRP3 inflammasome (Yan et al., 2015; Zhang et al., 2014). By regulating cell death in this way, P2X7R can regulate the turnover of the cells upon which it is expressed, including granulocytes (Le Feuvre et al., 2002; Wang et al., 2004). Granulocytes, such as leukocytes, are vital in the normal regulation of a sustained inflammation, and dysregulation can promote disease (Walker et al., 2005). Indeed, scid mice lacking lymphocytes show an attenuated hypertensive phenotype upon angiotensin II administration (Crowley et al., 2010). Furthermore, P2X7R deficient mice lack leukocyte responses to ATP seen in wild type mice and exhibit attenuated inflammatory responses, renal injury and hypertension (Ji et al., 2012b; Labasi et al., 2002). Add to this the finding that administration of the immunosuppressant, mycophenolate mofetil, in hypertensive mice leads to rescue of an impaired PN response, a key regulator of long term blood pressure (Franco et al., 2013). However, P2X7R is not the only purinergic receptor that may contribute in such scenarios. A recent study found increased expression of P2X4R in renal tubule cells from patients with diabetic nephropathy
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(Chen et al., 2013). P2X4R-mediated activation of the NLRP3 inflammasome in ex vivo cell studies and receptor expression had a strong positive correlation with renal excretion of IL-1β in diabetic patients. P2X4R also promotes apoptosis in human mesangial cells (Solini et al., 2013), a process that contributes to glomerular injury in chronic renal disease. P2X4R deficient mice are also protected against inflammation in models of arthritis (Li et al., 2014): it's role in kidney disease is not clear as a recent study found that P2X4R deficient mice displayed an exaggerated injury response to unilateral ureteric obstruction, a model of chronic renal inflammatory disease (Kim et al., 2014). These contrasting results highlight the complexity of inflammation and fibrosis and the roles individual receptors may play therein. The most likely explanation for such discrepancy is the delicate balance between immune cell-mediated pathways, in which activation of different macrophage types such as M1 pro-inflammatory macrophages and M2 pro-fibrotic macrophages largely dictate the end result (Lee et al., 2011). Further insight into pathway-specific macrophages and their roles in renal disease progression is required to pick apart this conundrum. P2X4R and P2X7R are also expressed in a variety of other, nonimmune, cell types including both vascular and tubular structures in the kidney (Shirley et al., 2013). The expression and roles of these receptors in the renal vasculature is discussed in more detail below. P2X4R is expressed throughout the tubule but its underlying physiological role is not fully delineated. P2X4R may influence sodium transport mediated by the epithelial sodium channel (Wildman et al., 2005; Zhang et al., 2007). The actions of tubular P2X7R are even less clear and such expression is normally very low. However, injured renal cells can promote necrotic death of interstitial fibroblasts through release of ATP and activation of P2X7R (Ponnusamy et al., 2011), hindering the ability of the kidney to recover following injury. Despite substantial existing evidence supporting the inflammatory role of P2X7R in renal injury and disease, exploiting P2X7R antagonists in clinical trials for basic inflammatory diseases, such as rheumatoid arthritis, have failed, with no significant benefit of using the drug seen compared to the placebo (Arulkumaran et al., 2011; Keystone et al., 2012; Stock et al., 2012). This indicates that there are other pathways acting in such diseases that may act independently of inflammation to drive the pathological phenotype. 3. P2X receptors and vascular dysfunction One promising complementary contributor of P2XR to renal disease is their vascular role. The vasoactive effects of nucleotides have been well-documented and whether constriction or dilation of vessels is stimulated depends on a number of factors. The source of ATP, location or type of P2R and the basal vascular tone all influence the overall effect. In terms of renal disease, P2R are involved in key regulatory processes in the kidney which, if disrupted, can have significant effects on renal function. P2X1R, for example, is a key mediator of autoregulation in the kidney (Inscho et al., 2003). Upon increased systemic BP, increase in renal blood flow is buffered by P2X1R-mediated vasoconstriction in the afferent arteriole, protecting the