The Adenosinergic System in Diabetic Retinopathy

Vindeirinho, J.; Santiago, A. R.; Cavadas, C.; Ambrósio, A. F.; Santos, P. F.

doi:https://doi.org/10.1155/2016/4270301

Journal of Diabetes Research

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Review Article | Open Access

Volume 2016 | Article ID 4270301 | https://doi.org/10.1155/2016/4270301

The Adenosinergic System in Diabetic Retinopathy

J. Vindeirinho,^1,2,3A. R. Santiago,^3,4,5C. Cavadas,^1,3,6A. F. Ambrósio,^3,4,5and P. F. Santos^3,4,7

Academic Editor: Sarah Zhang

Received10 Nov 2015

Accepted29 Dec 2015

Published29 Feb 2016

Abstract

The neurodegenerative and inflammatory environment that is prevalent in the diabetic eye is a key player in the development and progression of diabetic retinopathy. The adenosinergic system is widely regarded as a significant modulator of neurotransmission and the inflammatory response, through the actions of the four types of adenosine receptors (A₁R, A_2AR, A_2BR, and A₃R), and thus could be revealed as a potential player in the events unfolding in the early stages of diabetic retinopathy. Herein, we review the studies that explore the impact of diabetic conditions on the retinal adenosinergic system, as well as the role of the said system in ameliorating or exacerbating those conditions. The experimental results described suggest that this system is heavily affected by diabetic conditions and that the modulation of its components could reveal potential therapeutic targets for the treatment of diabetic retinopathy, particularly in the early stages of the disease.

1. Introduction

Diabetic retinopathy (DR) is the most common complication of diabetes [1] and one of the leading causes of visual impairment and preventable blindness in working age adults in the world [2, 3]. In fact, DR is highly prevalent in both type 1 and type 2 diabetic patients: nearly 77% of type 1 diabetic patients present some degree of the disease [3], and over 60% of type 2 diabetic patients (T2DM) after 20 years with diabetes present retinopathy to some degree [4]. The predominant view of DR has been that diabetes primarily affected the retinal microvasculature and this then caused secondary damage and degeneration. However, over the years, this notion has been contested, with several studies demonstrating that the neural retina is also affected early in diabetes [5], and vision impairments are detected earlier than the vascular changes [6], suggesting that neural changes are a result of diabetes and not a consequence of BRB breakdown [5]. In fact, DR shares many similarities with neurodegenerative diseases, such alterations in glutamatergic system [7–11], apoptosis [12–15], glial activation [6], and inflammation [16–19]. Studies showed a correlation between the toxic levels of extracellular glutamate and the increased damage and higher apoptotic levels in retinal neurons observed in diabetic conditions [20, 21]. The altered levels of several neurotrophic factors in diabetic conditions can also exacerbate the damage occurring in retinal neurons, affect glucose metabolism, and contribute to an inflammatory environment [22–25]. This inflammatory environment has characteristics that are usually associated with chronic inflammatory conditions such as an increase in leukostasis, microglial cell activation, activation of NF-κB leading to the amplified production and release of proinflammatory cytokines, chemokines, and other inflammatory mediator proteins [6, 26, 27]. Cytokines such as TNF, interleukin-1β (IL-1β), and interleukin-6 (IL-6) are increased in DR and connected to retinal leukostasis, BRB breakdown, and the higher levels of apoptosis present in DR [16, 17, 19, 28].

2. The Retina

The retina is a part of the central nervous system (CNS) that lines the inner, posterior surface of the eye, containing four types of cells: neuronal cells, macroglial and microglial cells, and blood vessel cells. There are several types of neuronal cells in the retina: photoreceptors, bipolar, amacrine, horizontal, and ganglion cells. Photoreceptors mediate phototransduction, while a complex signaling network existing between the different neurons modulates and communicates nerve impulses. These are then transmitted to the brain across the axons of retinal ganglion cells that form the nerve fiber layer and optic nerve. The two main types of macroglial cells present in the retina are Müller cells and astrocytes, and they are involved not only in retinal metabolism but also in the modulation of the activity of both neurons and blood vessels. Müller cells cross the width of the neural retina, forming a connection between retinal neurons, the vitreous body, and blood vessels, by being key regulators of neuronal function, extracellular ionic balance, and glutamate metabolism. Astrocytes are present in the nerve fiber layer and their processes wrap blood vessels and retinal ganglion cells. Macroglial cells are then vital in the communication between the vascular and the neuronal parts of the retina. Microglial cells are the resident immune cells of the central nervous system, surveying the retinal parenchyma and being highly sensitive to alterations in the homeostatic environment. The blood vessels are composed of pericytes, involved in the regulation of vascular flow, and endothelial cells, vital for hemostatic functions and the formation of the blood-retinal barrier (BRB). The activity of these cells and the interaction between them are necessary for normal retinal function, and if their normal functions are impaired, this can result in loss of visual capacity [29, 30].

3. The Adenosinergic System

Adenosine is a purine nucleoside essential to all living cells. Beyond its role in metabolism and genetic transmission of information, adenosine is also a messenger that regulates numerous physiological processes in several tissues, particularly in the cardiovascular and nervous systems. Studies have shown the importance of adenosine in both normal and pathological situations, from regulation of sleep and linking energy demands to cerebral blood flow to inflammatory responses and in neuroprotection against ischemia and epilepsy [31–33]. In the retina, most knowledge of adenosine function is based on research in pathological contexts, but nevertheless, a picture is forming of a signaling system involved in neurotransmission modulation [34], vascular processes [35], control of osmotic alterations [36], and inflammatory response [37], as a background modulatory system, or in transient responses to alterations to the homeostasis.

