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Olivier E, Rat P. Role of Oxysterols in Ocular Degeneration Mechanisms and Involvement of P2X7 Receptor. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1440:277-292. [PMID: 38036885 DOI: 10.1007/978-3-031-43883-7_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Abstract
Ocular degeneration, including cataracts, glaucoma, macular degeneration, and diabetic retinopathy, is a major public health challenge, as it affects the quality of life of millions of people worldwide and, in its advanced stages, leads to blindness. Ocular degeneration, although it can affect different parts of the eye, shares common characteristics such as oxysterols and the P2X7 receptor. Indeed, oxysterols, which are cholesterol derivatives, are associated with ocular degeneration pathogenesis and trigger inflammation and cell death pathways. Activation of the P2X7 receptor is also linked to ocular degeneration and triggers the same pathways. In age-related macular degeneration, these two key players have been associated, but further studies are needed to extrapolate this interrelationship to other ocular degenerations.
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Affiliation(s)
| | - Patrice Rat
- Université Paris Cité, CNRS, CiTCoM, Paris, France
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2
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Sluyter R, Adriouch S, Fuller SJ, Nicke A, Sophocleous RA, Watson D. Animal Models for the Investigation of P2X7 Receptors. Int J Mol Sci 2023; 24:ijms24098225. [PMID: 37175933 PMCID: PMC10179175 DOI: 10.3390/ijms24098225] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 04/21/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
The P2X7 receptor is a trimeric ligand-gated cation channel activated by extracellular adenosine 5'-triphosphate. The study of animals has greatly advanced the investigation of P2X7 and helped to establish the numerous physiological and pathophysiological roles of this receptor in human health and disease. Following a short overview of the P2X7 distribution, roles and functional properties, this article discusses how animal models have contributed to the generation of P2X7-specific antibodies and nanobodies (including biologics), recombinant receptors and radioligands to study P2X7 as well as to the pharmacokinetic testing of P2X7 antagonists. This article then outlines how mouse and rat models have been used to study P2X7. These sections include discussions on preclinical disease models, polymorphic P2X7 variants, P2X7 knockout mice (including bone marrow chimeras and conditional knockouts), P2X7 reporter mice, humanized P2X7 mice and P2X7 knockout rats. Finally, this article reviews the limited number of studies involving guinea pigs, rabbits, monkeys (rhesus macaques), dogs, cats, zebrafish, and other fish species (seabream, ayu sweetfish, rainbow trout and Japanese flounder) to study P2X7.
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Affiliation(s)
- Ronald Sluyter
- Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
- Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia
| | - Sahil Adriouch
- UniRouen, INSERM, U1234, Pathophysiology, Autoimmunity, and Immunotherapy, (PANTHER), Univ Rouen Normandie, University of Rouen, F-76000 Rouen, France
| | - Stephen J Fuller
- Sydney Medical School Nepean, Faculty of Medicine and Health, The University of Sydney, Nepean Hospital, Kingswood, NSW 2750, Australia
| | - Annette Nicke
- Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, LMU Munich, 80336 Munich, Germany
| | - Reece A Sophocleous
- Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
- Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia
| | - Debbie Watson
- Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
- Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia
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Longitudinal effects of common carotid artery stenosis on ocular hemodynamics assessed using laser speckle flowgraphy in a rabbit model. Sci Rep 2020; 10:15829. [PMID: 32985560 PMCID: PMC7522272 DOI: 10.1038/s41598-020-72556-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 08/31/2020] [Indexed: 11/10/2022] Open
Abstract
Real-time impairment of ocular blood flow (OBF) under common carotid artery stenosis (CCAS) has not been ascertained. We aimed to longitudinally assess the impact of CCAS on OBF using a rabbit model. About 75% stenosis was created by tying the common carotid artery with a plastic mandrel using a nylon suture. The plastic mandrel was gently removed, leaving a ligature. Neurological and behavioral assessments were recorded as the clinical indicator of stroke severity. With laser speckle flowgraphy, the pulse waveform parameters namely mean blur rate (MBR), blowout score (BOS), blowout time (BOT), rising rate, S1-area, falling rate (FR), S2-area, flow acceleration index (FAI), acceleration time index, resistive index (RI) and the difference between the maximum and minimum values of MBR (AC) were assessed in overall, vessel, and tissue regions of the optic nerve head (ONH). Longitudinally, BOS significantly increased until day 19 post-surgery, whereas FAI, RI, and AC significantly decreased. Beyond day 19, BOS, BOT, FR, FAI, RI, and AC significantly decreased. We defined two stages representing impaired vessel conditions, namely the vessel resistance phase, where BOS increases and FAI, RI, and AC decrease, and the vessel elasticity phase where BOS, BOT, FR, FAI, RI and AC decrease. These stages provide information about atherosclerosis, assessable non-invasively through the eye.