glomerulus from pressure induced injury. Vessels from P2X1R null mice exhibit blunted vasoconstriction which leads to failure of autoregulation and resultant barotrauma (Inscho et al., 2003). Autoregulation is a vital process in the kidney, but has been shown to be more effective in the cortex than the medulla, meaning that increased renal perfusion will increase blood flow in the vasa recta (Cowley et al., 1992). An increase in BP in the medullary vasa recta leads to release of nitric oxide (NO) via a sheer stress response, which promotes sodium retention, leading to an impaired PN and thus hypertension and injury (O'Conner and Cowley Jr., 2010). Indeed, inhibition of NO release under these circumstances reduces medullary blood flow (Mattson et al., 1992). However, NO inhibition does not alter the PN response, suggesting that NO is not the sole mediator of a renal injury
Please cite this article as: Howarth, A.R., et al., Vascular and inflammatory actions of P2X receptors in renal injury, Auton. Neurosci. (2015), http:// dx.doi.org/10.1016/j.autneu.2015.05.001
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observed following a medullary BP increase. Under these circumstances, ATP and purinergic receptors may also contribute to a disease phenotype and evidence for this is building, including findings of P2XR expression in the microvasculature. P2X1R, P2X4R and P2X7R have all been identified in rat renal vessels (Lewis and Evans, 2001) with P2X4R and P2X7R expression observed in the pre-glomerular microvasculature as well as in the smooth muscle of larger vessels (Menzies et al., 2013). In human endothelial cells, P2X4R is identified as the most abundant P2XR, followed by P2X7R (Yamamoto et al., 2000b). The observation of these receptors in both the smooth muscle and endothelial layers of vasculature imply direct roles in both signalling and vascular tone. These findings therefore strongly suggest a major role for P2XR in the renal vasculature, both physiologically and pathophysiologically. In terms of vasoactivity, P2X4R has a vasodilatory effect, consistent with its role in NO release (Yamamoto et al., 2006), but has also been shown to act in conjunction with P2X1R to cause sustained constriction in cerebral arteries and regulate vascular tone in renal smooth muscle cells (Harhun et al., 2010, 2014). P2X7R has been shown to cause vasoconstriction in rat retinal vessels via pericytes, with similar vasoactive roles suggested in the kidney (Kawamura et al., 2003; Menzies et al., 2013). Blockade of P2XR leads to altered control of pericyte-mediated vascular tone in the kidney (Crawford et al., 2013) and picking apart the role of each P2XR subtype could give great insight into the contribution of these receptors to modulated vasoactivity and thus, BP and renal injury. Evidence of P2XR vascular involvement in renal pathophysiology is also building. Both P2X4R and P2X7R have been identified via microarray analysis as key molecules in renal injury susceptibility in rodents, presenting a pathophysiological function (Menzies et al., 2013). P2X4R deficiency has been shown to induce loss of BP control in response to altered blood flow, presenting a primary candidate for the correlation between renal ATP levels and vascular resistance (Nishiyama et al., 2000; Yamamoto et al., 2006). P2X4R has also been identified as a receptor that mediates NO release under shear stress, meaning that its dysregulation could have severe effects of sodium control and hence BP control (Yamamoto et al., 2000a). These studies provide evidence for the role of P2XR in renal vasculature control, with strong support that impaired control through these receptors may have consequences for PN, hypertension and resultant renal injury. This is shown most clearly by Ji and colleagues whereby P2X7R deficiency in DOCA-salt treated mice and P2X7R inhibition in Dahl salt-sensitive rats both lead to attenuated hypertension and, although the authors suggest an inflammatory mechanism behind this, the studies portrayed here suggest an alternative vascular explanation (Ji et al., 2012a,2012b). P2X7R deficiency in mice has been implicated in lipopolysaccharideinduced vascular dysfunction, reducing downstream production of inflammatory agents (Chiao et al., 2008, 2013), further supporting the theory that P2XR-mediated vascular dysfunction is the priming step in the setup of CKD. However, the vasoactivity of these receptors on different vessels and vascular surfaces needs to be further clarified before any solid mechanisms can be revealed: inflammatory or vascular.