Several components are involved in this regulatory system: the actions of adenosine are mediated via four G protein-coupled receptors (GPCR), namely, the A₁, A_2A, A_2B, and A₃ adenosine receptors, although some G-protein-independent effects have also been reported [38, 39]. The adenosine receptors are abundant throughout the organism, but particularly in the CNS where the receptors can be found in all brain areas [32]. In the retina, most neuronal cells express A₁R and/or A_2AR, with retinal ganglion cells also expressing A₃R [40–42]; Müller cells have all but one receptor type present, with no direct A₃R detection so far [43], while astrocytes and microglial cells express all four receptors [44–47]; pericytes express A₁R and A_2AR and endothelial cells express A_2AR and A_2BR [48, 49] while epithelial cells can express all four receptors [40, 50, 51].

A₁R and A_2AR have generally opposing signaling effects: A₁R activation has a largely inhibitory action, especially in neurons, where A₁R signaling causes a decrease in the release of neurotransmitters and overall excitability [32, 39]. A_2AR activation, on the other hand, has a more excitatory role in neurons, being responsible for the potentiation of synaptic transmitter release [32, 39]. In other systems, however, the activation of A_2AR can also have inhibitory actions [38].

A_2BR and A₃R, due to their more recent discovery and characterization, have roles that are less understood. A_2BR, much like A_2AR, has been linked to increased neurotransmission in the central nervous system and anti-inflammatory pathways, although some reports show a potential proinflammatory action in some circumstances [38, 39, 52].

A₃R is probably the receptor that is less known, with several studies showing a double nature in different pathophysiological conditions, often going from protective to destructive depending on the agonist concentration or experiment time-frame [53].

The different adenosine receptors have distinct but frequently overlapping distributions. The proximity of different adenosine receptors means that adenosine can activate multiple signaling pathways and create a self-modulating environment in several cases, with A_2AR and A_2BR activating adenylate cyclase and A₁R and A₃R inhibiting it. In the case of A_2AR and A_2BR, the interactions may be synergistic, with the lower affinity A_2BR supporting the higher affinity A_2AR, which may suffer desensitization faster [39].

3.1. Management of Adenosine Levels

The intra- and extracellular levels of adenosine are controlled by several enzymes and transporters, allowing a regulation that is fine-tuned to disturbances in homeostasis, as illustrated in Figure 1.

The release of adenine nucleotides and its posterior extracellular conversion into adenosine is one of the mechanisms that can lead to an increase in the extracellular levels of adenosine. ATP is an important source of extracellular adenosine, being released, not only in normal conditions, but also in response to different forms of stress and during necrosis or apoptosis [54]. Several extracellular enzymes handle the conversion of released adenine nucleotides: nucleoside triphosphate diphosphohydrolases (NTPDase), ecto-nucleotide pyrophosphatase/phosphodiesterases (ecto-NPP), and apyrases create a chain where adenine nucleotides can be dephosphorylated to 5′-AMP fairly quickly, which is then dephosphorylated to adenosine by 5′-ectonucleotidase (5′-eN) [31]. These enzymes are present in the CNS [31, 55], including the retina [56, 57], where Müller cells, in particular, have this enzyme chain best characterized [36, 56].

Another mechanism by which extracellular adenosine levels increase is the release of intracellular adenosine by bidirectional nucleoside transporters: equilibrative nucleoside transporters (ENTs) and concentrative nucleoside transporters (CNTs). The ENTs consist of four characterized isoforms (ENT1–4) and mediate a facilitated bidirectional diffusion of nucleosides through the plasma membrane, transporting naturally occurring nucleosides with broad selectivity. All of them are widely distributed, but ENT2 levels are higher in brain and skeletal muscle, while ENT4 has a more marked presence in heart, liver, and brain [58]. The CNTs, consisting of three isoforms (CNT1–3), perform a secondary active transport function, where the inward transport of a nucleoside is coupled with a transmembrane sodium gradient. Of the three, only CNT2 is expressed in brain [58]. As for the retina, studies have shown the expression of ENT1-2 and CNT1-2 in whole retina extracts from rats [59] and also a rat Müller cell line [60]. In a rat retinal capillary endothelial cell line, the expression of ENT1-2 and CNT2-3 was also detected [59]. Due to the presence of ENTs, the transport of adenosine can be made following concentration gradients [61], which means that the concentration of intracellular adenosine can directly affect the extracellular levels of this nucleoside, making the regulation of the intracellular enzymes involved in the adenosine cycle also an important step in the control of extracellular adenosine levels.

Beyond nucleotide degradation and transporter release, one group found evidence to support the existence of a mechanism for the direct release of adenosine in the cerebellum of mice, through adenosine-filled vesicles [62].

