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Upregulation of the endothelin A (ETA) receptor and its association with neurodegeneration in a rodent model of glaucoma.
BMC Neurosci. 2017 03 01; 18(1):27.BN

Abstract

BACKGROUND

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 ETA receptor overexpression on RGC viability in vitro.

RESULTS

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 ETA receptors 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 ETA receptor expression was found in the retina, primarily in the inner plexiform layer and ganglion cells. A modest increase in staining for ETA receptors was also found in the outer plexiform layer in the retina of rats with IOP elevation. Cell culture studies showed that overexpression of ETA receptors in 661W cells as well as primary RGCs decreases cell viability, compared to empty vector transfected cells. Adeno-associated virus mediated overexpression of the ETA receptor produced an increase in the ETB receptor in primary RGCs.

CONCLUSIONS

Elevated IOP results in an appreciable change in ETA receptor expression in the retina. Overexpression of the ETA receptor results in an overall decrease in cell viability, accompanied by an increase in ETB receptor levels, suggesting the involvement of both ETA and ETB receptors in mediating cell death. These findings raise possibilities for the development of ETA/ETB dual receptor antagonists as neuroprotective treatments for glaucomatous neuropathy.

Authors+Show Affiliations

North Texas Eye Research Institute, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.North Texas Eye Research Institute, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.North Texas Eye Research Institute, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.North Texas Eye Research Institute, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.Texas College of Osteopathic Medicine, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

28249604

Citation

McGrady, Nolan R., et al. "Upregulation of the Endothelin a (ETA) Receptor and Its Association With Neurodegeneration in a Rodent Model of Glaucoma." BMC Neuroscience, vol. 18, no. 1, 2017, p. 27.
McGrady NR, Minton AZ, Stankowska DL, et al. Upregulation of the endothelin A (ETA) receptor and its association with neurodegeneration in a rodent model of glaucoma. BMC Neurosci. 2017;18(1):27.
McGrady, N. R., Minton, A. Z., Stankowska, D. L., He, S., Jefferies, H. B., & Krishnamoorthy, R. R. (2017). Upregulation of the endothelin A (ETA) receptor and its association with neurodegeneration in a rodent model of glaucoma. BMC Neuroscience, 18(1), 27. https://doi.org/10.1186/s12868-017-0346-3
McGrady NR, et al. Upregulation of the Endothelin a (ETA) Receptor and Its Association With Neurodegeneration in a Rodent Model of Glaucoma. BMC Neurosci. 2017 03 1;18(1):27. PubMed PMID: 28249604.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Upregulation of the endothelin A (ETA) receptor and its association with neurodegeneration in a rodent model of glaucoma. AU - McGrady,Nolan R, AU - Minton,Alena Z, AU - Stankowska,Dorota L, AU - He,Shaoqing, AU - Jefferies,Hayden B, AU - Krishnamoorthy,Raghu R, Y1 - 2017/03/01/ PY - 2016/12/22/received PY - 2017/02/16/accepted PY - 2017/3/3/entrez PY - 2017/3/3/pubmed PY - 2017/9/19/medline KW - Endothelin receptor A (ETA) KW - Endothelin receptor B (ETB) KW - Endothelin-1 (ET-1) KW - Endothelin-3 (ET-3) KW - Intraocular pressure (IOP) KW - Neurodegeneration KW - Primary open angle glaucoma (POAG) KW - Retinal ganglion cells (RGCs) SP - 27 EP - 27 JF - BMC neuroscience JO - BMC Neurosci VL - 18 IS - 1 N2 - BACKGROUND: 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 ETA receptor overexpression on RGC viability in vitro. RESULTS: 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 ETA receptors 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 ETA receptor expression was found in the retina, primarily in the inner plexiform layer and ganglion cells. A modest increase in staining for ETA receptors was also found in the outer plexiform layer in the retina of rats with IOP elevation. Cell culture studies showed that overexpression of ETA receptors in 661W cells as well as primary RGCs decreases cell viability, compared to empty vector transfected cells. Adeno-associated virus mediated overexpression of the ETA receptor produced an increase in the ETB receptor in primary RGCs. CONCLUSIONS: Elevated IOP results in an appreciable change in ETA receptor expression in the retina. Overexpression of the ETA receptor results in an overall decrease in cell viability, accompanied by an increase in ETB receptor levels, suggesting the involvement of both ETA and ETB receptors in mediating cell death. These findings raise possibilities for the development of ETA/ETB dual receptor antagonists as neuroprotective treatments for glaucomatous neuropathy. SN - 1471-2202 UR - https://www.unboundmedicine.com/medline/citation/28249604/Upregulation_of_the_endothelin_A__ETA__receptor_and_its_association_with_neurodegeneration_in_a_rodent_model_of_glaucoma_ L2 - https://bmcneurosci.biomedcentral.com/articles/10.1186/s12868-017-0346-3 DB - PRIME DP - Unbound Medicine ER -