trials have failed, rather than what the role of each individual sub-type of P2XR is. For example, it is evident that these receptors do not act alone. Weinhold and colleagues have shown that knock down of P2X4R increases mRNA levels of P2X7R and vice versa in mouse lung epithelial cells (Weinhold et al., 2010). A contrasting effect has been seen in mouse kidneys where P2X4R deficiency leads to a reduction in P2X7R mRNA (Craigie et al., 2013). Although in these cases, opposite effects are seen, this is likely tissue dependant and shows the influence that each receptor has over the other, which may be compensatory under certain biological circumstances. P2X4R can also modulate the efficacy of P2X7R-mediated inflammation, which is enhanced when P2X4R is knocked down in macrophages (Kawano et al., 2012). When coexpressed in HEK cells, P2X4R and P2X7R response to ATP, as monitored by fluorescent dye uptake, is altered compared to single expression of each (Casas-Pruneda et al., 2009). These studies, and more (as reviewed by Craigie et al., 2013), exhibit the functional relationship between the two receptors, and as a result, there has been much speculation on whether the two receptors in fact physically interact. Functional P2XR are comprised of three different subunits, forming one functional heterotrimeric receptor (Kawate et al., 2009). It was originally believed that P2X7R could not form a heterotrimer with other subunits in this fashion and only formed homotrimeric receptors made entirely of P2X7R (Torres et al., 1999). However, recent research has suggested otherwise. One study has suggested that a previously undefined epithelial P2XR in the airways is actually comprised of both P2X4R and P2X7R subunits (Ma et al., 2006). Further studies have used co-immunoprecipitation to support this theory, also suggesting that P2X4R and P2X7R form heterotrimeric receptors (Guo et al., 2007). However, other groups have proposed that the subunits remain separate interacting only as individual, homotrimeric receptors (Antonio et al., 2011; Nicke, 2008). Elucidating the functional and physical interaction between the P2X4R and P2X7R will provide insight into the clinical applications of antagonists as the nature of any interaction observed will affect pharmacokinetic requirements of therapeutic drugs. It is possible that both receptors may require simultaneous targeting in clinical trials to effectively combat their associated detrimental effects in renal disease. There is additional complexity in studying these receptors, as a number of splice variants of P2X7R have also been reported, both in rodents and humans (Cheewatrakoolpong et al., 2005; Masin et al., 2012). Such splice variants have been deemed responsible for a range of altered phenotypes, including varied pain responses, differential response to agonists and even mistargeted gene knockout (Hansen et al., 2011; Nicke et al., 2009; Xu et al., 2012). P2X7R splice variants have also been shown to vary in their interaction with pannexin-1, which, as mentioned, plays an important role in the inflammatory action of P2X7R (Hung et al., 2013; Pelegrin and Surprenant, 2006; Xu et al., 2012). The number of splice variants observed across different species and the functional significance they may have in disease is still unclear and must be further investigated in order to effectively target any unfavourable action of P2X7R.
4. Clinical applications of P2X receptor antagonists 5. Concluding remarks The arguments for the inflammatory roles of P2XR versus their vascular role in CKD have been proposed, yet the likelihood is that they work in conjunction, especially since clinical trials for the P2X7R antagonists, AZD9056 and CE-224,535, in inflammatory treatment have thus far failed to show any benefit over the placebo (Keystone et al., 2012; Stock et al., 2012). Although P2X7R antagonists have been shown to be well-tolerated in humans, inefficacy of the drug have prevented progression of these clinical trials beyond Phase 3 (Arulkumaran et al., 2011). Under such circumstances, it may be more sensible to take a clinical perspective on this and question why these
Although purinergic receptors are now recognised as biologically important molecules and many of their roles in the body have been elucidated, their complexity and variety have presented a challenging field of research. Even with convincing rodent studies, the underperformance of P2X7R antagonists in clinical trials serve as a reminder of this complexity. However, as they remain promising drug targets for many diseases including CKD, P2XR research will continue to be vigorously pursued. With further insight into the genetic regulation of P2X4R and P2X7R expression and continued studies into their interaction, it is feasible that
Please cite this article as: Howarth, A.R., et al., Vascular and inflammatory actions of P2X receptors in renal injury, Auton. Neurosci. (2015), http:// dx.doi.org/10.1016/j.autneu.2015.05.001
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Contents lists available at ScienceDirect
Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu
Vascular and inflammatory actions of P2X receptors in renal injury Amelia R. Howarth, Bryan R. Conway, Matthew A. Bailey ⁎ British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, United Kingdom
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Available online xxxx Keywords: P2 receptors Renal inflammation Hypertension Pressure natriuresis Macrophage
a b s t r a c t P2 purinergic receptors are activated by extracellular ATP and subserve a plethora of roles in the body, including metabolism, inflammation and neuronal signalling. This review focuses on renal purinergic receptors and how different roles that they play may contribute to renal dysfunction and the progression of chronic kidney disease. Numerous studies have linked P2 receptors, particularly the P2X4R and P2X7R subtypes, to kidney injury and damage. However, the mechanisms underlying this association are not fully defined. Several studies show that activation of P2X4R and particularly P2X7R can have a pro-inflammatory effect, causing or exacerbating damage to renal tissue. However, clinical trials aiming to utilise P2X7R antagonists to treat inflammatory disease have been unsuccessful, and it is possible that other mechanisms besides inflammation tie P2X7R activation to disease progression. In this context, purinergic signalling is also involved in the control of vascular tone and our recent studies suggest that activation of P2X4R/P2X7R causes renal vascular dysfunction and contributes to chronic kidney disease. This brief review aims to summarise the complementary inflammatory and vascular roles of P2X receptors in the kidney, with emphasis on the subtypes P2X4R and P27XR, and how each contributes to and presents therapeutic targets in the progression of chronic kidney disease. © 2015 Elsevier B.V. All rights reserved.