The nucleoside transporters are also involved in the reuptake of adenosine by neurons and neighboring cells to prevent unwanted receptor activation. Intracellularly, adenosine can be either phosphorylated by adenosine kinase (AK) to form AMP or degradated by adenosine deaminase (ADA). Both enzymes are present in rat retina [63]. Due to its lower (2 μM for AK while ADA features a of 17–45 μM, in rat whole brain) it is probable that phosphorylation by AK is the principal pathway of adenosine removal in physiological conditions, while deamination may be more relevant in pathological conditions (when adenosine concentrations rise) [31, 55].

Apart from reuptake, extracellular adenosine can also be removed by deamination to inosine by extracellular ADA, although most of the extracellular adenosine is cleared by reuptake in normal conditions [31]. During hypoxia and ischemia ecto-ADA may gain a more prominent role in the control of extracellular adenosine concentrations, since these situations raise the intracellular levels of adenosine, affecting the gradient concentration and disrupting the inward flow of nucleotides through the transporters [31].

4. Adenosine and Diabetic Retinopathy

Various forms of stress and pathological conditions, from ischemia and hypoxia to epilepsy can affect the adenosinergic system, hinting at a pattern of alterations to the density and distribution of adenosine receptors that is induced by such conditions [64]. Diabetes is no exception, with several studies investigating the effect of diabetes and hyperglycemia on adenosinergic system components in various tissues and models [65–68]. However, only in recent years did some studies reveal the extent of the effect that diabetic conditions have on the adenosinergic system in the retina.

Changes in the retina have been reported in retinal neural cells exposed to elevated glucose concentration and in diabetic rats. Recently, studies revealed that the expression and density of A₁R suffer alterations in diabetic conditions in the retina: both mRNA and protein levels of this receptor are increased in rat retinal cell cultures subjected to high glucose conditions, and the density of A₁R is also increased in rat retinas after 4 weeks of diabetes [63]; in that period the retinal mRNA levels of A₁R are not significantly different from the control animals. However, when diabetes was sustained for a longer period of time (12 weeks) a decrease in the expression of this receptor was observed [69].

A_2AR has become a focus of study in the diabetic retina, mainly due to its potential role in the inflammatory conditions in early diabetic retinopathy. In mouse, rat, and pig, this receptor is shown to be upregulated in diabetic conditions, both in retinal cell cultures and diabetic retinas [63, 70, 71].

As for the A₃R receptor, one study showed that the expression and density of this receptor show a transient increase in diabetic rat retinas, after one week of diabetes, and a significant decrease after 4 weeks of diabetes [63].

The enzymes involved in the regulation of adenosine levels are also very sensitive to metabolic and homeostatic alterations. Both nucleotide degrading (NTPDases, 5′-eN) and adenosine degrading (ADA, AK) enzymes were shown to be affected by diabetes in several tissues [72–76].

A study performed in the retina of diabetic rats showed that adenosine is heavily involved in the control of osmotic glial swelling during diabetes and that diabetic conditions prompt a differential expression of the nucleotide degrading enzyme NTPDase1, which hydrolyzes both ATP and ADP in equal measure, from being restricted to blood vessels in control animals to being present in retinal glial cells in diabetic animals [36]. The same study revealed an increase in mRNA levels of NTPDase1 in diabetic retinas, while NTPDase2 and 5′-eN expression were the same.

Another factor that may affect extracellular adenosine levels is the increase in ATP release. In fact, it was reported in rat retinal neural cells cultured with elevated glucose concentration that the depolarization-evoked release of ATP increases. The same study demonstrated that ATP degradation is impaired in the same conditions [18].

In diabetic rat Müller cells, glutamate signaling can cause an increase in the extracellular generation of adenosine, through 5′-eN [36], probably due to the alterations in expression and distribution of NTPDase1, which drives an increase in AMP availability for degradation by 5′-eNT.

In diabetic rat retinas after 4 weeks ADA expression and density are decreased, while in retinal cultures exposed to high glucose the activity of this enzyme is severely decreased, which could be responsible for the high levels of extracellular adenosine found in those conditions [63]. On the other hand, a study in human and pig retinas indicates that, while the isoenzyme ADA1 remains unchanged in diabetic conditions, the protein levels of the isoenzyme ADA2 are increased. Furthermore, in porcine retinas, the activity of ADA2 is increased [71].

Although AK expression and density levels were unaltered in rat retinal cultures exposed to high glucose and in rat diabetic retinas at 1 week of diabetes, there was a decrease observed at 4 weeks of diabetes [63]. Similarly, in the diabetic retinas of mice, AK protein levels were decreased after 8 weeks of diabetes, and this decrease is reduced by the inhibition of AK itself [70].

In a study performed in T2DM patients with DR, an increase in plasma levels of adenosine was observed, but not in patients without DR, leading the authors to suggest adenosine as a biomarker for the diagnosis of DR [77].

These alterations, as shown in Figure 2, occurring at several levels of the adenosinergic system in the diabetic retina may result in functional alterations to the processes controlled or modulated by adenosine.

The osmotic swelling of glial cells present in diabetic retinas is prevented by administration of adenosine (10 μM) in rats, but this prevention is suppressed by using DPCPX, an A₁R antagonist [36], while the blockade of A_2AR had no effect. This suggests that the action of adenosine is mediated by activation of A₁R, which opens potassium and chloride channels in the outer membrane of glial cells. The same study showed that the purinergic signaling that prevents swelling under osmotic stress is inactive in diabetic conditions, although the receptors involved are functional and the mechanism works upon adenosine administration (as mentioned above).

