Emerging Roles for G Protein-Coupled Estrogen Receptor 1 in Cardio-Renal Health: Implications for Aging

Abstract

Cardiovascular (CV) and renal diseases are increasingly prevalent in the United States and globally. CV-related mortality is the leading cause of death in the United States, while renal-related mortality is the 8th. Despite advanced therapeutics, both diseases persist, warranting continued exploration of disease mechanisms to develop novel therapeutics and advance clinical outcomes for cardio-renal health. CV and renal diseases increase with age, and there are sex differences evident in both the prevalence and progression of CV and renal disease. These age and sex differences seen in cardio-renal health implicate sex hormones as potentially important regulators to be studied. One such regulator is G protein-coupled estrogen receptor 1 (GPER1). GPER1 has been implicated in estrogen signaling and is expressed in a variety of tissues including the heart, vasculature, and kidney. GPER1 has been shown to be protective against CV and renal diseases in different experimental animal models. GPER1 actions involve multiple signaling pathways: interaction with aldosterone and endothelin-1 signaling, stimulation of the release of nitric oxide, and reduction in oxidative stress, inflammation, and immune infiltration. This review will discuss the current literature regarding GPER1 and cardio-renal health, particularly in the context of aging. Improving our understanding of GPER1-evoked mechanisms may reveal novel therapeutics aimed at improving cardio-renal health and clinical outcomes in the elderly.

Keywords: GPR30; RAAS; ROS; endothelin-1; heart; kidney; nitric oxide; postmenopausal women.

Figure 1

GPER1 expression in the cardio-renal system; impact of age. Abbreviations: GPER1—G protein-coupled estrogen receptor 1. VSMC—Vascular smooth muscle cell. Created with BioRender.com, accessed on 28 January 2022.

Figure 2

Pharmacological tools to study GPER1 function. Abbreviations: GPER1—G protein-coupled estrogen receptor 1. ERα/ERβ—Estrogen receptor alpha/beta. CAMP—Cyclic adenosine monophosphate. PI3K—Phosphoinositide 3-kinase. AKT—Protein kinase B. ERK—Extracellular signal-regulated kinases. [Ca²⁺]_i—Intracellular calcium. Created with BioRender.com, accessed on 23 February 2022.

Figure 3

Mediators of GPER1 actions within the cardiovascular and renal systems. Observations reported in only one sex are denoted with the corresponding sex symbol. Observations reported in both sexes have no special designation. * Denotes sex-specific observations. # Denotes observations with unspecified sex. Abbreviations: GPER1—G protein-coupled estrogen receptor 1. Ang II—Angiotensin II. ACE—Angiotensin converting enzyme. MR—Mineralocorticoid receptor. ET-1—Endothelin 1. NO—Nitric oxide. ET_B—Endothelin receptor B. Ca²⁺—Calcium. VSMC—Vascular smooth muscle cell. PTP—Permeability transition pore. IL—Interleukin. T-reg—Regulatory T cell. CRP—C reactive protein. NLR3P—NLR family pyrin domain containing 3. Created with BioRender.com, accessed on 23 February 2022.