title: Upregulation of the endothelin A (ETA) receptor and its association with neurodegeneration in a rodent model of glaucoma.
abstract: Primary open angle glaucoma is a heterogeneous group of optic neuropathies that results in optic nerve degeneration and a loss of retinal ganglion cells (RGCs) ultimately causing blindness if allowed to progress. Elevation of intraocular pressure (IOP) is the most attributable risk factor for developing glaucoma and lowering of IOP is currently the only available therapy. However, despite lowering IOP, neurodegenerative effects persist in some patients. Hence, it would be beneficial to develop approaches to promote neuroprotection of RGCs in addition to IOP lowering therapies. The endothelin system is a key target for intervention against glaucomatous neurodegeneration. The endothelin family of peptides and receptors, particularly endothelin-1 (ET-1) and endothelin B (ETB) receptor, has been shown to have neurodegenerative roles in glaucoma. The purpose of this study was to examine changes in endothelin A (ETA) receptor protein expression in the retinas of adult male Brown Norway rats following IOP elevation by the Morrison's model of ocular hypertension and the impact of ETAreceptor overexpression on RGC viability in vitro.
  
  
  
  IOP elevation was carried out in one eye of Brown Norway rats by injection of hypertonic saline through episcleral veins. After 2 weeks of IOP elevation, immunohistochemical analysis of retinal sections from rat eyes showed an increasing trend in immunostaining for ETAreceptors in multiple retinal layers including the inner plexiform layer, ganglion cell layer and outer plexiform layer. Following 4 weeks of IOP elevation, a significant increase in immunostaining for ETAreceptor expression was found in the retina, primarily in the inner plexiform layer and ganglion cells. A modest increase in staining for ETAreceptors was also found in the outer plexiform layer in the retina of rats with IOP elevation. Cell culture studies showed that overexpression of ETAreceptors in 661W cells as well as primary RGCs decreases cell viability, compared to empty vector transfected cells. Adeno-associated virus mediated overexpression of the ETAreceptor produced an increase in the ETBreceptor in primary RGCs.
  
  
  
  Elevated IOP results in an appreciable change in ETAreceptor expression in the retina. Overexpression of the ETAreceptor results in an overall decrease in cell viability, accompanied by an increase in ETBreceptor levels, suggesting the involvement of both ETAand ETBreceptors in mediating cell death. These findings raise possibilities for the development of ETA/ETBdual receptor antagonists as neuroprotective treatments for glaucomatous neuropathy.
authors.affiliation: North Texas Eye Research Institute, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.
authors.forename: Nolan R
authors.initials: NR
authors.lastname: McGrady
authors.affiliation: North Texas Eye Research Institute, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.
authors.forename: Alena Z
authors.initials: AZ
authors.lastname: Minton
authors.affiliation: North Texas Eye Research Institute, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.
authors.forename: Dorota L
authors.initials: DL
authors.lastname: Stankowska
authors.affiliation: North Texas Eye Research Institute, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.
authors.forename: Shaoqing
authors.initials: S
authors.lastname: He
authors.affiliation: Texas College of Osteopathic Medicine, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.
authors.forename: Hayden B
authors.initials: HB
authors.lastname: Jefferies
authors.affiliation: North Texas Eye Research Institute, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA. raghu.krishnamoorthy@unthsc.edu.
authors.forename: Raghu R
authors.initials: RR
authors.lastname: Krishnamoorthy
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005822:Genetic Vectors; D005901:Glaucoma / Q000378:metabolism* / Q000473:pathology; D007429:Intraocular Pressure / Q000502:physiology; D008297:Male; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D000066829:Neuroprotection / Q000502:physiology; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D015854:Up-Regulation
chemical_list: D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B
keywords: Endothelin receptor A (ETA); Endothelin receptor B (ETB); Endothelin-1 (ET-1); Endothelin-3 (ET-3); Intraocular pressure (IOP); Neurodegeneration; Primary open angle glaucoma (POAG); Retinal ganglion cells (RGCs)