Regulatory Effects of <i>GPR158</i> Overexpression in Trabecular Meshwork Cells of the Eye’s Aqueous Outflow Pathways
Elevated intraocular pressure (IOP), the major risk factor for glaucoma, is caused by decreased outflow through the trabecular meshwork (TM). The pathophysiology of ocular hypertension has been linked to stress pathways, including fibrosis, calcification and the unfolded protein response (UPR). In a...
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MDPI AG
2023-09-01
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| Series: | Stresses |
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| Online Access: | https://www.mdpi.com/2673-7140/3/3/44 |
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| author | Maria Fernanda Suarez Tatsuo Itakura Satyabrata Pany Shinwu Jeong Shravan K. Chintala Michael B. Raizman Steven Riesinger Tsvetelina Lazarova José Echenique Horacio M. Serra W. Daniel Stamer M. Elizabeth Fini |
| author_facet | Maria Fernanda Suarez Tatsuo Itakura Satyabrata Pany Shinwu Jeong Shravan K. Chintala Michael B. Raizman Steven Riesinger Tsvetelina Lazarova José Echenique Horacio M. Serra W. Daniel Stamer M. Elizabeth Fini |
| author_sort | Maria Fernanda Suarez |
| collection | DOAJ |
| description | Elevated intraocular pressure (IOP), the major risk factor for glaucoma, is caused by decreased outflow through the trabecular meshwork (TM). The pathophysiology of ocular hypertension has been linked to stress pathways, including fibrosis, calcification and the unfolded protein response (UPR). In a pharmacogenomic screen, we previously identified the novel G-protein-coupled receptor (GPCR), GPR158, showed that expression is upregulated in TM cells by glucocorticoid stress hormones, and showed that overexpression protects against oxidative stress. We also found that loss of <i>Gpr158</i> in knockout mice negates IOP reduction due to treatment with the catecholamine stress hormone, epinephrine. An increase in GPR158 would be expected to alter the activity of GPR158-regulated pathways. Here, we profiled gene expression changes due to <i>GPR158</i> overexpression by microarray, then conducted pathway analysis. We identified five upstream stress regulators relevant to ocular hypertension: dexamethasone and TGFB1 (fibrosis), XBP1 and ATF4 (UPR), and TP53 (cell cycle arrest). Key genes in the first three pathways were downregulated by <i>GPR158</i> overexpression, but not enough to inhibit dexamethasone-induced fibrosis or calcification in TM cells, and loss of <i>Gpr158</i> in knockout mice only minimally protected against dexamethasone-induced ocular hypertension. Depending on dose, <i>GPR158</i> overexpression down- or upregulated the TP53 pathway, suggesting the mechanism for previously observed effects on cell proliferation. A sixth upstream regulator we identified was a GPCR: the beta-adrenergic receptor ADRB1. Adrenergic receptors serve as targets for IOP-lowering drugs, including epinephrine. These data provide new information about pathways regulated by GPR158. |
| first_indexed | 2024-03-10T21:59:48Z |
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| institution | Directory Open Access Journal |
| issn | 2673-7140 |
| language | English |
| last_indexed | 2024-03-10T21:59:48Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
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| series | Stresses |
| spelling | doaj.art-d7b8cb97eb0046e480769cd972be43a12023-11-19T13:00:58ZengMDPI AGStresses2673-71402023-09-013362965210.3390/stresses3030044Regulatory Effects of <i>GPR158</i> Overexpression in Trabecular Meshwork Cells of the Eye’s Aqueous Outflow PathwaysMaria Fernanda Suarez0Tatsuo Itakura1Satyabrata Pany2Shinwu Jeong3Shravan K. Chintala4Michael B. Raizman5Steven Riesinger6Tsvetelina Lazarova7José Echenique8Horacio M. Serra9W. Daniel Stamer10M. Elizabeth Fini11Department of Ophthalmology, Tufts University School of Medicine at Tufts Medical Center, Boston, MA 02111, USAUSC Institute for Genetic Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90007, USADepartment of Ophthalmology, Tufts University School of Medicine at Tufts Medical Center, Boston, MA 02111, USADepartment of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90007, USAUSC Institute for