Sustained elevation of extracellular ATP in aqueous humor from humans with primary chronic angle-closure glaucoma

Li, Ang; Zhang, Xiulan; Zheng, Danying; Ge, Jian; Laties, Alan M.; Mitchell, Claire H.

doi:10.1016/j.exer.2011.06.020

Cited by 58 publications

(49 citation statements)

References 49 publications

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“…To complicate the complexity of dinucleotides in the regulation of aqueous humour dynamics even more, studies have shown that glaucomatous patients present increased levels of Ap 4 A in their aqueous humour [7], which were almost 15 times higher in glaucoma patients than in healthy individuals. This increase in the dinucleotide levels has also been described in the case of ATP [15].…”

Section: Introductionsupporting

confidence: 69%

Diadenosine tetraphosphate as a potential therapeutic nucleotide to treat glaucoma

Fonseca

Martínez-Águila

Lara

et al. 2016

Purinergic Signalling

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Glaucoma is a neurodegenerative disease that produces blindness. The main factor associated with this disease is an abnormally elevated intraocular pressure (IOP). To date, some attempts have been made to demonstrate the role of nucleotides modulating IOP, but never in a model of glaucoma. The DBA/2J mouse is an animal that develops the pathology spontaneously, starting from the typical rise in IOP at 9 months of age. Using this animal model, together with a control mouse, C57BL/6J, it has been possible to monitor the elevation in IOP in the glaucomatous mice and to check the ability of the dinucleotide diadenosine tetraphosphate AKA Ap 4 A to reduce IOP. The topical application of Ap 4 A when IOP is maximal (9-12 months) reduced IOP 30.6 ± 6.6% in the DBA/2J and 17.9 ± 4.0% in the C57BL/ 6J mice. Concentration response curves in both animal strains produced similar pD2 values; these being 4.9 ± 0.5 and 5.1 ± 0.4 for the normotensive C57BL/6J and the glaucomatous DBA/2J respectively. Antagonist studies showed differences between the control and the glaucomatous animals. In particular, the main receptor reducing IOP in the control animal was the P2Y 1 receptor and in the glaucomatous model the P2Y 6 , although the participation of other P2 receptors cannot be ruled out. The long-term effect of Ap 4 A applied three times a week for 3 months showed a clear stop in the elevation of IOP in the glaucomatous model, thus indicating the possibility of using Ap 4 A as an effective compound for the treatment of glaucoma.

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Section: Introductionsupporting

confidence: 69%

Diadenosine tetraphosphate as a potential therapeutic nucleotide to treat glaucoma

Fonseca

Martínez-Águila

Lara

et al. 2016

Purinergic Signalling

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“…We have previously demonstrated that humans with primary chronic angle closure glaucoma (PCACG) have a 14-fold increase in ATP levels in the anterior chamber. 26 While this finding supports the theory that a chronic elevation in IOP leads to a sustained elevation in extracellular ATP release, it was not possible to confirm this increase in the human retina as sampling was only justified from the anterior segment in these patients and not in the vitreal chamber. As the pathological changes to the retina and optic nerve head are most directly associated with vision loss, it is important to determine whether elevated extracellular levels of ATP also occur in the posterior eye during a chronic rise in IOP.…”

Section: Discussionmentioning

confidence: 72%

Rat, Mouse, and Primate Models of Chronic Glaucoma Show Sustained Elevation of Extracellular ATP and Altered Purinergic Signaling in the Posterior Eye