The potential anti-inflammatory action of adenosine was evaluated in the retina: in retinal microglia cultures, exposure to Amadori-glycated albumin (AGA) triggers the inflammatory response seen in diabetic conditions, namely, the increased expression and release of TNF, and this effect of AGA was successfully blocked by activation of A_2AR in mice [78], rat [70], and pig [71] retinal microglial cells. In mice, the activation of A_2AR with CGS21680, a selective agonist, also reduced TNF levels and decreased cell death in diabetic retinas [78].

In a study performed in diabetic mice, treatment with ABT-702, an AK inhibitor decreased ENT1 protein levels, cell death, and the expression of Iba1 (a microglia/macrophage marker that is upregulated upon activation), suggesting a decrease in microglia reactivity [70]. The same study showed that, in rat retinal microglial cell cultures, the inhibition of AK had a more substantial effect than ADA inhibition in decreasing TNF release.

These results point out to a protective, anti-inflammatory effect of adenosine and A_2AR activation in particular. This protective effect, however, is contentious, with at least one other study showing conflicting results: the treatment of rMC-1, a rat Müller cell line, incubated in hyperglycemic-like conditions with either ATP or adenosine scavengers reduced the proinflammatory caspase-1 activation [79]. A nonselective adenosine receptor antagonist (DPCPX at a concentration of 10 μM) also reduced caspase-1 activation, which was mimicked with an A_2BR selective antagonist (MRS1754). Taken together, the existing data on the role of adenosine in the retina during diabetes remains controversial and the effects of the modulation of this system most likely will depend on the target receptors and/or cell types and be influenced by the experimental approach. However, a picture of dysregulation is already apparent, one that may impact on excitotoxicity, osmotic regulation, and inflammation, all of which can impair cell survival and visual function in diabetic conditions.

5. Conclusions

In this review we covered the numerous alterations that occur to the adenosinergic system in the diabetic retina, from receptor expression and enzyme distribution and activity to adenosine levels. Such modifications to a system that is highly sensible to disruptions of homeostasis will necessarily have repercussions, especially in inflammatory and excitotoxic situations. The potential protection or damage that these alterations may cause is contentious, but the modulation of this system seems to be a promising path to combating the inflammatory and excitotoxic environment and reducing cell death in early DR.

Conflict of Interests

The authors have declared that no competing interests exist.

Acknowledgments

This work was supported by FCT (Fundação para a Ciência e a Tecnologia) grants SFRH/BD/43968/2008 and PEst-C/SAU/LA0001/2013-201. J. Vindeirinho is a recipient of a Ph.D. fellowship from FCT (SFRH/BD/51195/2010).