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Zhou R, Dang X, Sprague RS, Mustafa SJ, Zhou Z. Alteration of purinergic signaling in diabetes: Focus on vascular function. J Mol Cell Cardiol 2020; 140:1-9. [PMID: 32057736 DOI: 10.1016/j.yjmcc.2020.02.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 01/02/2020] [Accepted: 02/09/2020] [Indexed: 12/11/2022]
Abstract
Diabetes is an important risk factor for the development of cardiovascular disease including atherosclerosis and ischemic heart disease. Vascular complications including macro- and micro-vascular dysfunction are the leading causes of morbidity and mortality in diabetes. Disease mechanisms at present are unclear and no ideal therapies are available, which urgently calls for the identification of novel therapeutic targets/agents. An altered nucleotide- and nucleoside-mediated purinergic signaling has been implicated to cause diabetes-associated vascular dysfunction in major organs. Alteration of both purinergic P1 and P2 receptor sensitivity rather than the changes in receptor expression accounts for vascular dysfunction in diabetes. Activation of P2X7 receptors plays a crucial role in diabetes-induced retinal microvascular dysfunction. Recent findings have revealed that both ecto-nucleotidase CD39, a key enzyme hydrolyzing ATP, and CD73, an enzyme regulating adenosine turnover, are involved in the renal vascular injury in diabetes. Interestingly, erythrocyte dysfunction in diabetes by decreasing ATP release in response to physiological stimuli may serve as an important trigger to induce vascular dysfunction. Nucleot(s)ide-mediated purinergic activation also exerts long-term actions including inflammatory and atherogenic effects in hyperglycemic and diabetic conditions. This review highlights the current knowledge regarding the altered nucleot(s)ide-mediated purinergic signaling as an important disease mechanism for the diabetes-associated vascular complications. Better understanding the role of key receptor-mediated signaling in diabetes will provide more insights into their potential as targets for the treatment.
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Affiliation(s)
- Rui Zhou
- Institute of Cardiovascular Research, The Key Laboratory of Medical Electrophysiology of Ministry of Education, Southwest Medical University, Luzhou, PR China
| | - Xitong Dang
- Institute of Cardiovascular Research, The Key Laboratory of Medical Electrophysiology of Ministry of Education, Southwest Medical University, Luzhou, PR China
| | - Randy S Sprague
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - S Jamal Mustafa
- Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV, USA
| | - Zhichao Zhou
- Division of Cardiology, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
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Zhang CM, Huang X, Lu HL, Meng XM, Song NN, Chen L, Kim YC, Chen J, Xu WX. Diabetes-induced damage of gastric nitric oxide neurons mediated by P2X7R in diabetic mice. Eur J Pharmacol 2019; 851:151-160. [PMID: 30796903 DOI: 10.1016/j.ejphar.2019.02.033] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 02/17/2019] [Accepted: 02/20/2019] [Indexed: 02/03/2023]
Abstract
It is generally considered that enteric neuropathy is one of the causative factors in diabetic gastroparesis. Our previous study demonstrated that there is a loss of NOS neurons in diabetic mice. However, the underlying mechanism remains unclear. The present study was designed to clarify the relationship between neuronal P2X7R and NOS neuron damage. The effect of P2X7R on diabetes-induced gastric NOS neurons damage and its mechanism were investigated by using quantitative RT-PCR，immunofluorescence, western blot, isometric force recording, intracellular calcium ([Ca2+]i) measurement and whole-cell patch clamp techniques. The immunohistochemistry and western blot results showed that nNOS expression was significantly down-regulated in diabetic mice, meanwhile, electric field stimulation-induced NOS sensitive relaxation was significantly suppressed. Myenteric neurons expressed P2X7R and pannexin1, and the mRNA and protein level of P2X7R and pannexin1 were up-regulated in diabetic mice. BzATP, a P2X7R activator, evoked [Ca2+]i increase in Hek293 cells with heterologous expression of P2X7R (Hek293-P2X7R cells) and the same dose of ATP-induced [Ca2+]i was more obvious in Hek293-P2X7R cells than in Hek293 cells. Application of BzATP activated an inward current of Hek293-P2X7R in a dose dependent manner. Hek293-P2X7R but not untransfected Hek293 cells could take up of YO-PRO-1. In addition, the uptake of YO-PRO-1 by Hek293-P2X7R was blocked by oxATP, a P2X7 antagonist and CBX, a pannexin1 inhibitor. The results suggest that the P2X7R of enteric neurons may be involved in diabetes-induced NOS neuron damage via combining with pannexin-1 to form transmembrane pores which induce macromolecular substances and calcium into the cells.
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Affiliation(s)
- Chun-Mei Zhang
- Department of Pediatric Surgery, Xin Hua Hospital, Affiliated to Shanghai JiaoTong University School of Medicine, 1665 Kong Jiang Road, 200092 Shanghai, India; Department of Physiology, Shanghai Jiaotong University School of Medicine, Shanghai 200240, China
| | - Xu Huang
- Department of Physiology, Shanghai Jiaotong University School of Medicine, Shanghai 200240, China
| | - Hong-Li Lu
- Department of Physiology, Shanghai Jiaotong University School of Medicine, Shanghai 200240, China
| | - Xiang-Min Meng
- Department of Physiology, Shanghai Jiaotong University School of Medicine, Shanghai 200240, China
| | - Ni-Na Song
- Department of Physiology, Shanghai Jiaotong University School of Medicine, Shanghai 200240, China
| | - Lu Chen
- Department of Physiology, Shanghai Jiaotong University School of Medicine, Shanghai 200240, China
| | - Young-Chul Kim
- Department of Physiology, Chungbuk National University College of Medicine, Cheongju, Chungbuk 361-763, Republic of Korea
| | - Jie Chen
- Department of Pediatric Surgery, Xin Hua Hospital, Affiliated to Shanghai JiaoTong University School of Medicine, 1665 Kong Jiang Road, 200092 Shanghai, India.
| | - Wen-Xie Xu
- Department of Physiology, Shanghai Jiaotong University School of Medicine, Shanghai 200240, China.
