Rat, mouse, and primate models of chronic glaucoma show sustained elevation of extracellular ATP and altered purinergic signaling in the posterior eye

Wennan Lu, Huiling Hu, Jean Sévigny, B’ann T. Gabelt, Paul L. Kaufman, Elaine Johnson, John Morrison, Gulab S. Zode, Val C. Sheffield, Xiulan Zhang, Alan M. Laties, Claire H. Mitchell

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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-MyocY437H 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.

Original languageEnglish (US)
Pages (from-to)3075-3083
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume56
Issue number5
DOIs
StatePublished - 2015

Fingerprint

Glaucoma
Primates
Adenosine Triphosphate
Astrocytes
Retinal Neurons
Trabecular Meshwork
Wit and Humor
Macaca fascicularis
Light Coagulation
Optic Disk
Optic Nerve
Luciferases
Veins
Lasers
Up-Regulation
Animal Models
Immunohistochemistry
Inflammation
Neurons
Injections

Keywords

  • ATP release
  • Mechanosensitive
  • Retina

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Rat, mouse, and primate models of chronic glaucoma show sustained elevation of extracellular ATP and altered purinergic signaling in the posterior eye. / Lu, Wennan; Hu, Huiling; Sévigny, Jean; Gabelt, B’ann T.; Kaufman, Paul L.; Johnson, Elaine; Morrison, John; Zode, Gulab S.; Sheffield, Val C.; Zhang, Xiulan; Laties, Alan M.; Mitchell, Claire H.

In: Investigative Ophthalmology and Visual Science, Vol. 56, No. 5, 2015, p. 3075-3083.

Research output: Contribution to journalArticle

Lu, Wennan ; Hu, Huiling ; Sévigny, Jean ; Gabelt, B’ann T. ; Kaufman, Paul L. ; Johnson, Elaine ; Morrison, John ; Zode, Gulab S. ; Sheffield, Val C. ; Zhang, Xiulan ; Laties, Alan M. ; Mitchell, Claire H. / Rat, mouse, and primate models of chronic glaucoma show sustained elevation of extracellular ATP and altered purinergic signaling in the posterior eye. In: Investigative Ophthalmology and Visual Science. 2015 ; Vol. 56, No. 5. pp. 3075-3083.
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abstract = "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-MyocY437H 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.",
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T1 - Rat, mouse, and primate models of chronic glaucoma show sustained elevation of extracellular ATP and altered purinergic signaling in the posterior eye

AU - Lu, Wennan

AU - Hu, Huiling

AU - Sévigny, Jean

AU - Gabelt, B’ann T.

AU - Kaufman, Paul L.

AU - Johnson, Elaine

AU - Morrison, John

AU - Zode, Gulab S.

AU - Sheffield, Val C.

AU - Zhang, Xiulan

AU - Laties, Alan M.

AU - Mitchell, Claire H.

PY - 2015

Y1 - 2015

N2 - 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-MyocY437H 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.

AB - 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-MyocY437H 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.

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KW - Mechanosensitive

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