Inhibiting endoplasmic reticulum stress by activation of G‐protein‐coupled estrogen receptor to protect retinal astrocytes under hyperoxia

Abstract

Retinal vascularization is arrested at the early (hyperoxia) stage in retinopathy of prematurity (ROP), a leading cause of blindness in children. Estrogen was reported to alleviate ROP by inhibiting reactive oxygen species, the upstream signaling molecules of endoplasmic reticulum stress (ERS). Astrocytes have long been proposed to guide angiogenesis, because they form a reticular network that provides a substrate for migrating endothelial cells. However, the factors that control the vascularization of the immature retina and the therapeutic mechanism of estrogen in early ROP remain poorly understood. This study aimed to investigate the role of G‐protein‐coupled estrogen receptor (GPER), an estrogen receptor distributed in the endoplasmic reticulum (ER), in protecting retinal astrocytes under hyperoxia and the association with ERS. The results showed that GPER was widely expressed in retinal astrocytes. GPER activation increases cell viability, decreases apoptosis, and autophagy of retinal astrocytes, decreases inositol‐1,4,5‐triphosphate receptor activity, and increases Ca2+ concentration in ER of astrocytes under hyperoxia. GPER blockade reversed all of these changes. Together, our findings indicate that GPER can protect the survival of retinal astrocytes by inhibiting ERS under hyperoxia.

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

“…Its presence has been demonstrated in various areas of the body (e.g., the reproductive, nervous, endocrine, immune and cardiovascular systems) and in the retina. [10,11] Evidence has been reported that GPER-1 plays a crucial role in metabolic regulation (lipids and glucose homeostasis, insulin production and action, etc. ), blood pressure, and immune functions.…”

“…), 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.…”

“…It has also been revealed that this bene cial effect on microglia is reduced with G-15, which is a GPER-1 antagonist. Rong et al [10] suggest that activating GPER-1 reduces ROS production by decreasing mitochondrial damage and, thus, increasing neuronal survival.…”

“…[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. [11] Oxidative stress deteriorates the homeostatic balance, causing protein damage and, thus, stressing the ER.…”

“…[12] However, prior research has shown that GPER-1 activation causes ROS to decrease, which rapidly reduces the stress being placed on the ER. [10,12] Currently, various treatment methods (e.g., anti-vascular endothelial growth factor [anti-VEGF], steroid and laser therapies) are used to reduce the oxidation and in ammatory mediators of DR pathogenesis. [6,13] However, retinal neurodegeneration could be an independent pathophysiological component of DR, and new molecular mechanisms should be investigated to detect early damage and initiate treatment.…”