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Altered Purinergic Receptor Sensitivity in Type 2 Diabetes-Associated Endothelial Dysfunction and Up₄A-Mediated Vascular Contraction. Int J Mol Sci 2018; 19:ijms19123942. [PMID: 30544633 PMCID: PMC6320923 DOI: 10.3390/ijms19123942] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 12/05/2018] [Accepted: 12/07/2018] [Indexed: 02/06/2023] Open
Abstract
Purinergic signaling may be altered in diabetes accounting for endothelial dysfunction. Uridine adenosine tetraphosphate (Up4A), a novel dinucleotide substance, regulates vascular function via both purinergic P1 and P2 receptors (PR). Up4A enhances vascular contraction in isolated arteries of diabetic rats likely through P2R. However, the precise involvement of PRs in endothelial dysfunction and the vasoconstrictor response to Up4A in diabetes has not been fully elucidated. We tested whether inhibition of PRs improved endothelial function and attenuated Up4A-mediated vascular contraction using both aortas and mesenteric arteries of type 2 diabetic (T2D) Goto Kakizaki (GK) rats vs. control Wistar (WT) rats. Endothelium-dependent (EDR) but not endothelium-independent relaxation was significantly impaired in both aortas and mesenteric arteries from GK vs. WT rats. Non-selective inhibition of P1R or P2R significantly improved EDR in aortas but not mesenteric arteries from GK rats. Inhibition of A1R, P2X7R, or P2Y6R significantly improved EDR in aortas. Vasoconstrictor response to Up4A was enhanced in aortas but not mesenteric arteries of GK vs. WT rats via involvement of A1R and P2X7R but not P2Y6R. Depletion of major endothelial component nitric oxide enhanced Up4A-induced aortic contraction to a similar extent between WT and GK rats. No significant differences in protein levels of A1R, P2X7R, and P2Y6R in aortas from GK and WT rats were observed. These data suggest that altered PR sensitivity accounts for endothelial dysfunction in aortas in diabetes. Modulating PRs may represent a potential therapy for improving endothelial function.
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Chen Z, He L, Li L, Chen L. The P2X7 purinergic receptor: An emerging therapeutic target in cardiovascular diseases. Clin Chim Acta 2018; 479:196-207. [PMID: 29366837 DOI: 10.1016/j.cca.2018.01.032] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 01/19/2018] [Accepted: 01/19/2018] [Indexed: 10/24/2022]
Abstract
The P2X7 purinergic receptor, a calcium permeable cationic channel, is activated by extracellular ATP. Most studies show that P2X7 receptor plays an important role in the nervous system diseases, immune response, osteoporosis and cancer. Mounting evidence indicates that P2X7 receptor is also associated with cardiovascular disease. For example, the P2X7 receptor activated by ATP can attenuate myocardial ischemia-reperfusion injury. By contrast, inhibition of P2X7 receptor decreases arrhythmia after myocardial infarction, prolongs cardiac survival after a long term heart transplant, alleviates the dilated cardiomyopathy and the autoimmune myocarditis process. The P2X7 receptor also mitigates vascular diseases including atherosclerosis, hypertension, thrombosis and diabetic retinopathy. This review focuses on the latest research on the role and therapeutic potential of P2X7 receptor in cardiovascular diseases.
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Affiliation(s)
- Zhe Chen
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China
| | - Lu He
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China
| | - Lanfang Li
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China.
| | - Linxi Chen
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China.
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Mancini JE, Ortiz G, Potilinstki C, Salica JP, Lopez ES, Croxatto JO, Gallo JE. Possible neuroprotective role of P2X2 in the retina of diabetic rats. Diabetol Metab Syndr 2018; 10:31. [PMID: 29682007 PMCID: PMC5898034 DOI: 10.1186/s13098-018-0332-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 04/04/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Purinergic receptors are expressed in different tissues including the retina. These receptors are involved in processes like cell growth, proliferation, activation and survival. ATP is the major activator of P2 receptors. In diabetes, there is a constant ATP production and this rise of ATP leads to a persistent activation of purinergic receptors. Antagonists of these receptors are used to evaluate their inhibition effects. Recently, the P2X2 has been reported to have a neuroprotective role. METHODS We carried out a study in groups of diabetic and non-diabetic rats (N = 5) treated with intraperitoneal injections of PPADS, at 9 and 24 weeks of diabetes. Control group received only the buffer. Animals were euthanized at 34 weeks of diabetes or at a matching age. Rat retinas were analyzed with immunohistochemistry and western blot using antibodies against GFAP, P2X2, P2Y2 and VEGF-A. RESULTS Diabetic animals treated with PPADS disclosed a much more extended staining of VEGF-A than diabetics without treatment. A lower protein expression of VEGF-A was found at the retina of diabetic animals without treatment of purinergic antagonists compared to diabetics with the antagonist treatment. Inhibition of P2X2 receptor by PPADS decreases cell death in the diabetic rat retina. CONCLUSION Results might be useful for better understanding the pathophysiology of diabetic retinopathy.
