Maria Fernanda Suarez, Tatsuo Itakura, Satyabrata Pany, Shinwu Jeong, S. Chintala, Michael B. Raizman, Steven Riesinger, Tsvetelina Lazarova, José Echenique, Horacio M. Serra, W. D. Stamer, M. Fini
{"title":"GPR158过表达在眼水流出通路小梁网细胞中的调控作用","authors":"Maria Fernanda Suarez, Tatsuo Itakura, Satyabrata Pany, Shinwu Jeong, S. Chintala, Michael B. Raizman, Steven Riesinger, Tsvetelina Lazarova, José Echenique, Horacio M. Serra, W. D. Stamer, M. Fini","doi":"10.3390/stresses3030044","DOIUrl":null,"url":null,"abstract":"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 Gpr158 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 GPR158 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 GPR158 overexpression, but not enough to inhibit dexamethasone-induced fibrosis or calcification in TM cells, and loss of Gpr158 in knockout mice only minimally protected against dexamethasone-induced ocular hypertension. Depending on dose, GPR158 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.","PeriodicalId":54759,"journal":{"name":"Journal of Thermal Stresses","volume":null,"pages":null},"PeriodicalIF":2.6000,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Regulatory Effects of GPR158 Overexpression in Trabecular Meshwork Cells of the Eye’s Aqueous Outflow Pathways\",\"authors\":\"Maria Fernanda Suarez, Tatsuo Itakura, Satyabrata Pany, Shinwu Jeong, S. Chintala, Michael B. Raizman, Steven Riesinger, Tsvetelina Lazarova, José Echenique, Horacio M. Serra, W. D. Stamer, M. Fini\",\"doi\":\"10.3390/stresses3030044\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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 Gpr158 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 GPR158 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 GPR158 overexpression, but not enough to inhibit dexamethasone-induced fibrosis or calcification in TM cells, and loss of Gpr158 in knockout mice only minimally protected against dexamethasone-induced ocular hypertension. Depending on dose, GPR158 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.\",\"PeriodicalId\":54759,\"journal\":{\"name\":\"Journal of Thermal Stresses\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.6000,\"publicationDate\":\"2023-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Thermal Stresses\",\"FirstCategoryId\":\"5\",\"ListUrlMain\":\"https://doi.org/10.3390/stresses3030044\",\"RegionNum\":3,\"RegionCategory\":\"工程技术\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"MECHANICS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Thermal Stresses","FirstCategoryId":"5","ListUrlMain":"https://doi.org/10.3390/stresses3030044","RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MECHANICS","Score":null,"Total":0}
Regulatory Effects of GPR158 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 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 Gpr158 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 GPR158 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 GPR158 overexpression, but not enough to inhibit dexamethasone-induced fibrosis or calcification in TM cells, and loss of Gpr158 in knockout mice only minimally protected against dexamethasone-induced ocular hypertension. Depending on dose, GPR158 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.
期刊介绍:
The first international journal devoted exclusively to the subject, Journal of Thermal Stresses publishes refereed articles on the theoretical and industrial applications of thermal stresses. Intended as a forum for those engaged in analytic as well as experimental research, this monthly journal includes papers on mathematical and practical applications. Emphasis is placed on new developments in thermoelasticity, thermoplasticity, and theory and applications of thermal stresses. Papers on experimental methods and on numerical methods, including finite element methods, are also published.