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . . . . 1.1. Chronic kidney disease: hypoxia and inflammation 1.2. P2X receptors and renal disease . . . . . . . . . 2. P2X receptors and inflammation in kidney disease . . . . 3. P2X receptors and vascular dysfunction . . . . . . . . . 4. Clinical applications of P2X receptor antagonists . . . . . 5. Concluding remarks . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction In the forty years since their discovery, purinergic receptors have evolved from a contentious biological concept (Burnstock, 1972) to druggable targets for a number of diseases (Arulkumaran et al., 2011). In this brief review, we discuss the role of purinergic signalling within the kidney and briefly explore the role of P2X receptors (P2XR) in the progression of chronic kidney disease (CKD) via vascular and inflammatory pathways. (See Fig. 1.) ⁎ Corresponding author at: BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, EH16 4TJ, United Kingdom. Tel.: +44 131 242 9233. E-mail address: [email protected] (M.A. Bailey).
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Two categories of purinergic receptor are defined; P1, which bind adenosine and P2, which can be activated by purine or pyrimidine nucleotides. P2R are further subdivided: P2Y are G-protein coupled receptors and the 8 subtypes have differential selectivity for ATP, ADP, UTP and UDP; P2XR are ligand-gated ion channels (International Union of Basic and Clinical Pharmacology database: http://www. iuphar-db.org/) activated by ATP. Most P2R subtypes are expressed in the kidney and purinergic signalling exerts marked physiological effects on renal blood flow and epithelial transport properties, as reviewed in detail elsewhere (Burnstock et al., 2014; Shirley et al., 2013). It is increasingly recognised that ATP signalling via P2R contributes to a variety of pathophysiological conditions, ranging from hypertension (Menzies et al., 2015) to transplant rejection and polycystic kidney disease (Solini et al., 2013).
http://dx.doi.org/10.1016/j.autneu.2015.05.001 1566-0702/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Howarth, A.R., et al., Vascular and inflammatory actions of P2X receptors in renal injury, Auton. Neurosci. (2015), http:// dx.doi.org/10.1016/j.autneu.2015.05.001
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Fig. 1. Vascular and inflammatory pathways of establishing renal injury and the role that P2X4 receptors (R) and P2X7R may play in each. Expression of P2X4R and P2X7R on renal vascular may mediate vascular tone and hence renal blood flow and pressure. Increased expression of P2XR may lead to abnormal regulation of these functions and thus loss of microvasculature, hypoxia and renal injury. Expression of P2X4R and P2X7R on immune cells contributes to release and modulation of cytokines, such as interleukin (IL)-1β, IL-18 and tumour necrosis factor α (TNFα). Upregulation of these P2XR may lead to increased inflammation, which results in renal injury. SMC, smooth muscle cell.