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Affiliation(s)
- Jorge E. Mancini
- Department of Ophthalmology, Nanomedicine & Vision Group, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Juan D. Perón 1500, B1629AHJ Pilar, Buenos Aires Argentina
- Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral, Consejo Nacional de Investigaciones Científicas y Técnicas (UA-CONICET), Pilar, Buenos Aires, Argentina
| | - Gustavo Ortiz
- Department of Ophthalmology, Nanomedicine & Vision Group, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Juan D. Perón 1500, B1629AHJ Pilar, Buenos Aires Argentina
- Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral, Consejo Nacional de Investigaciones Científicas y Técnicas (UA-CONICET), Pilar, Buenos Aires, Argentina
| | - Constanza Potilinstki
- Department of Ophthalmology, Nanomedicine & Vision Group, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Juan D. Perón 1500, B1629AHJ Pilar, Buenos Aires Argentina
- Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral, Consejo Nacional de Investigaciones Científicas y Técnicas (UA-CONICET), Pilar, Buenos Aires, Argentina
| | - Juan P. Salica
- Department of Ophthalmology, Nanomedicine & Vision Group, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Juan D. Perón 1500, B1629AHJ Pilar, Buenos Aires Argentina
- Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral, Consejo Nacional de Investigaciones Científicas y Técnicas (UA-CONICET), Pilar, Buenos Aires, Argentina
| | - Emiliano S. Lopez
- Department of Ophthalmology, Nanomedicine & Vision Group, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Juan D. Perón 1500, B1629AHJ Pilar, Buenos Aires Argentina
- Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral, Consejo Nacional de Investigaciones Científicas y Técnicas (UA-CONICET), Pilar, Buenos Aires, Argentina
| | - J. Oscar Croxatto
- Department of Ocular Pathology, Fundación Oftalmlógica Argentina “Jorge Malbran”, Buenos Aires, Argentina
- Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral, Consejo Nacional de Investigaciones Científicas y Técnicas (UA-CONICET), Pilar, Buenos Aires, Argentina
| | - Juan E. Gallo
- Department of Ophthalmology, Nanomedicine & Vision Group, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Juan D. Perón 1500, B1629AHJ Pilar, Buenos Aires Argentina
- Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral, Consejo Nacional de Investigaciones Científicas y Técnicas (UA-CONICET), Pilar, Buenos Aires, Argentina
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Moriyama S, Hiasa M. Expression of Vesicular Nucleotide Transporter in the Mouse Retina. Biol Pharm Bull 2017; 39:564-9. [PMID: 27040629 DOI: 10.1248/bpb.b15-00872] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Vesicular nucleotide transporter (VNUT) is a membrane protein that is responsible for vesicular storage and subsequent vesicular release of nucleotides, such as ATP, and plays an essential role in purinergic chemical transmission. In the present study, we investigated whether VNUT is present in the rodent retina to define the site(s) of vesicular ATP release. In the mouse retina, reverse transcription polymerase chain reaction (RT-PCR) and immunological analyses using specific anti-VNUT antibodies indicated that VNUT is expressed as a polypeptide with an apparent molecular mass of 59 kDa. VNUT is widely distributed throughout the inner and outer retinal layers, particularly in the outer segment of photoreceptors, outer plexiform layer, inner plexiform layer, and ganglion cell layer. VNUT is colocalized with vesicular glutamate transporter 1 and synaptophysin in photoreceptor cells, while it is colocalized with vesicular γ-aminobutyric acid (GABA) transporter in amacrine cells and bipolar cells. VNUT is also present in astrocytes and Müller cells. The retina from VNUT knockout (VNUT(-/-)) mice showed the loss of VNUT immunoreactivity. The retinal membrane fraction took up radiolabeled ATP in diisothiocyanate stilbene disulfonic acid (DIDS)-, an inhibitor of VNUT, and bafilomycin A1-, a vacuolar adenosine triphosphatase (ATPase) inhibitor, in a sensitive manner, while membranes from VNUT(-/-) mice showed the loss of DIDS-sensitive ATP uptake. Taken together, these results indicate that functional VNUT is expressed in the rodent retina and suggest that ATP is released from photoreceptor cells, bipolar cells, amacrine cells, and astrocytes as well as Müller cells to initiate purinergic chemical transmission.
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Affiliation(s)
- Satomi Moriyama
- Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
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10
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Carracedo G, Crooke A, Guzman-Aranguez A, Pérez de Lara MJ, Martin-Gil A, Pintor J. The role of dinucleoside polyphosphates on the ocular surface and other eye structures. Prog Retin Eye Res 2016; 55:182-205. [PMID: 27421962 DOI: 10.1016/j.preteyeres.2016.07.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Revised: 06/30/2016] [Accepted: 07/05/2016] [Indexed: 11/17/2022]
Abstract
Dinucleoside polyphosphates comprises a group of dinucleotides formed by two nucleosides linked by a variable number of phosphates, abbreviated NpnN (where n represents the number of phosphates). These compounds are naturally occurring substances present in tears, aqueous humour and in the retina. As the consequence of their presence, these dinucleotides contribute to many ocular physiological processes. On the ocular surface, dinucleoside polyphosphates can stimulate tear secretion, mucin release from goblet cells and they help epithelial wound healing by accelerating cell migration rate. These dinucleotides can also stimulate the presence of proteins known to protect the ocular surface against microorganisms, such as lysozyme and lactoferrin. One of the latest discoveries is the ability of some dinucleotides to facilitate the paracellular way on the cornea, therefore allowing the delivery of compounds, such as antiglaucomatous ones, more easily within the eye. The compound Ap4A has been described being abnormally elevated in patient's tears suffering of dry eye, Sjogren syndrome, congenital aniridia, or after refractive surgery, suggesting this molecule as biomarker for dry eye condition. At the intraocular level, some diadenosine polyphosphates are abnormally elevated in glaucoma patients, and this can be related to the stimulation of a P2Y2 receptor that increases the chloride efflux and water movement in the ciliary epithelium. In the retina, the dinucleotide dCp4U, has been proven to be useful to help in the recovery of retinal detachments. Altogether, dinucleoside polyphosphates are a group of compounds which present relevant physiological actions but which also can perform promising therapeutic benefits.
