G-protein coupled estrogen receptor activation protects the viability of hyperoxia-treated primary murine retinal microglia by reducing ER stress

Abstract

In this study, we investigated the effects of G-protein coupled estrogen receptor (GPER) activation in the early phase of retinopathy of prematurity (ROP) and its association with endoplasmic reticulum (ER) stress using primary murine retinal microglia as an experimental model. Fluorescence microscopy results show that the CD11c-positive primary retinal microglia in vitro cultured for 14 days were GPER-positive. GPER activation using GPER-agonist G-1 reduced autophagy and increased the viability of the hyperoxia-treated primary murine retinal microglia. Furthermore, GPER activation reduced the expression of ER stress-related proteins, IRE1α, PERK and ATF6 in the hyperoxia-treated primary murine retinal microglia compared to the corresponding controls. GPER activation significantly reduced a time-dependent increase in IP3R-dependent calcium release from the ER, thereby maintaining higher calcium levels in the ER of hyperoxia-treated primary retinal microglia. However, the protective effects of G-1 on the hyperoxia-treated primary retinal microglia were eliminated by inactivation of GPER using the GPER-antagonist, G-15. In conclusion, our study demonstrates that GPER activation enhances the survival of hyperoxia-treated primary retinal microglia by reducing ER stress. Our study demonstrates the therapeutic potential of GPER agonists such as G-1 in the early phase of ROP.

The Research Advances in G-Protein-Coupled Estrogen Receptor

“…Thus, ERS irritated by hyperoxia was mitigated by G1 administration. These results suggest that GPER agonists may have therapeutic potential in the early stage of ROP [98][99][100].…”

Selective Modulation of the Keratoconic Stromal Microenvironment by FSH and LH

“…GPER is a membrane ER that is involved in nongenomic estrogen activity and is associated with cell growth and proliferation. 53 , 54 , 55 , 56 , 57 Although LH has been shown to increase GPER expression in other cell types, 58 , 59 , 60 , 61 this was the first evidence of LH impacting GPER in the cornea. Based on these results, the effects of gonadotropins in KC were determined to be primarily LH driven.…”

Comparing the Impact of Serum GPER-1 and Oxidant/Antioxidant Levels on Retinopathy in Diabetic Patients and Healthy Individuals: A Pilot Study

“…[1,12] GPER-1 is a rapidly acting, membrane-bound oestrogen receptor, independent of gene regulation. [8,9] Though GPER-1 has been reported to mediate more than one type of oestrogen activity in vivo, growing evidence indicates that GPER-1 also has gender-independent effects. [18].…”

“…), blood pressure, and immune functions. [9,10,18] Previous studies indicate that GPER-1 activation increases the e ciency of glucose transporters, reduces oxidative stress products, and regulates the in ammatory response; thus, it plays a neuroprotective role. [1,[11][12] In diabetic patients, the oxidant/antioxidant balance changes in favour of oxidation due to increased oxidative stress in the body.…”

“…[5][6][7] GPER-1 is a transmembrane oestrogen receptor, localised in the endoplasmic reticulum (ER), which binds with high a nity to 17β-oestradiol. [8][9] It is present in various areas of the body, including the reproductive, nervous, endocrine, immune and cardiovascular systems. [10] GPER-1 expression has also been found in the retina.…”