In this review we focus on the role of P2XR in the onset and progression of CKD. CKD is a global disease affecting 10% of the population and its patients are one of the most ‘at-risk’ groups for the progression of cardiovascular diseases (Eckardt et al., 2013; Gansevoort et al., 2013). Diabetes and hypertension are leading risk factors for CKD, but this is a complex condition with many contributors to its progression, including hypoxia, inflammation and vascular dysfunction (Nakayama et al., 2011). Despite high socio-economic burden and widespread prevalence, treatment options for CKD are limited and hypertension remains the major modifiable risk factor for the disease. There is therefore an unmet need to identify new druggable targets to expand CKD treatment options (Remuzzi et al., 2013). P2XR may offer new avenues for treatment. P2X7R in particular has strong therapeutic potential: this receptor is expressed in cells of the immune system and plays a key role in the normal immune response (Lister et al., 2007). Aberrant P2X7R activation is linked to a number of inflammatory conditions and, as we discuss, CKD has a strong inflammatory component. 1.1. Chronic kidney disease: hypoxia and inflammation An extensive literature places sustained tubulointerstitial inflammation at the heart of CKD. Such inflammation primes the kidney for a cycle of injury and fibrosis and can impair the acute pressure natriuresis response (PN), the physiological processes through which the kidney regulates long-term blood pressure (BP) (Franco et al., 2013). Under normal circumstances, an increase in BP leads to increased renal arterial perfusion, which stimulates the kidney to excrete sodium, reducing
extracellular fluid volume and intravascular vascular volume and hence normalizing BP. If the PN response becomes impaired, long term BP control is lost, leading to hypertension. This is one way in which hypertension can be established and, under these circumstances, barotrauma of the renal microvasculature can provoke a further cycle of injury and inflammation (Ivy and Bailey, 2014). Subclinical inflammation and its effect on PN may therefore be a common early event on the pathway to renal injury. However, the process that initiates inflammation remains unclear. In 1998, one hypothesis was proposed that suggested CKD has causation at the vasculature. Fine and colleagues suggested that primary glomerular diseases, such as hypertension, lead to alterations in microvasculature which compromises renal blood supply, generating a local hypoxic environment at the tubule-interstitium. Hypoxia encourages production of hypoxia-inducible factor-1α, which acts as a transcription factor for a multitude of pro-fibrotic factors that act to build the extracellular matrix, induce fibrosis and promote further loss of vasculature and decline of renal blood flow (Norman and Fine, 2006). Thus, the ‘chronic hypoxia hypothesis’ posits that renal microvascular dysfunction and/or rarefaction creates a hostile, pro-inflammatory environment in the renal medulla and locks the kidney in a cycle of declining renal function (Fine et al., 1998). Whether or not this cycle of progressive renal disease has a single point of entry is not established but it is likely that interstitial inflammation is an important early event underlying vascular dysfunction (Johnson et al., 2005; Rodríguez-Iturbe et al., 2014). Anti-inflammatory strategies can restore the acute PN response and improve blood pressure
Please cite this article as: Howarth, A.R., et al., Vascular and inflammatory actions of P2X receptors in renal injury, Auton. Neurosci. (2015), http:// dx.doi.org/10.1016/j.autneu.2015.05.001
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control in hypertensive rodents (Franco et al., 2013; Ji et al., 2012a, 2012b). In the rest of this review we discuss how P2R signalling contributes to these events and highlight pathways linking P2XR activation to kidney disease. 1.2. P2X receptors and renal disease Purinergic receptors are present in both renal vascular tissue and immune cells and the role of P2XR in both locations has been explored (Lewis and Evans, 2001; Menzies et al., 2013; North, 2002). Increased P2X4R and P2X7R activation in particular are strongly associated with kidney disease and elevated expression of these receptors in the “normal” state increases the susceptibility to hypertensive renal vascular injury (Menzies et al., 2013). P2X7R expression is also upregulated in rodent models of type 1 diabetes and hypertension, as well as in human and experimental glomerulonephritis (Taylor et al., 2009; Turner et al., 2007; Vonend et al., 2004). Human studies are limited, but genetic association studies in human populations have uncovered significant association between a singular P2X7 single nuclear polymorphism and increased blood pressure (Palomino-Doza et al., 2008). This research points towards the idea that it may be hypertension that builds a ‘bridge’ between upregulated P2XR expression, particularly P2X7R, and development of CKD. Many theories have been proposed to explain the progression of CKD and the role of hypertension within that progression. In this review we discuss the “vascular” and the “inflammatory”, which are predicated on either vascular physiological dysfunction or localised tissue inflammation as the initial disease mechanism. Both possibilities are discussed, with emphasis on P2XR as the mediators of these effects. It is likely however, that there is considerable interaction between vascular and inflammatory events. 