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Affiliation(s)
- Gonzalo Carracedo
- Department of Optics II (Optometry and Vision), Faculty of Optics and Optometry, Universidad Complutense de Madrid, Madrid, Spain
| | - Almudena Crooke
- Department of Biochemistry and Molecular Biology IV, Faculty of Optics and Optometry, Universidad Complutense de Madrid, Madrid, Spain
| | - Ana Guzman-Aranguez
- Department of Biochemistry and Molecular Biology IV, Faculty of Optics and Optometry, Universidad Complutense de Madrid, Madrid, Spain
| | - Maria J Pérez de Lara
- Department of Biochemistry and Molecular Biology IV, Faculty of Optics and Optometry, Universidad Complutense de Madrid, Madrid, Spain
| | - Alba Martin-Gil
- Department of Biochemistry and Molecular Biology IV, Faculty of Optics and Optometry, Universidad Complutense de Madrid, Madrid, Spain
| | - Jesús Pintor
- Department of Biochemistry and Molecular Biology IV, Faculty of Optics and Optometry, Universidad Complutense de Madrid, Madrid, Spain.
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11
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Chavda S, Luthert PJ, Salt TE. P2X 7R modulation of visually evoked synaptic responses in the retina. Purinergic Signal 2016; 12:611-625. [PMID: 27393519 PMCID: PMC5123999 DOI: 10.1007/s11302-016-9522-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 06/24/2016] [Indexed: 10/29/2022] Open
Abstract
P2X7Rs are distributed throughout all layers of the retina, and thus, their localisation on various cell types puts into question their specific site(s) of action. Using a dark-adapted, ex vivo mouse retinal whole mount preparation, the present study aimed to characterise the effect of P2X7R activation on light-evoked, excitatory RGC ON-field excitatory post-synaptic potentials (fEPSPs) and on outer retinal electroretinogram (ERG) responses under comparable conditions. The pharmacologically isolated NMDA receptor-mediated RGC ON-fEPSP was reduced in the presence of BzATP, an effect which was significantly attenuated by A438079 and other selective P2X7R antagonists A804598 or AF27139. In physiological Krebs medium, BzATP induced a significant potentiation of the ERG a-wave, with a concomitant reduction in the b-wave and the power of the oscillatory potentials. Conversely, in the pharmacologically modified Mg2+-free perfusate, BzATP reduced both the a-wave and b-wave. The effects of BzATP on the ERG components were suppressed by A438079. A role for P2X7R function in visual processing in both the inner and outer retina under physiological conditions remains controversial. The ON-fEPSP was significantly reduced in the presence of A804598 but not by A438079 or AF27139. Furthermore, A438079 did not have any effect on the ERG components in physiological Krebs but potentiated and reduced the a-wave and b-wave, respectively, when applied to the pharmacologically modified medium. Therefore, activation of P2X7Rs affects the function in the retinal ON pathway. The presence of a high concentration of extracellular ATP would most likely contribute to the modulation of visual transmission in the retina in the pathophysiological microenvironment.
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Affiliation(s)
- Seetal Chavda
- Visual Neuroscience, UCL Institute of Ophthalmology, London, EC1V 9EL, UK
| | - Philip J Luthert
- Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, London, EC1V 9EL, UK.,NIHR Biomedical Research Centre in Ophthalmology, London, EC1V 9EL, UK
| | - Thomas E Salt
- Visual Neuroscience, UCL Institute of Ophthalmology, London, EC1V 9EL, UK.
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Riis-Vestergaard MJ, Bek T. Purinergic mechanisms and prostaglandin E receptors involved in ATP-induced relaxation of porcine retinal arterioles in vitro. Ophthalmic Res 2015; 54:135-42. [PMID: 26376245 DOI: 10.1159/000438905] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Accepted: 07/22/2015] [Indexed: 11/19/2022]
Abstract
PURPOSE Adenosine triphosphate (ATP) is involved in the tone regulation of retinal arterioles, and the effect may be direct, through ATP degradation or mediated by cyclo-oxygenase products. However, the relative contribution of these mechanisms and the extent to which the mechanisms are active in the retinal vascular wall or depend on the perivascular retinal tissue are unknown. METHODS Porcine retinal arterioles with perivascular retinal tissue were mounted in a wire myograph for isometric tone recordings. The relaxing effects of ATP and the non-degradable analogue ATP-x03B3;S were studied in the presence of antagonists to ATP, adenosine and prostaglandin E (EP) receptors. The experiments were repeated after removal of the perivascular retinal tissue. RESULTS ATP induced a significant concentration-dependent relaxation of retinal arterioles (p < 0.05) which was reduced after removal of perivascular retinal tissue. The effect was due to non-degraded ATP and a degradation product of ATP acting via adenosine receptors. Relaxation was reduced by ibuprofen and blocking of EP1 receptors. CONCLUSION ATP-induced relaxation of retinal arterioles is mediated by ATP, ATP degradation products and by stimulation of EP1 receptors, involving both the perivascular retina and the vascular wall. The findings emphasize the complexity of purinergic effects in the regulation of retinal vascular tone.