Genetic Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90007, USADepartment of Ophthalmology, Tufts University School of Medicine at Tufts Medical Center and Ophthalmic Consultants of Boston, Boston, MA 02111, USAMedChem Partners, Lexington, MA 02421, USAMedChem Partners, Lexington, MA 02421, USACentro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Department of Clinical Biochemistry, Faculty of Chemistry, National University of Córdoba, Córdoba 5000, ArgentinaCentro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Department of Clinical Biochemistry, Faculty of Chemistry, National University of Córdoba, Córdoba 5000, ArgentinaDepartment of Ophthalmology, Duke University, Durham, NC 27708, USADepartment of Ophthalmology, Tufts University School of Medicine at Tufts Medical Center and Programs in Pharmacology & Drug Development and Genetics, Molecular & Cellular Biology, Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USAElevated intraocular pressure (IOP), the major risk factor for glaucoma, is caused by decreased outflow through the trabecular meshwork (TM). The pathophysiology of ocular hypertension has been linked to stress pathways, including fibrosis, calcification and the unfolded protein response (UPR). In a pharmacogenomic screen, we previously identified the novel G-protein-coupled receptor (GPCR), GPR158, showed that expression is upregulated in TM cells by glucocorticoid stress hormones, and showed that overexpression protects against oxidative stress. We also found that loss of <i>Gpr158</i> in knockout mice negates IOP reduction due to treatment with the catecholamine stress hormone, epinephrine. An increase in GPR158 would be expected to alter the activity of GPR158-regulated pathways. Here, we profiled gene expression changes due to <i>GPR158</i> overexpression by microarray, then conducted pathway analysis. We identified five upstream stress regulators relevant to ocular hypertension: dexamethasone and TGFB1 (fibrosis), XBP1 and ATF4 (UPR), and TP53 (cell cycle arrest). Key genes in the first three pathways were downregulated by <i>GPR158</i> overexpression, but not enough to inhibit dexamethasone-induced fibrosis or calcification in TM cells, and loss of <i>Gpr158</i> in knockout mice only minimally protected against dexamethasone-induced ocular hypertension. Depending on dose, <i>GPR158</i> overexpression down- or upregulated the TP53 pathway, suggesting the mechanism for previously observed effects on cell proliferation. A sixth upstream regulator we identified was a GPCR: the beta-adrenergic receptor ADRB1. Adrenergic receptors serve as targets for IOP-lowering drugs, including epinephrine. These data provide new information about pathways regulated by GPR158.https://www.mdpi.com/2673-7140/3/3/44ocular hypertensionglaucomaG-protein-coupled receptorGPR158dexamethasoneTGFB1 |
| spellingShingle | Maria Fernanda Suarez Tatsuo Itakura Satyabrata Pany Shinwu Jeong Shravan K. Chintala Michael B. Raizman Steven Riesinger Tsvetelina Lazarova José Echenique Horacio M. Serra W. Daniel Stamer M. Elizabeth Fini Regulatory Effects of <i>GPR158</i> Overexpression in Trabecular Meshwork Cells of the Eye’s Aqueous Outflow Pathways Stresses ocular hypertension glaucoma G-protein-coupled receptor GPR158 dexamethasone TGFB1 |
| title | Regulatory Effects of <i>GPR158</i> Overexpression in Trabecular Meshwork Cells of the Eye’s Aqueous Outflow Pathways |
| title_full | Regulatory Effects of <i>GPR158</i> Overexpression in Trabecular Meshwork Cells of the Eye’s Aqueous Outflow Pathways |
| title_fullStr | Regulatory Effects of <i>GPR158</i> Overexpression in Trabecular Meshwork Cells of the Eye’s Aqueous Outflow Pathways |
| title_full_unstemmed | Regulatory Effects of <i>GPR158</i> Overexpression in Trabecular Meshwork Cells of the Eye’s Aqueous Outflow Pathways |
| title_short | Regulatory Effects of <i>GPR158</i> Overexpression in Trabecular Meshwork Cells of the Eye’s Aqueous Outflow Pathways |
| title_sort | regulatory effects of i gpr158 i overexpression in trabecular meshwork cells of the eye s aqueous outflow pathways |
| topic | ocular hypertension glaucoma G-protein-coupled receptor GPR158 dexamethasone TGFB1 |
| url | https://www.mdpi.com/2673-7140/3/3/44 |
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