References

R. Simó and C. Hernández, “Neurodegeneration in the diabetic eye: new insights and therapeutic perspectives,” Trends in Endocrinology & Metabolism, vol. 25, no. 1, pp. 23–33, 2014.
View at: Publisher Site | Google Scholar
N. Cheung, P. Mitchell, and T. Y. Wong, “Diabetic retinopathy,” The Lancet, vol. 376, no. 9735, pp. 124–136, 2010.
View at: Publisher Site | Google Scholar
J. W. Y. Yau, S. L. Rogers, R. Kawasaki et al., “Global prevalence and major risk factors of diabetic retinopathy,” Diabetes Care, vol. 35, no. 3, pp. 556–564, 2012.
View at: Publisher Site | Google Scholar
D. S. Fong, L. Aiello, T. W. Gardner et al., “Diabetic retinopathy,” Diabetes Care, vol. 26, supplement 1, pp. S99–S102, 2003.
View at: Google Scholar
D. A. Antonetti, A. J. Barber, S. K. Bronson et al., “Diabetic retinopathy: seeing beyond glucose-induced microvascular disease,” Diabetes, vol. 55, no. 9, pp. 2401–2411, 2006.
View at: Publisher Site | Google Scholar
A. J. Barber, “A new view of diabetic retinopathy: a neurodegenerative disease of the eye,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 27, no. 2, pp. 283–290, 2003.
View at: Publisher Site | Google Scholar
A. F. Castilho, J. T. Liberal, F. I. Baptista, J. M. Gaspar, A. L. Carvalho, and A. F. Ambrósio, “Elevated glucose concentration changes the content and cellular localization of AMPA receptors in the retina but not in the hippocampus,” Neuroscience, vol. 219, pp. 23–32, 2012.
View at: Publisher Site | Google Scholar
A. R. Santiago, J. M. Gaspar, F. I. Baptista et al., “Diabetes changes the levels of ionotropic glutamate receptors in the rat retina,” Molecular Vision, vol. 15, pp. 1620–1630, 2009.
View at: Google Scholar
A. R. Santiago, J. M. Hughes, W. Kamphuis, R. O. Schlingemann, and A. F. Ambrósio, “Diabetes changes ionotropic glutamate receptor subunit expression level in the human retina,” Brain Research, vol. 1198, pp. 153–159, 2008.
View at: Publisher Site | Google Scholar
A. R. Santiago, T. S. Pereira, M. J. Garrido, A. J. Cristóvão, P. F. Santos, and A. F. Ambrósio, “High glucose and diabetes increase the release of [3H]-d-aspartate in retinal cell cultures and in rat retinas,” Neurochemistry International, vol. 48, no. 6-7, pp. 453–458, 2006.
View at: Publisher Site | Google Scholar
A. R. Santiago, S. C. Rosa, P. F. Santos, A. J. Cristóvão, A. J. Barber, and A. F. Ambrósio, “Elevated glucose changes the expression of ionotropic glutamate receptor subunits and impairs calcium homeostasis in retinal neural cells,” Investigative Ophthalmology and Visual Science, vol. 47, no. 9, pp. 4130–4137, 2006.
View at: Publisher Site | Google Scholar
A. J. Barber, E. Lieth, S. A. Khin, D. A. Antonetti, A. G. Buchanan, and T. W. Gardner, “Neural apoptosis in the retina during experimental and human diabetes: early onset and effect of insulin,” The Journal of Clinical Investigation, vol. 102, no. 4, pp. 783–791, 1998.
View at: Publisher Site | Google Scholar
E. C. Leal, C. A. Aveleira, Á. F. Castilho et al., “High glucose and oxidative/nitrosative stress conditions induce apoptosis in retinal endothelial cells by a caspase-independent pathway,” Experimental Eye Research, vol. 88, no. 5, pp. 983–991, 2009.
View at: Publisher Site | Google Scholar
S.-H. Park, J.-W. Park, S.-J. Park et al., “Apoptotic death of photoreceptors in the streptozotocin-induced diabetic rat retina,” Diabetologia, vol. 46, no. 9, pp. 1260–1268, 2003.
View at: Publisher Site | Google Scholar
A. R. Santiago, A. J. Cristóvão, P. F. Santos, C. M. Carvalho, and A. F. Ambrósio, “High glucose induces caspase-independent cell death in retinal neural cells,” Neurobiology of Disease, vol. 25, no. 3, pp. 464–472, 2007.
View at: Publisher Site | Google Scholar
C. Aveleira, Á. Castilho, F. Baptista et al., “High glucose and interleukin-1β downregulate interleukin-1 type I receptor (IL-1RI) in retinal endothelial cells by enhancing its degradation by a lysosome-dependent mechanism,” Cytokine, vol. 49, no. 3, pp. 279–286, 2010.
View at: Publisher Site | Google Scholar
C. A. Aveleira, C.-M. Lin, S. F. Abcouwer, A. F. Ambrósio, and D. A. Antonetti, “TNF-α signals through PKCζ/NF-κB to alter the tight junction complex and increase retinal endothelial cell permeability,” Diabetes, vol. 59, no. 11, pp. 2872–2882, 2010.
View at: Publisher Site | Google Scholar
G. Costa, T. Pereira, A. M. Neto, A. J. Cristóvão, A. F. Ambrósio, and P. F. Santos, “High glucose changes extracellular adenosine triphosphate levels in rat retinal cultures,” Journal of Neuroscience Research, vol. 87, no. 6, pp. 1375–1380, 2009.
View at: Publisher Site | Google Scholar
G. N. Costa, J. Vindeirinho, C. Cavadas, A. F. Ambrósio, and P. F. Santos, “Contribution of TNF receptor 1 to retinal neural cell death induced by elevated glucose,” Molecular and Cellular Neuroscience, vol. 50, no. 1, pp. 113–123, 2012.
View at: Publisher Site | Google Scholar