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Reichenbach A, Bringmann A. Purinergic signaling in retinal degeneration and regeneration. Neuropharmacology 2015; 104:194-211. [PMID: 25998275 DOI: 10.1016/j.neuropharm.2015.05.005] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 05/07/2015] [Accepted: 05/07/2015] [Indexed: 02/01/2023]
Abstract
Purinergic signaling is centrally involved in mediating the degeneration of the injured and diseased retina, the induction of retinal gliosis, and the protection of the retinal tissue from degeneration. Dysregulated calcium signaling triggered by overactivation of P2X7 receptors is a crucial step in the induction of neuronal and microvascular cell death under pathogenic conditions like ischemia-hypoxia, elevated intraocular pressure, and diabetes, respectively. Overactivation of P2X7 plays also a pathogenic role in inherited and age-related photoreceptor cell death and in the age-related dysfunction and degeneration of the retinal pigment epithelium. Gliosis of micro- and macroglial cells, which is induced and/or modulated by purinergic signaling and associated with an impaired homeostatic support to neurons, and the ATP-mediated propagation of retinal gliosis from a focal injury into the surrounding noninjured tissue are involved in inducing secondary cell death in the retina. On the other hand, alterations in the glial metabolism of extracellular nucleotides, resulting in a decreased level of ATP and an increased level of adenosine, may be neuroprotective in the diseased retina. Purinergic signals stimulate the proliferation of retinal glial cells which contributes to glial scarring which has protective effects on retinal degeneration and adverse effects on retinal regeneration. Pharmacological modulation of purinergic receptors, e.g., inhibition of P2X and activation of adenosine receptors, may have clinical importance for the prevention of photoreceptor, neuronal, and microvascular cell death in diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration, and glaucoma, respectively, for the clearance of retinal edema, and the inhibition of dysregulated cell proliferation in proliferative retinopathies. This article is part of a Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'.
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Affiliation(s)
- Andreas Reichenbach
- Paul Flechsig Institute of Brain Research, University of Leipzig, Leipzig, Germany.
| | - Andreas Bringmann
- Department of Ophthalmology and Eye Hospital, University of Leipzig, Leipzig, Germany
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Sugiyama T. Role of P2X 7 receptors in the development of diabetic retinopathy. World J Diabetes 2014; 5:141-145. [PMID: 24748927 PMCID: PMC3990313 DOI: 10.4239/wjd.v5.i2.141] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 12/04/2013] [Accepted: 01/06/2014] [Indexed: 02/05/2023] Open
Abstract
The P2X7 receptor is one of the members of the family of purinoceptors which are ligand-gated membrane ion channels activated by extracellular adenosine 5’-triphosphate. A unique feature of the P2X7 receptor is that its activation can result in the formation of large plasma membrane pores that allow not only the flux of ions but also of hydrophilic molecules of up to 900 Da. Recent studies indicate that P2X7-mediated signaling can trigger apoptotic cell death after ischemia and during the course of certain neurodegenerative disorders. Expression of the P2X7 receptor has been demonstrated in most types of cells in the retina. This purinoceptor mediates the contraction of pericytes and regulates the spatial and temporal dynamics of the vasomotor response through cell-to-cell electrotonic transmission within the microvascular networks. Of potential clinical significance, investigators have found that diabetes markedly boosts the vulnerability of retinal microvessels to the lethal effect of P2X7 receptor activation. This purinergic vasotoxicity may result in reduced retinal blood flow and disrupted vascular function in the diabetic retina. With recent reports indicating an association between P2X7 receptor activation and inflammatory cytokine expression in the retina, this receptor may also exacerbate the development of diabetic retinopathy by a mechanism involving inflammation.
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Abstract
The pancreas is an organ with a central role in nutrient breakdown, nutrient sensing and release of hormones regulating whole body nutrient homeostasis. In diabetes mellitus, the balance is broken-cells can be starving in the midst of plenty. There are indications that the incidence of diabetes type 1 and 2, and possibly pancreatogenic diabetes, is rising globally. Events leading to insulin secretion and action are complex, but there is emerging evidence that intracellular nucleotides and nucleotides are not only important as intracellular energy molecules but also as extracellular signalling molecules in purinergic signalling cascades. This signalling takes place at the level of the pancreas, where the close apposition of various cells-endocrine, exocrine, stromal and immune cells-contributes to the integrated function. Following an introduction to diabetes, the pancreas and purinergic signalling, we will focus on the role of purinergic signalling and its changes associated with diabetes in the pancreas and selected tissues/organ systems affected by hyperglycaemia and other stress molecules of diabetes. Since this is the first review of this kind, a comprehensive historical angle is taken, and common and divergent roles of receptors for nucleotides and nucleosides in different organ systems will be given. This integrated picture will aid our understanding of the challenges of the potential and currently used drugs targeted to specific organ/cells or disorders associated with diabetes.