2. P2X receptors and inflammation in kidney disease Enhanced P2XR signalling has long been thought to be contributory in chronic inflammatory disease (Turner et al., 2009). P2X7R is expressed on many immune cells, including macrophages and other antigen-presenting cells (Surprenant et al., 1996). Activation of P2X7R on such cells via ATP leads to release of interleukin-1β (IL-1β), interleukin-18 (IL-18) and tumour necrosis factor α which generate a pro-inflammatory environment conducive to kidney tissue degeneration, injury and cell death (Fadok et al., 1998; Gonçalves et al., 2006; Le Feuvre et al., 2002; Pelegrin and Surprenant, 2006). This effect is mediated through activation of the NLPR3 inflammasome, potentially by a P2X7R/P2X4R/pannexin-1 complex that initiates pore formation, priming the cell for apoptosis (Hung et al., 2013; Pelegrin and Surprenant, 2006; Solini et al., 2013). P2X7R blockade actually protects against renal nephrotoxic injury by reducing inflammatory response, reducing apoptosis and the NLRP3 inflammasome (Yan et al., 2015; Zhang et al., 2014). By regulating cell death in this way, P2X7R can regulate the turnover of the cells upon which it is expressed, including granulocytes (Le Feuvre et al., 2002; Wang et al., 2004). Granulocytes, such as leukocytes, are vital in the normal regulation of a sustained inflammation, and dysregulation can promote disease (Walker et al., 2005). Indeed, scid mice lacking lymphocytes show an attenuated hypertensive phenotype upon angiotensin II administration (Crowley et al., 2010). Furthermore, P2X7R deficient mice lack leukocyte responses to ATP seen in wild type mice and exhibit attenuated inflammatory responses, renal injury and hypertension (Ji et al., 2012b; Labasi et al., 2002). Add to this the finding that administration of the immunosuppressant, mycophenolate mofetil, in hypertensive mice leads to rescue of an impaired PN response, a key regulator of long term blood pressure (Franco et al., 2013). However, P2X7R is not the only purinergic receptor that may contribute in such scenarios. A recent study found increased expression of P2X4R in renal tubule cells from patients with diabetic nephropathy
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(Chen et al., 2013). P2X4R-mediated activation of the NLRP3 inflammasome in ex vivo cell studies and receptor expression had a strong positive correlation with renal excretion of IL-1β in diabetic patients. P2X4R also promotes apoptosis in human mesangial cells (Solini et al., 2013), a process that contributes to glomerular injury in chronic renal disease. P2X4R deficient mice are also protected against inflammation in models of arthritis (Li et al., 2014): it's role in kidney disease is not clear as a recent study found that P2X4R deficient mice displayed an exaggerated injury response to unilateral ureteric obstruction, a model of chronic renal inflammatory disease (Kim et al., 2014). These contrasting results highlight the complexity of inflammation and fibrosis and the roles individual receptors may play therein. The most likely explanation for such discrepancy is the delicate balance between immune cell-mediated pathways, in which activation of different macrophage types such as M1 pro-inflammatory macrophages and M2 pro-fibrotic macrophages largely dictate the end result (Lee et al., 2011). Further insight into pathway-specific macrophages and their roles in renal disease progression is required to pick apart this conundrum. P2X4R and P2X7R are also expressed in a variety of other, nonimmune, cell types including both vascular and tubular structures in the kidney (Shirley et al., 2013). The expression and roles of these receptors in the renal vasculature is discussed in more detail below. P2X4R is expressed throughout the tubule but its underlying physiological role is not fully delineated. P2X4R may influence sodium transport mediated by the epithelial sodium channel (Wildman et al., 2005; Zhang et al., 2007). The actions of tubular P2X7R are even less clear and such expression is normally very low. However, injured renal cells can promote necrotic death of interstitial fibroblasts through release of ATP and activation of P2X7R (Ponnusamy et al., 2011), hindering the ability of the kidney to recover following injury. Despite substantial existing evidence supporting the inflammatory role of P2X7R in renal injury and disease, exploiting P2X7R antagonists in clinical trials for basic inflammatory diseases, such as rheumatoid arthritis, have failed, with no significant benefit of using the drug seen compared to the placebo (Arulkumaran et al., 2011; Keystone et al., 2012; Stock et al., 2012). This indicates that there are other pathways acting in such diseases that may act independently of inflammation to drive the pathological phenotype. 