R. A. Kowluru, R. L. Engerman, G. L. Case, and T. S. Kern, “Retinal glutamate in diabetes and effect of antioxidants,” Neurochemistry International, vol. 38, no. 5, pp. 385–390, 2001.
View at: Publisher Site | Google Scholar
J. Kusari, S. Zhou, E. Padillo, K. G. Clarke, and D. W. Gil, “Effect of memantine on neuroretinal function and retinal vascular changes of streptozotocin-induced diabetic rats,” Investigative Ophthalmology & Visual Science, vol. 48, no. 11, pp. 5152–5159, 2007.
View at: Publisher Site | Google Scholar
A. M. Abu El-Asrar, G. Mohammad, G. De Hertogh et al., “Neurotrophins and neurotrophin receptors in proliferative diabetic retinopathy,” PLoS ONE, vol. 8, no. 6, Article ID e65472, 2013.
View at: Publisher Site | Google Scholar
K. S. Krabbe, A. R. Nielsen, R. Krogh-Madsen et al., “Brain-derived neurotrophic factor (BDNF) and type 2 diabetes,” Diabetologia, vol. 50, no. 2, pp. 431–438, 2007.
View at: Publisher Site | Google Scholar
Y. Liu, L. Tao, X. Fu, Y. Zhao, and X. Xu, “BDNF protects retinal neurons from hyperglycemia through the TrkB/ERK/MAPK pathway,” Molecular Medicine Reports, vol. 7, no. 6, pp. 1773–1778, 2013.
View at: Publisher Site | Google Scholar
B. A. Mysona, M. M. H. Al-Gayyar, S. Matragoon et al., “Modulation of p $75^{NTR}$ prevents diabetes- and proNGF-induced retinal inflammation and blood-retina barrier breakdown in mice and rats,” Diabetologia, vol. 56, no. 10, pp. 2329–2339, 2013.
View at: Publisher Site | Google Scholar
J. K. Krady, A. Basu, C. M. Allen et al., “Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy,” Diabetes, vol. 54, no. 5, pp. 1559–1565, 2005.
View at: Publisher Site | Google Scholar
K. Miyamoto, S. Khosrof, S.-E. Bursell et al., “Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 19, pp. 10836–10841, 1999.
View at: Publisher Site | Google Scholar
A. P. Adamis and A. J. Berman, “Immunological mechanisms in the pathogenesis of diabetic retinopathy,” Seminars in Immunopathology, vol. 30, no. 2, pp. 65–84, 2008.
View at: Publisher Site | Google Scholar
A. Crooke, A. Guzmán-Aranguez, A. Peral, M. K. A. Abdurrahman, and J. Pintor, “Nucleotides in ocular secretions: their role in ocular physiology,” Pharmacology and Therapeutics, vol. 119, no. 1, pp. 55–73, 2008.
View at: Publisher Site | Google Scholar
T. W. Gardner, D. A. Antonetti, A. J. Barber, K. F. LaNoue, and S. W. Levison, “Diabetic retinopathy: more than meets the eye,” Survey of Ophthalmology, vol. 47, supplement 2, pp. S253–S262, 2002.
View at: Publisher Site | Google Scholar
T. V. Dunwiddie and S. A. Masino, “The role and regulation of adenosine in the central nervous system,” Annual Review of Neuroscience, vol. 24, pp. 31–55, 2001.
View at: Publisher Site | Google Scholar
A. M. Sebastião and J. A. Ribeiro, “Adenosine receptors and the central nervous system,” in Adenosine Receptors in Health and Disease, vol. 193 of Handbook of Experimental Pharmacology, pp. 471–534, Springer, Berlin, Germany, 2009.
View at: Publisher Site | Google Scholar
J. Wardas, “Neuroprotective role of adenosine in the CNS,” Polish Journal of Pharmacology, vol. 54, no. 4, pp. 313–326, 2002.
View at: Google Scholar
M. Matos, E. Augusto, P. Agostinho, R. A. Cunha, and J.-F. Chen, “Antagonistic interaction between adenosine $A_{2A}$ Receptors and Na⁺/K⁺-ATPase-α₂ controlling glutamate uptake in astrocytes,” Journal of Neuroscience, vol. 33, no. 47, pp. 18492–18502, 2013.
View at: Publisher Site | Google Scholar
X.-L. Liu Xiao-Ling, R. Zhou, Q.-Q. Pan et al., “Genetic inactivation of the adenosine A_2A receptor attenuates pathologic but not developmental angiogenesis in the mouse retina,” Investigative Ophthalmology and Visual Science, vol. 51, no. 12, pp. 6625–6632, 2010.
View at: Publisher Site | Google Scholar
A. Wurm, I. Iandiev, M. Hollborn et al., “Purinergic receptor activation inhibits osmotic glial cell swelling in the diabetic rat retina,” Experimental Eye Research, vol. 87, no. 4, pp. 385–393, 2008.
View at: Publisher Site | Google Scholar
A. R. Santiago, F. I. Baptista, P. F. Santos et al., “Role of microglia adenosine A_2A receptors in retinal and brain neurodegenerative diseases,” Mediators of Inflammation, vol. 2014, Article ID 465694, 13 pages, 2014.
View at: Publisher Site | Google Scholar
G. Haskó, J. Linden, B. Cronstein, and P. Pacher, “Adenosine receptors: therapeutic aspects for inflammatory and immune diseases,” Nature Reviews Drug Discovery, vol. 7, no. 9, pp. 759–770, 2008.
View at: Publisher Site | Google Scholar
V. Ralevic and G. Burnstock, “Receptors for purines and pyrimidines,” Pharmacological Reviews, vol. 50, no. 3, pp. 413–492, 1998.
View at: Google Scholar
G. D. Housley, A. Bringmann, and A. Reichenbach, “Purinergic signaling in special senses,” Trends in Neurosciences, vol. 32, no. 3, pp. 128–141, 2009.
View at: Publisher Site | Google Scholar
P.-C. Huang, Y.-T. Hsiao, S.-Y. Kao et al., “Adenosine A2A receptor up-regulates retinal wave frequency via starburst amacrine cells in the developing rat retina,” PLoS ONE, vol. 9, no. 4, Article ID e95090, 2014.