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Affiliation(s)
- Geoffrey Burnstock
- Autonomic Neuroscience Centre, University College Medical School, Rowland Hill Street, London, NW3 2PF UK
- Department of Pharmacology, Melbourne University, Melbourne, Australia
| | - Ivana Novak
- Molecular and Integrative Physiology, Department of Biology, University of Copenhagen, August Krogh Building, Universitetsparken 13, 2100 Copenhagen Ø, Denmark
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Guzman-Aranguez A, Santano C, Martin-Gil A, Fonseca B, Pintor J. Nucleotides in the eye: focus on functional aspects and therapeutic perspectives. J Pharmacol Exp Ther 2013; 345:331-41. [PMID: 23504005 DOI: 10.1124/jpet.112.202473] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The presence and activity of nucleotides and dinucleotides in the physiology of most, if not all, organisms, from bacteria to humans, have been recognized by the scientific community, and the eye is no exception. Nucleotides in the dynamic fluids interact with many ocular structures, such as the tears and aqueous humor. Moreover, high concentrations of nucleotides in these secretions may reflect disease states such as dry eye and glaucoma. Apart from the nucleotide concentration in these fluids, P2 purinergic receptors have been described on the ocular surface (cornea and conjunctiva), anterior pole (ciliary body, trabecular meshwork), and posterior pole (retina). P2X and P2Y purinergic receptors are essential in maintaining the homeostasis of ocular processes, such as tear secretion, aqueous humor production, or retinal modulation. When they are functioning properly, they allow the eye to do its job (to see), but in some cases, a lack or an excess of nucleotides or a malfunction in the corresponding purinergic receptors leads to disease. This Perspective is focused on the nucleotides and dinucleotides and the P2 purinergic receptors in the eye and how they contribute to normal and disease states. We also emphasize the action of nucleotides and their receptors and antagonists as potential therapeutic agents.
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Affiliation(s)
- Ana Guzman-Aranguez
- Department of Biochemistry and Molecular Biology, Faculty of Optics and Optometry, Universidad Complutense Madrid, C/Arcos de Jalón 118, 28037 Madrid, Spain
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Ziganshina AP, Ziganshin BA, Ziganshin AU. Dual effects of ATP on isolated arteries of the bovine eye. Pharmacol Res 2012; 66:170-6. [PMID: 22521505 DOI: 10.1016/j.phrs.2012.04.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Revised: 04/03/2012] [Accepted: 04/03/2012] [Indexed: 01/22/2023]
Abstract
Although the presence of purinoreceptors has been shown in many human and animal arteries, there is few data yet about their role in the arteries of the eye. The purpose of the present study was to evaluate the effects of several agonists of purinoreceptors on isolated arteries of the bovine eye. Responses of isolated preparations of bovine ophthalmic (OA) and posterior ciliary arteries (PCA) to agonists of purinoreceptors (ATP, α,β-methylene-ATP-α,β-meATP, 2-methylthioATP-2meSATP, uridine-5'-triphosphate-UTP) as well as agonists of adreno-, cholino-, adenosine and histamine receptors were recorded by a standard organ bath method. ATP induced contractions of the intact vessels but caused relaxation of α,β-meATP-pretreated arteries. Contractile responses of PCA to high concentrations of ATP and α,β-meATP were significantly stronger than responses of OA, as well as relaxative responses to ATP and adenosine were significantly stronger in PCA than in OA. We suggest that there are several subtypes of functionally active purinoreceptors in both OA and PCA, although the potency of agonists of purinoreceptors to produce mechanical responses is higher in PCA than in OA. Purinoreceptors can be potential targets for new drugs, treating vascular pathology of the eye.
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Affiliation(s)
- Anna P Ziganshina
- Kazan State Medical University, 49 Butlerov Str., Kazan 420012, Russia
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Charles BA, Conley YP, Chen G, Miller RG, Dorman JS, Gorin MB, Ferrell RE, Sereika SM, Rotimi CN, Orchard TJ. Variants of the adenosine A(2A) receptor gene are protective against proliferative diabetic retinopathy in patients with type 1 diabetes. Ophthalmic Res 2010; 46:1-8. [PMID: 21088442 PMCID: PMC2997447 DOI: 10.1159/000317057] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2010] [Accepted: 06/09/2010] [Indexed: 11/19/2022]
Abstract
AIMS The adenosine A(2A) receptor (ADORA(2A)) may ameliorate deleterious physiologic effects associated with tissue injury in individuals with diabetes. We explored associations between variants of the ADORA(2A) gene and proliferative diabetic retinopathy (PDR) in a cohort of patients with type 1 diabetes (T1D). METHODS The participants were from the Pittsburgh Epidemiology of Diabetes Complications prospective study of childhood-onset T1D. Stereoscopic photographs of the retinal fundus taken at baseline, then biennially, for 10 years were used to define PDR according to the modified Airlie House system. Two tagging single nucleotide polymorphisms (tSNPs; rs2236624-C/T and rs4822489-G/T) in the ADORA(2A) gene were selected using the HapMap (haplotype map) reference database. RESULTS A significant association was observed between SNP rs2236624 and PDR in the recessive genetic model. Participants homozygous for the T allele displayed a decreased risk of developing prevalent PDR (odds ratio, OR = 0.36; p = 0.04) and incident PDR (hazard ratio = 0.156; p = 0.009), and for all cases of PDR combined (OR = 0.23; p = 0.001). The protective effect of T allele homozygosity remained after adjusting for covariates. Similarly, for SNP rs4822489, an association between PDR and T allele homozygosity was observed following covariate adjustment (OR = 0.55; 95% CI: 0.31-0.92; p = 0.04). CONCLUSION Genetic variants of ADORA(2A) offer statistically significant protection against PDR development in patients with T1D.