3. P2X receptors and vascular dysfunction One promising complementary contributor of P2XR to renal disease is their vascular role. The vasoactive effects of nucleotides have been well-documented and whether constriction or dilation of vessels is stimulated depends on a number of factors. The source of ATP, location or type of P2R and the basal vascular tone all influence the overall effect. In terms of renal disease, P2R are involved in key regulatory processes in the kidney which, if disrupted, can have significant effects on renal function. P2X1R, for example, is a key mediator of autoregulation in the kidney (Inscho et al., 2003). Upon increased systemic BP, increase in renal blood flow is buffered by P2X1R-mediated vasoconstriction in the afferent arteriole, protecting the glomerulus from pressure induced injury. Vessels from P2X1R null mice exhibit blunted vasoconstriction which leads to failure of autoregulation and resultant barotrauma (Inscho et al., 2003). Autoregulation is a vital process in the kidney, but has been shown to be more effective in the cortex than the medulla, meaning that increased renal perfusion will increase blood flow in the vasa recta (Cowley et al., 1992). An increase in BP in the medullary vasa recta leads to release of nitric oxide (NO) via a sheer stress response, which promotes sodium retention, leading to an impaired PN and thus hypertension and injury (O'Conner and Cowley Jr., 2010). Indeed, inhibition of NO release under these circumstances reduces medullary blood flow (Mattson et al., 1992). However, NO inhibition does not alter the PN response, suggesting that NO is not the sole mediator of a renal injury
Please cite this article as: Howarth, A.R., et al., Vascular and inflammatory actions of P2X receptors in renal injury, Auton. Neurosci. (2015), http:// dx.doi.org/10.1016/j.autneu.2015.05.001
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observed following a medullary BP increase. Under these circumstances, ATP and purinergic receptors may also contribute to a disease phenotype and evidence for this is building, including findings of P2XR expression in the microvasculature. P2X1R, P2X4R and P2X7R have all been identified in rat renal vessels (Lewis and Evans, 2001) with P2X4R and P2X7R expression observed in the pre-glomerular microvasculature as well as in the smooth muscle of larger vessels (Menzies et al., 2013). In human endothelial cells, P2X4R is identified as the most abundant P2XR, followed by P2X7R (Yamamoto et al., 2000b). The observation of these receptors in both the smooth muscle and endothelial layers of vasculature imply direct roles in both signalling and vascular tone. These findings therefore strongly suggest a major role for P2XR in the renal vasculature, both physiologically and pathophysiologically. In terms of vasoactivity, P2X4R has a vasodilatory effect, consistent with its role in NO release (Yamamoto et al., 2006), but has also been shown to act in conjunction with P2X1R to cause sustained constriction in cerebral arteries and regulate vascular tone in renal smooth muscle cells (Harhun et al., 2010, 2014). P2X7R has been shown to cause vasoconstriction in rat retinal vessels via pericytes, with similar vasoactive roles suggested in the kidney (Kawamura et al., 2003; Menzies et al., 2013). Blockade of P2XR leads to altered control of pericyte-mediated vascular tone in the kidney (Crawford et al., 2013) and picking apart the role of each P2XR subtype could give great insight into the contribution of these receptors to modulated vasoactivity and thus, BP and renal injury. Evidence of P2XR vascular involvement in renal pathophysiology is also building. Both P2X4R and P2X7R have been identified via microarray analysis as key molecules in renal injury susceptibility in rodents, presenting a pathophysiological function (Menzies et al., 2013). P2X4R deficiency has been shown to induce loss of BP control in response to altered blood flow, presenting a primary candidate for the correlation between renal ATP levels and vascular resistance (Nishiyama et al., 2000; Yamamoto et al., 2006). P2X4R has also been identified as a receptor that mediates NO release under shear stress, meaning that its dysregulation could have severe effects of sodium control and hence BP control (Yamamoto et al., 2000a). These studies provide evidence for the role of P2XR in renal vasculature control, with strong support that impaired control through these receptors may have consequences for PN, hypertension and resultant renal injury. This is shown most clearly by Ji and colleagues whereby P2X7R deficiency in DOCA-salt treated mice and P2X7R inhibition in Dahl salt-sensitive rats both lead to attenuated hypertension and, although the authors suggest an inflammatory mechanism behind this, the studies portrayed here suggest an alternative vascular explanation (Ji et al., 2012a,2012b). P2X7R deficiency in mice has been implicated in lipopolysaccharideinduced vascular dysfunction, reducing downstream production of inflammatory agents (Chiao et al., 2008, 2013), further supporting the theory that P2XR-mediated vascular dysfunction is the priming step in the setup of CKD. However, the vasoactivity of these receptors on different vessels and vascular surfaces needs to be further clarified before any solid mechanisms can be revealed: inflammatory or vascular.