Sévigny

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Lu W, Hu H, Sévigny J, et al. Rat, mouse, and primate models of chronic glaucoma show sustained elevation of extracellular ATP and altered purinergic signaling in the posterior eye. Invest Ophthalmol Vis Sci. 2015;56:3075-3083. DOI:10.1167/iovs.14-15891 PURPOSE. The cellular mechanisms linking elevated IOP with glaucomatous damage remain unresolved. Mechanical strains and short-term increases in IOP can trigger ATP release from retinal neurons and astrocytes, but the response to chronic IOP elevation is unknown. As excess extracellular ATP can increase inflammation and damage neurons, we asked if sustained IOP elevation was associated with a sustained increase in extracellular ATP in the posterior eye. METHODS.No ideal animal model of chronic glaucoma exists, so three different models were used. Tg-Myoc Y437H mice were examined at 40 weeks, while IOP was elevated in rats following injection of hypertonic saline into episcleral veins and in cynomolgus monkeys by laser photocoagulation of the trabecular meshwork. The ATP levels were measured using the luciferin-luciferase assay while levels of NTPDase1 were assessed using qPCR, immunoblots, and immunohistochemistry.RESULTS. The ATP levels were elevated in the vitreal humor of rats, mice, and primates after a sustained period of IOP elevation. The ecto-ATPase NTPDase1 was elevated in optic nerve head astrocytes exposed to extracellular ATP for an extended period. NTPDase1 was also elevated in the retinal tissue of rats, mice, and primates, and in the optic nerve of rats, with chronic elevation in IOP. CONCLUSIONS.A sustained elevation in extracellular ATP, and upregulation of NTPDase1, occurs in the posterior eye of rat, mouse, and primate models of chronic glaucoma. This suggests the elevation in extracellular ATP may be sustained in chronic glaucoma, and implies a role for altered purinergic signaling in the disease.Keywords: ATP release, mechanosensitive, retina G laucoma is one of the leading causes of blindness in humans and is characterized by damage to retinal ganglion cells (RGCs) and the optic nerve.1,2 While abnormally high IOP is a widely recognized risk factor, 3,4 the molecular pathways linking elevated IOP and RGC loss are complex. Although several inroads toward understanding the mechanisms have recently been made, 5-13 much remains to be learned, particularly regarding the responses in chronic injury. Extracellular ATP is a likely candidate to link the elevated IOP in glaucoma to perturbed signaling in the retina and optic nerve. Throughout the body, released ATP conveys information about mechanical strain and accompanies shear stress, swelling, and stretch. [14][15][16][17][18] This mechanosensitive release of ATP can initiate a series of physiological and pathological responses including cell death, volume regulation, pain, inflammatory responses, and neuroprotection by activating ionotropic P2X and metabotropic P2Y receptors. 19Evidence is accumulating for an increased release of ATP following IOP elevation in glaucoma. For instance...

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“…Pintor's group has extensively studied nucleotide-mediated IOP changes (18)(19)(20)39), and our data showing a hypotensive UDP effect was consistent with their results. In addition to the physiological roles of extracellular nucleotides, intraocular nucleotide levels have been reported to be elevated in the aqueous humor of glaucoma patients (13,14,40), indicating the pathological roles of dysregulated purinergic signaling in glaucoma. However, before this study, it was unclear whether the dysregulation of purinergic signaling contributed to the pathogenesis of glaucoma.…”

Section: Discussionmentioning

confidence: 99%

“…Nucleotides are released from various tissues and cells, including lens (6), trabecular meshwork (7), whole retina (8), corneal endothelial cells (9), retinal ganglion cells (RGCs) (10), retinal astrocytes (11), and ciliary body (CB) (12). ATP levels in the aqueous humor are highly elevated in glaucoma patients (13,14), and although IOP and ATP levels in the aqueous humor are positively correlated in patients (14), their interaction is undefined. Extracellular nucleotides including ATP bind to purinergic P2 receptors (15).…”

Section: Introductionmentioning

confidence: 99%

Purinergic dysregulation causes hypertensive glaucoma–like optic neuropathy

Shinozaki¹,

Kashiwagi²,

Namekata³

et al. 2017

JCI Insight

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Sustained elevation of extracellular ATP in aqueous humor from humans with primary chronic angle-closure glaucoma

Cited by 58 publications

References 49 publications

Diadenosine tetraphosphate as a potential therapeutic nucleotide to treat glaucoma

Diadenosine tetraphosphate as a potential therapeutic nucleotide to treat glaucoma

Rat, Mouse, and Primate Models of Chronic Glaucoma Show Sustained Elevation of Extracellular ATP and Altered Purinergic Signaling in the Posterior Eye

Purinergic dysregulation causes hypertensive glaucoma–like optic neuropathy

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