View at: Publisher Site | Google Scholar
H. Li, Z. Zhang, M. R. Blackburn, S. W. Wang, C. P. Ribelayga, and J. O'Brien, “Adenosine and dopamine receptors coregulate photoreceptor coupling via gap junction phosphorylation in mouse retina,” Journal of Neuroscience, vol. 33, no. 7, pp. 3135–3150, 2013.
View at: Publisher Site | Google Scholar
A. Wurm, T. Pannicke, I. Iandiev et al., “Purinergic signaling involved in Müller cell function in the mammalian retina,” Progress in Retinal and Eye Research, vol. 30, no. 5, pp. 324–342, 2011.
View at: Publisher Site | Google Scholar
P. J. Gebicke-Haerter, F. Christoffel, J. Timmer, H. Northoff, M. Berger, and D. Van Calker, “Both adenosine A1- and A2-receptors are required to stimulate microglial proliferation,” Neurochemistry International, vol. 29, no. 1, pp. 37–42, 1996.
View at: Publisher Site | Google Scholar
C. Hammarberg, G. Schulte, and B. B. Fredholm, “Evidence for functional adenosine A3 receptors in microglia cells,” Journal of Neurochemistry, vol. 86, no. 4, pp. 1051–1054, 2003.
View at: Publisher Site | Google Scholar
G. Haskó, P. Pacher, E. S. Vizi, and P. Illes, “Adenosine receptor signaling in the brain immune system,” Trends in Pharmacological Sciences, vol. 26, no. 10, pp. 511–516, 2005.
View at: Publisher Site | Google Scholar
B. Koscsó, B. Csóka, Z. Selmeczy et al., “Adenosine augments IL-10 production by microglial cells through an A2B adenosine receptor-mediated process,” The Journal of Immunology, vol. 188, no. 1, pp. 445–453, 2012.
View at: Publisher Site | Google Scholar
M. B. Grant, R. W. Tarnuzzer, S. Caballero et al., “Adenosine receptor activation induces vascular endothelial growth factor in human retinal endothelial cells,” Circulation Research, vol. 85, no. 8, pp. 699–706, 1999.
View at: Publisher Site | Google Scholar
G. A. Lutty and D. S. McLeod, “Retinal vascular development and oxygen-induced retinopathy: a role for adenosine,” Progress in Retinal and Eye Research, vol. 22, no. 1, pp. 95–111, 2003.
View at: Publisher Site | Google Scholar
A. Kvanta, S. Seregard, S. Sejersen, B. Kull, and B. B. Fredholm, “Localization of adenosine receptor messenger RNAs in the rat eye,” Experimental Eye Research, vol. 65, no. 5, pp. 595–602, 1997.
View at: Publisher Site | Google Scholar
W.-J. Wan, D.-M. Cui, X. Yang et al., “Expression of adenosine receptors in human retinal pigment epithelium cells in vitro,” Chinese Medical Journal, vol. 124, no. 8, pp. 1139–1144, 2011.
View at: Publisher Site | Google Scholar
L. M. Kreckler, T. C. Wan, Z.-D. Ge, and J. A. Auchampach, “Adenosine inhibits tumor necrosis factor-alpha release from mouse peritoneal macrophages via A2A and A2B but not the A3 adenosine receptor,” Journal of Pharmacology and Experimental Therapeutics, vol. 317, no. 1, pp. 172–180, 2006.
View at: Publisher Site | Google Scholar
S. Gessi, S. Merighi, K. Varani, E. Leung, S. Mac Lennan, and P. A. Borea, “The A₃ adenosine receptor: an enigmatic player in cell biology,” Pharmacology and Therapeutics, vol. 117, no. 1, pp. 123–140, 2008.
View at: Publisher Site | Google Scholar
M. R. Elliott, F. B. Chekeni, P. C. Trampont et al., “Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance,” Nature, vol. 461, no. 7261, pp. 282–286, 2009.
View at: Publisher Site | Google Scholar
S. Latini and F. Pedata, “Adenosine in the central nervous system: release mechanisms and extracellular concentrations,” Journal of Neurochemistry, vol. 79, no. 3, pp. 463–484, 2001.
View at: Publisher Site | Google Scholar
I. Iandiev, A. Wurm, T. Pannicke et al., “Ectonucleotidases in Müller glial cells of the rodent retina: involvement in inhibition of osmotic cell swelling,” Purinergic Signalling, vol. 3, no. 4, pp. 423–433, 2007.
View at: Publisher Site | Google Scholar
M. J. Ricatti, L. D. Alfie, É. G. Lavoie, J. Sévigny, P. J. Schwarzbaum, and M. P. Faillace, “Immunocytochemical localization of NTPDases1 and 2 in the neural retina of mouse and zebrafish,” Synapse, vol. 63, no. 4, pp. 291–307, 2009.
View at: Publisher Site | Google Scholar
J.-S. Choi and A. J. Berdis, “Nucleoside transporters: biological insights and therapeutic applications,” Future Medicinal Chemistry, vol. 4, no. 11, pp. 1461–1478, 2012.
View at: Publisher Site | Google Scholar
K. Nagase, M. Tomi, M. Tachikawa, and K.-I. Hosoya, “Functional and molecular characterization of adenosine transport at the rat inner blood-retinal barrier,” Biochimica et Biophysica Acta (BBA)—Biomembranes, vol. 1758, no. 1, pp. 13–19, 2006.
View at: Publisher Site | Google Scholar
S.-I. Akanuma, T. Soutome, E. Hisada, M. Tachikawa, Y. Kubo, and K.-I. Hosoya, “Na⁺-independent nucleoside transporters regulate adenosine and hypoxanthine levels in Müller cells and the inner blood–retinal barrier,” Investigative Ophthalmology and Visual Science, vol. 54, no. 2, pp. 1469–1477, 2013.
View at: Publisher Site | Google Scholar
