G Protein-Coupled Estrogen Receptor 1 (GPER1) Mediates Aldosterone-Induced Endothelial Inflammation in a Mineralocorticoid Receptor-Independent Manner

Objective. It has been increasingly appreciated that G protein-coupled estrogen receptor 1 (GPER1) mediates both proinflammatory and anti-inflammatory response of estrogen. It is also involved in some rapid vascular effects of aldosterone in a mineralocorticoid receptor (MR) independent manner. However, whether GPER1 mediates aldosterone-induced inflammation response in endothelial cells and its relationship with MR are yet undetermined and therefore require further explanation. Method. Based on the hypothesis that GPER1 plays a role in the aldosterone-related vascular inflammation, the present study utilized a model of human umbilical vein endothelial cells transfected with MR siRNA and induced for inflammatory response with increasing concentration of aldosterone. Results. It was discovered that induction of aldosterone had no effect on the expression of GPER1 but promoted the expression of MR. Suppression of MR did not influence GPER1 expression, and GPER1 was capable of mediating part of aldosterone-induced endothelial inflammatory response. This effect may involve phosphoinositide 3-kinases (PI3K) pathway signaling. Conclusion. These findings not only demonstrated the role of GPER1 in aldosterone-induced vascular inflammation but also suggested an alternative for pharmaceutical treatment of hyperaldosteronism considering the unsatisfying effect on cardiovascular risks with MR antagonists.

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Activation of G Protein-Coupled Estrogen Receptor 1 Ameliorates Proximal Tubular Injury and Proteinuria in Dahl Salt-Sensitive Female Rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00267.2020 ◽

2021 ◽

Author(s):

Eman Y Gohar ◽

Rawan N Almutlaq ◽

Elizabeth M. Daugherty ◽

Maryam K. Butt ◽

Chunhua Jin ◽

...

Keyword(s):

Blood Pressure ◽

Estrogen Receptor ◽

Proximal Tubule ◽

G Protein ◽

Brush Border ◽

Kidney Injury ◽

Female Rats ◽

Independent Manner ◽

G Protein Coupled ◽

Estrogen Receptor 1

Recent evidence indicates a crucial role for G protein-coupled estrogen receptor 1 (GPER1) in the maintenance of cardiovascular and kidney health in females. The current study tested whether GPER1 activation ameliorates hypertension and kidney damage in female Dahl salt-sensitive (SS) rats fed a high-salt (HS) diet. Adult female rats were implanted with telemetry transmitters for monitoring blood pressure and osmotic minipumps releasing G1 (selective GPER1 agonist, 400 μg/kg/day, intraperitoneal) or vehicle. Two weeks after pump implantation, rats were shifted from a normal salt diet (NS, 0.4% NaCl) to a matched HS diet (4.0% NaCl) for 2 weeks. 24-hour urine samples were collected during both diet periods and urinary markers of kidney injury were assessed. Histological assessment of kidney injury was conducted after the 2-week HS diet period. Compared with values during the NS diet, 24-hour mean arterial pressure markedly increased in response to HS, reaching similar values in vehicle-treated and G1-treated rats. HS also significantly increased urinary excretion of protein, albumin, nephrin (podocyte damage marker) and KIM-1 (proximal tubule injury marker) in vehicle-treated rats. Importantly, G1 treatment prevented the HS-induced proteinuria, albuminuria and increase in KIM-1 excretion but not nephrinuria. Histological analysis revealed that HS-induced glomerular damage did not differ between groups. However, G1 treatment preserved proximal tubule brush border integrity in HS-fed rats. Collectively, our data suggest that GPER1 activation protects against HS-induced proteinuria and albuminuria in female Dahl SS rats by preserving proximal tubule brush border integrity in a blood pressure-independent manner.

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G protein‐coupled estrogen receptor 1 inhibits the epithelial‐mesenchymal transition of goat mammary epithelial cells via NF‐κB signaling pathway

Reproduction in Domestic Animals ◽

10.1111/rda.13957 ◽

2021 ◽

Author(s):

Ying Zhao ◽

Zhenshan Yang ◽

Yuyang Miao ◽

Mingzhen Fan ◽

Xiaoe Zhao ◽

...

Keyword(s):

Estrogen Receptor ◽

Epithelial Cells ◽

G Protein ◽

Epithelial Mesenchymal Transition ◽

Mammary Epithelial Cells ◽

Mammary Epithelial ◽

Mesenchymal Transition ◽

G Protein Coupled ◽

Estrogen Receptor 1 ◽

Goat Mammary Epithelial Cells

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G Protein-Coupled Estrogen Receptor 1 (GPER) as a Novel Target for Schizophrenia Drug Treatment

Schizophrenia Bulletin Open ◽

10.1093/schizbullopen/sgaa062 ◽

2020 ◽

Vol 1 (1) ◽

Author(s):

Danielle S Macêdo ◽

Lia Lira Olivier Sanders ◽

Raimunda das Candeias ◽

Cyntia de Freitas Montenegro ◽

David Freitas de Lucena ◽

...

Keyword(s):

Estrogen Receptor ◽

Estrogen Receptors ◽

G Protein ◽

Brain Inflammation ◽

Antipsychotic Treatment ◽

New Class ◽

Estrogen Receptor Modulators ◽

Novel Target ◽

G Protein Coupled ◽

Estrogen Receptor 1

Abstract The observation that a person’s sex influences the onset age of schizophrenia, the course of the disease, and antipsychotic treatment response suggests a possible role for estrogen receptors in the pathophysiology of schizophrenia. Indeed, treatment with adjunctive estrogen or selective estrogen receptor modulators (SERMs) are known to reduce schizophrenia symptoms. While estrogen receptors (ER)α and ERβ have been studied, a third and more recently discovered estrogen receptor, the G protein-coupled estrogen receptor 1 (GPER), has been largely neglected. GPER is a membrane receptor that regulates non-genomic estrogen functions, such as the modulation of emotion and inflammatory response. This review discusses the possible role of GPER in brain impairments seen in schizophrenia and in its potential as a therapeutic target. We conducted a comprehensive literature search in the PubMed/MEDLINE database, using the following search terms: “Schizophrenia,” “Psychosis,” “GPER1 protein,” “Estrogen receptors,” “SERMS,” “GPER1 agonism, “Behavioral symptoms,” “Brain Inflammation.” Studies involving GPER in schizophrenia, whether preclinical or human studies, have been scarce, but the results are encouraging. Agonism of the GPER receptor could prove to be an essential mechanism of action for a new class of “anti-schizophrenia” drugs.

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