GPR158 Activates Cellular Stress Responses in Trabecular Meshwork Cells of the Eye’s Aqueous Outflow Pathways: Implications for Ocular Hypertension. GPR158 Activates Cellular Stress Responses in Trabecular Meshwork Cells of the Eye’s Aqueous Outflow Pathways: Implications for Ocular Hypertension

Background: the major risk factor for glaucoma is ocular hypertension, a disorder caused by reduced outflow of aqueous humor through the trabecular meshwork. In a previous pharmacogenomic screen for genes associated with ocular hypertension, we identified the novel G protein-coupled receptor, GPR158, and showed it protects against age-related ocular hypertension in mice. Here we show that the glucocorticoid, dexamethasone, increases the level of accumulated GPR158 protein in the trabecular meshwork of the human eye, ex vivo. Methods: we performed gene expression microarray profiling of TM-1 cells thar overexpress GPR158 Results: we show that the glucocorticoid, dexamethasone, increases the level of accumulated GPR158 protein in the trabecular meshwork of the human eye, ex vivo. Gene sets controlled by dexamethasone, TGFB1 and TP53 were identified, as well as genes asso-ciated with ossification. GPR158 over-expression in cells of the immortalized trabecular meshwork cell line TM-1 did not affect the fibrotic response to dexamethasone or cause ossification, and loss of GPR158 in knockout mice did not affect the development of glucocorticoid-induced ocular hypertension. However, GPR158 over-expression was cytoprotective. Discussion: Our findings suggest that GPR158 activated the cytoprotective branch of the unfolded protein response and bound the TP53-inducible protein PPP1R10, a regulatory subunit of PPI regulatory subunit of PPI. Our data support the idea that GPR158 protects the trabecular meshwork, and suggest possible mechanisms. Overall design: Microarray analysis of transcripts extracted from HTM cells treated with doxycycline for 24, 72 and 96 hs to overexpress GPR158. No antibiotic treatment and cells transfected with only lentivector were used as controls,