title: Rat, mouse, and primate models of chronic glaucoma show sustained elevation of extracellular ATP and altered purinergic signaling in the posterior eye.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States.
authors.forename: Wennan
authors.initials: W
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: HuiLing
authors.initials: H
authors.lastname: Hu
authors.affiliation: Département de Microbiologie-Infectiologie et D'immunologie, Faculté de Médecine, Université Laval, and Centre de Recherche du CHU de Québec, Québec, Québec, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Sévigny
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States.
authors.forename: B'Ann T
authors.initials: BT
authors.lastname: Gabelt
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Kaufman
authors.affiliation: Kenneth C. Swan Ocular Neurobiology Laboratory, Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, United States.
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Johnson
authors.affiliation: Kenneth C. Swan Ocular Neurobiology Laboratory, Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, United States.
authors.forename: John C
authors.initials: JC
authors.lastname: Morrison
authors.affiliation: 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.
authors.forename: Gulab S
authors.initials: GS
authors.lastname: Zode
authors.affiliation: Howard Hughes Medical Institute, University of Iowa, Iowa City, Iowa, United States.
authors.forename: Val C
authors.initials: VC
authors.lastname: Sheffield
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Xiulan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Laties
authors.affiliation: Department of Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States 2Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States.
authors.forename: Claire H
authors.initials: CH
authors.lastname: Mitchell
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D001081:Apyrase / Q000235:genetics* / Q000378:metabolism; D002452:Cell Count; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D005901:Glaucoma / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D007429:Intraocular Pressure / Q000502:physiology*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057972:Posterior Eye Segment / Q000378:metabolism*; D051381:Rats; D011914:Rats, Inbred BN; D060888:Real-Time Polymerase Chain Reaction; D012165:Retinal Ganglion Cells / Q000473:pathology; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; D000255:Adenosine Triphosphate; D001081:Apyrase; C067869:CD39 antigen