F. E. Parkinson, V. L. Damaraju, K. Graham et al., “Molecular biology of nucleoside transporters and their distributions and functions in the brain,” Current Topics in Medicinal Chemistry, vol. 11, no. 8, pp. 948–972, 2011.
View at: Publisher Site | Google Scholar
B. P. Klyuch, N. Dale, and M. J. Wall, “Deletion of ecto-5′-nucleotidase (CD73) reveals direct action potential-dependent adenosine release,” Journal of Neuroscience, vol. 32, no. 11, pp. 3842–3847, 2012.
View at: Publisher Site | Google Scholar
J. Vindeirinho, G. N. Costa, M. B. Correia, C. Cavadas, and P. F. Santos, “Effect of diabetes/hyperglycemia on the rat retinal adenosinergic system,” PLoS ONE, vol. 8, no. 6, Article ID e67499, 2013.
View at: Publisher Site | Google Scholar
B. B. Fredholm, “Adenosine, an endogenous distress signal, modulates tissue damage and repair,” Cell Death and Differentiation, vol. 14, no. 7, pp. 1315–1323, 2007.
View at: Publisher Site | Google Scholar
J. M. N. Duarte, C. R. Oliveira, A. F. Ambrósio, and R. A. Cunha, “Modification of adenosine A1 and A2A receptor density in the hippocampus of streptozotocin-induced diabetic rats,” Neurochemistry International, vol. 48, no. 2, pp. 144–150, 2006.
View at: Publisher Site | Google Scholar
M. Grden, M. Podgorska, A. Szutowicz, and T. Pawelczyk, “Diabetes-induced alterations of adenosine receptors expression level in rat liver,” Experimental and Molecular Pathology, vol. 83, no. 3, pp. 392–398, 2007.
View at: Publisher Site | Google Scholar
M. Grdeń, M. Podgórska, A. Szutowicz, and T. Pawełczyk, “Altered expression of adenosine receptors in heart of diabetic rat,” Journal of Physiology and Pharmacology, vol. 56, no. 4, pp. 587–597, 2005.
View at: Google Scholar
T. Pawelczyk, M. Grden, R. Rzepko, M. Sakowicz, and A. Szutowicz, “Region-specific alterations of adenosine receptors expression level in kidney of diabetic rat,” American Journal of Pathology, vol. 167, no. 2, pp. 315–325, 2005.
View at: Publisher Site | Google Scholar
J. C. M. Lau, R. A. Kroes, J. R. Moskal, and R. A. Linsenmeier, “Diabetes changes expression of genes related to glutamate neurotransmission and transport in the Long-Evans rat retina,” Molecular Vision, vol. 19, pp. 1538–1553, 2013.
View at: Google Scholar
N. M. Elsherbiny, S. Ahmad, M. Naime et al., “ABT-702, an adenosine kinase inhibitor, attenuates inflammation in diabetic retinopathy,” Life Sciences, vol. 93, no. 2-3, pp. 78–88, 2013.
View at: Publisher Site | Google Scholar
N. M. Elsherbiny, M. Naime, S. Ahmad et al., “Potential roles of adenosine deaminase-2 in diabetic retinopathy,” Biochemical and Biophysical Research Communications, vol. 436, no. 3, pp. 355–361, 2013.
View at: Publisher Site | Google Scholar
K. Kocbuch, M. Sakowicz-Burkiewicz, M. Grden, A. Szutowicz, and T. Pawelczyk, “Effect of insulin and glucose on adenosine metabolizing enzymes in human B lymphocytes,” Acta Biochimica Polonica, vol. 56, no. 3, pp. 439–446, 2009.
View at: Google Scholar
J.-G. Lee, D. G. Kang, J. R. Yu et al., “Changes in adenosine deaminase activity in patients with type 2 diabetes mellitus and effect of DPP-4 inhibitor treatment on ADA activity,” Diabetes and Metabolism Journal, vol. 35, no. 2, pp. 149–158, 2011.
View at: Publisher Site | Google Scholar
G. I. L. Lunkes, D. S. Lunkes, V. M. Morsch et al., “NTPDase and 5′-nucleotidase activities in rats with alloxan-induced diabetes,” Diabetes Research and Clinical Practice, vol. 65, no. 1, pp. 1–6, 2004.
View at: Publisher Site | Google Scholar
T. Pawelczyk, M. Sakowicz, M. Szczepanska-Konkel, and S. Angielski, “Decreased expression of adenosine kinase in streptozotocin-induced diabetes mellitus rats,” Archives of Biochemistry and Biophysics, vol. 375, no. 1, pp. 1–6, 2000.
View at: Publisher Site | Google Scholar
R. Schmatz, M. R. C. Schetinger, R. M. Spanevello et al., “Effects of resveratrol on nucleotide degrading enzymes in streptozotocin-induced diabetic rats,” Life Sciences, vol. 84, no. 11-12, pp. 345–350, 2009.
View at: Publisher Site | Google Scholar
J. Xia, Z. Wang, and F. Zhang, “Association between related purine metabolites and diabetic retinopathy in type 2 diabetic patients,” International Journal of Endocrinology, vol. 2014, Article ID 651050, 9 pages, 2014.
View at: Publisher Site | Google Scholar
A. S. Ibrahim, M. M. El-shishtawy, W. Zhang, R. B. Caldwell, and G. I. Liou, “A2A adenosine receptor (A2AAR) as a therapeutic target in diabetic retinopathy,” The American Journal of Pathology, vol. 178, no. 5, pp. 2136–2145, 2011.
View at: Publisher Site | Google Scholar
K. E. Trueblood, S. Mohr, and G. R. Dubyak, “Purinergic regulation of high-glucose-induced caspase-1 activation in the rat retinal Müller cell line rMC-1,” The American Journal of Physiology—Cell Physiology, vol. 301, no. 5, pp. C1213–C1223, 2011.
View at: Publisher Site | Google Scholar

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Copyright © 2016 J. Vindeirinho et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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