Regulatory Effects of <i>GPR158</i> Overexpression in Trabecular Meshwork Cells of the Eye’s Aqueous Outflow Pathways
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
Affiliations
Maria Fernanda Suarez
Department of Ophthalmology, Tufts University School of Medicine at Tufts Medical Center, Boston, MA 02111, USA
Tatsuo Itakura
USC Institute for Genetic Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90007, USA
Satyabrata Pany
Department of Ophthalmology, Tufts University School of Medicine at Tufts Medical Center, Boston, MA 02111, USA
Shinwu Jeong
Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90007, USA
Shravan K. Chintala
USC Institute for Genetic Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90007, USA
Michael B. Raizman
Department of Ophthalmology, Tufts University School of Medicine at Tufts Medical Center and Ophthalmic Consultants of Boston, Boston, MA 02111, USA
Steven Riesinger
MedChem Partners, Lexington, MA 02421, USA
Tsvetelina Lazarova
MedChem Partners, Lexington, MA 02421, USA
José Echenique
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Department of Clinical Biochemistry, Faculty of Chemistry, National University of Córdoba, Córdoba 5000, Argentina
Horacio M. Serra
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Department of Clinical Biochemistry, Faculty of Chemistry, National University of Córdoba, Córdoba 5000, Argentina
W. Daniel Stamer
Department of Ophthalmology, Duke University, Durham, NC 27708, USA
M. Elizabeth Fini
Department 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, USA
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.
