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 C Johnson; John C Morrison; Gulab S Zode; Val C Sheffield; Xiulan Zhang; Alan M Laties; Claire H Mitchell

doi:10.1167/iovs.14-15891

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

Journal article

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Peer reviewed

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 C Johnson, John C Morrison, Gulab S Zode, Val C Sheffield, Xiulan Zhang, …

Investigative ophthalmology & visual science, Vol.56(5), pp.3075-3083

05/2015

DOI: 10.1167/iovs.14-15891

PMCID: PMC4439132

PMID: 26024091

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Abstract

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. 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. 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. 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.

Immunohistochemistry

Signal Transduction

Cell Count

Macaca fascicularis

Immunoblotting

Male

Posterior Eye Segment - metabolism

Antigens, CD - genetics

Antigens, CD - metabolism

Retinal Ganglion Cells - pathology

Rats, Inbred BN

Adenosine Triphosphate - metabolism

Female

Glaucoma - metabolism

Real-Time Polymerase Chain Reaction

Disease Models, Animal

Mice, Inbred C57BL

Apyrase - metabolism

Intraocular Pressure - physiology

Rats

Mice, Transgenic

Animals

Apyrase - genetics

Mice

Chronic Disease

Details

Title: Subtitle: Rat, mouse, and primate models of chronic glaucoma show sustained elevation of extracellular ATP and altered purinergic signaling in the posterior eye
Creators: Wennan Lu - Department of Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
HuiLing Hu - Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States 3State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, People's Republic of China
Jean Sévigny - Département de Microbiologie-Infectiologie et D'immunologie, Faculté de Médecine, Université Laval, and Centre de Recherche du CHU de Québec, Québec, Québec, Canada
B'Ann T Gabelt - Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States
Paul L Kaufman - Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States
Elaine C Johnson - Kenneth C. Swan Ocular Neurobiology Laboratory, Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, United States
John C Morrison - Kenneth C. Swan Ocular Neurobiology Laboratory, Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, United States
Gulab S Zode - Howard Hughes Medical Institute, University of Iowa, Iowa City, Iowa, United States 8Department of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas, United States
Val C Sheffield - Howard Hughes Medical Institute, University of Iowa, Iowa City, Iowa, United States
Xiulan Zhang - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, People's Republic of China
Alan M Laties - Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Claire H Mitchell - Department of Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States 2Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Resource Type: Journal article
Publication Details: Investigative ophthalmology & visual science, Vol.56(5), pp.3075-3083
Publisher: United States
DOI: 10.1167/iovs.14-15891
PMID: 26024091
PMCID: PMC4439132
ISSN: 0146-0404
eISSN: 1552-5783
Grant note: EY016665 / NEI NIH HHS Howard Hughes Medical Institute R01 EY002698 / NEI NIH HHS EY013434 / NEI NIH HHS EY10564 / NEI NIH HHS R01 EY010145 / NEI NIH HHS EY10009 / NEI NIH HHS K99 EY022077 / NEI NIH HHS MOP-93683 / Canadian Institutes of Health Research P30 EY001583 / NEI NIH HHS EY001583 / NEI NIH HHS R01 EY015537 / NEI NIH HHS R01 EY024259 / NEI NIH HHS R01 EY013434 / NEI NIH HHS P30 EY010572 / NEI NIH HHS EY016866 / NEI NIH HHS R01 EY016866 / NEI NIH HHS EY02698 / NEI NIH HHS R00 EY022077 / NEI NIH HHS P30 EY016665 / NEI NIH HHS EY022077 / NEI NIH HHS EY010145 / NEI NIH HHS EY015537 / NEI NIH HHS R01 EY010009 / NEI NIH HHS R01 EY010564 / NEI NIH HHS
Language: English
Date published: 05/2015
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
Record Identifier: 9984065484002771

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