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Affiliation(s)
- Bashira A Charles
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-5635, USA.
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Extracellular high dosages of adenosine triphosphate induce inflammatory response and insulin resistance in rat adipocytes. Biochem Biophys Res Commun 2010; 402:455-60. [PMID: 20946888 DOI: 10.1016/j.bbrc.2010.10.028] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2010] [Accepted: 10/06/2010] [Indexed: 01/24/2023]
Abstract
Adenosine triphosphate (ATP), an important signaling molecule, participates in various pathophysiological processes via the activation of purinergic-receptors. Recent studies have shown that the expression and function of purinergic-receptors (P2-receptors) could be altered in diabetic or hyperinsulinemia conditions. To characterize the effect of ATP on insulin signaling, we treated primary rat adipocytes with varied concentrations of ATP. The pre-treatment led to impaired insulin signaling, i.e., blunted phosphorylation in Insulin Receptor Substrate-1 (IRS-1) tyrosine and Protein Kinase B (PKB) Ser473 in response to insulin treatment, when ATP concentration reached 1mM. We then observed that ATP dose-dependently reduced the level of IκB, a negative regulator of inflammatory response. Consistently, IRS-1 Ser307 phosphorylation in response to insulin treatment, a site for inflammatory pathway to interfere insulin signaling, was enhanced by ATP. Furthermore, effects of ATP on insulin signaling and IκB content were blocked by P2-receptor inhibition. Finally, insulin-stimulated glucose uptake was impaired by ATP in adipocytes but not in the L6 muscle cells. This study therefore shows for the first time the involvement of ATP-evoked P2-receptor activation in mediating the inflammatory response and the generation of insulin resistance in adipocytes.
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Sarman S, Mancini J, van der Ploeg I, Croxatto JO, Kvanta A, Gallo JE. Involvement of Purinergic P2 Receptors in Experimental Retinal Neovascularization. Curr Eye Res 2009; 33:285-91. [DOI: 10.1080/02713680701885470] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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P2X(7) Receptors in Neurological and Cardiovascular Disorders. Cardiovasc Psychiatry Neurol 2009; 2009:861324. [PMID: 20029634 PMCID: PMC2794459 DOI: 10.1155/2009/861324] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2009] [Revised: 04/26/2009] [Accepted: 04/27/2009] [Indexed: 01/22/2023] Open
Abstract
P2X receptors are ATP-gated cation channels that mediate fast excitatory transmission in diverse regions of the brain and spinal cord. Several P2X receptor subtypes, including P2X(7), have the unusual property of changing their ion selectivity during prolonged exposure to ATP, which results in a channel pore permeable to molecules as large as 900 daltons. The P2X(7) receptor was originally described in cells of hematopoietic origin, and mediates the influx of Ca(2+) and Na(+) and Ca(2+) and Na(+) ions as well as the release of proinflammatory cytokines. P2X(7) receptors may affect neuronal cell death through their ability to regulate the processing and release of interleukin-1beta, a key mediator in neurodegeneration, chronic inflammation, and chronic pain. Activation of P2X(7), a key mediator in neurodegeneration, chronic inflammation, and chronic pain. Activation of P2X(7) receptors provides an inflammatory stimulus, and P2X(7) receptor-deficient mice have substantially attenuated inflammatory responses, including models of neuropathic and chronic inflammatory pain. Moreover, P2X(7) receptor activity, by regulating the release of proinflammatory cytokines, may be involved in the pathophysiology of depression. Apoptotic cell death occurs in a number of vascular diseases, including atherosclerosis, restenosis, and hypertension, and may be linked to the release of ATP from endothelial cells, P2X(7) receptor activation, proinflammatory cytokine production, and endothelial cell apoptosis. In this context, the P2X(7) receptor may be viewed as a gateway of communication between the nervous, immune, and cardiovascular systems.
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Abstract
This review is focused on purinergic neurotransmission, i.e., ATP released from nerves as a transmitter or cotransmitter to act as an extracellular signaling molecule on both pre- and postjunctional membranes at neuroeffector junctions and synapses, as well as acting as a trophic factor during development and regeneration. Emphasis is placed on the physiology and pathophysiology of ATP, but extracellular roles of its breakdown product, adenosine, are also considered because of their intimate interactions. The early history of the involvement of ATP in autonomic and skeletal neuromuscular transmission and in activities in the central nervous system and ganglia is reviewed. Brief background information is given about the identification of receptor subtypes for purines and pyrimidines and about ATP storage, release, and ectoenzymatic breakdown. Evidence that ATP is a cotransmitter in most, if not all, peripheral and central neurons is presented, as well as full accounts of neurotransmission and neuromodulation in autonomic and sensory ganglia and in the brain and spinal cord. There is coverage of neuron-glia interactions and of purinergic neuroeffector transmission to nonmuscular cells. To establish the primitive and widespread nature of purinergic neurotransmission, both the ontogeny and phylogeny of purinergic signaling are considered. Finally, the pathophysiology of purinergic neurotransmission in both peripheral and central nervous systems is reviewed, and speculations are made about future developments.
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Affiliation(s)
- Geoffrey Burnstock
- Autonomic Neurscience Centre, Royal Free and University College Medical School, London, UK.
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