trials have failed, rather than what the role of each individual sub-type of P2XR is. For example, it is evident that these receptors do not act alone. Weinhold and colleagues have shown that knock down of P2X4R increases mRNA levels of P2X7R and vice versa in mouse lung epithelial cells (Weinhold et al., 2010). A contrasting effect has been seen in mouse kidneys where P2X4R deficiency leads to a reduction in P2X7R mRNA (Craigie et al., 2013). Although in these cases, opposite effects are seen, this is likely tissue dependant and shows the influence that each receptor has over the other, which may be compensatory under certain biological circumstances. P2X4R can also modulate the efficacy of P2X7R-mediated inflammation, which is enhanced when P2X4R is knocked down in macrophages (Kawano et al., 2012). When coexpressed in HEK cells, P2X4R and P2X7R response to ATP, as monitored by fluorescent dye uptake, is altered compared to single expression of each (Casas-Pruneda et al., 2009). These studies, and more (as reviewed by Craigie et al., 2013), exhibit the functional relationship between the two receptors, and as a result, there has been much speculation on whether the two receptors in fact physically interact. Functional P2XR are comprised of three different subunits, forming one functional heterotrimeric receptor (Kawate et al., 2009). It was originally believed that P2X7R could not form a heterotrimer with other subunits in this fashion and only formed homotrimeric receptors made entirely of P2X7R (Torres et al., 1999). However, recent research has suggested otherwise. One study has suggested that a previously undefined epithelial P2XR in the airways is actually comprised of both P2X4R and P2X7R subunits (Ma et al., 2006). Further studies have used co-immunoprecipitation to support this theory, also suggesting that P2X4R and P2X7R form heterotrimeric receptors (Guo et al., 2007). However, other groups have proposed that the subunits remain separate interacting only as individual, homotrimeric receptors (Antonio et al., 2011; Nicke, 2008). Elucidating the functional and physical interaction between the P2X4R and P2X7R will provide insight into the clinical applications of antagonists as the nature of any interaction observed will affect pharmacokinetic requirements of therapeutic drugs. It is possible that both receptors may require simultaneous targeting in clinical trials to effectively combat their associated detrimental effects in renal disease. There is additional complexity in studying these receptors, as a number of splice variants of P2X7R have also been reported, both in rodents and humans (Cheewatrakoolpong et al., 2005; Masin et al., 2012). Such splice variants have been deemed responsible for a range of altered phenotypes, including varied pain responses, differential response to agonists and even mistargeted gene knockout (Hansen et al., 2011; Nicke et al., 2009; Xu et al., 2012). P2X7R splice variants have also been shown to vary in their interaction with pannexin-1, which, as mentioned, plays an important role in the inflammatory action of P2X7R (Hung et al., 2013; Pelegrin and Surprenant, 2006; Xu et al., 2012). The number of splice variants observed across different species and the functional significance they may have in disease is still unclear and must be further investigated in order to effectively target any unfavourable action of P2X7R.
4. Clinical applications of P2X receptor antagonists 5. Concluding remarks The arguments for the inflammatory roles of P2XR versus their vascular role in CKD have been proposed, yet the likelihood is that they work in conjunction, especially since clinical trials for the P2X7R antagonists, AZD9056 and CE-224,535, in inflammatory treatment have thus far failed to show any benefit over the placebo (Keystone et al., 2012; Stock et al., 2012). Although P2X7R antagonists have been shown to be well-tolerated in humans, inefficacy of the drug have prevented progression of these clinical trials beyond Phase 3 (Arulkumaran et al., 2011). Under such circumstances, it may be more sensible to take a clinical perspective on this and question why these
Although purinergic receptors are now recognised as biologically important molecules and many of their roles in the body have been elucidated, their complexity and variety have presented a challenging field of research. Even with convincing rodent studies, the underperformance of P2X7R antagonists in clinical trials serve as a reminder of this complexity. However, as they remain promising drug targets for many diseases including CKD, P2XR research will continue to be vigorously pursued. With further insight into the genetic regulation of P2X4R and P2X7R expression and continued studies into their interaction, it is feasible that
Please cite this article as: Howarth, A.R., et al., Vascular and inflammatory actions of P2X receptors in renal injury, Auton. Neurosci. (2015), http:// dx.doi.org/10.1016/j.autneu.2015.05.001
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