Mineralocorticoid receptor actions in cardiovascular development and disease

2021 ◽  
Author(s):  
Morag J. Young ◽  
Colin D. Clyne

Abstract Mineralocorticoid receptors (MRs) are transcriptional regulators that mediate the diverse physiological and pathophysiological actions of corticosteroid hormones across many tissues. In the kidney aldosterone control of sodium/water resorption via DNA-binding actions of the MR is established. MRs also regulate tissues not involved in electrolyte homeostasis such as the heart, adipose tissue, brain, and inflammatory cells where the MRs can respond to both aldosterone and cortisol. The pathology of inappropriate MR activation in non-epithelial tissues are well-described, and steroidal antagonists of the MR have been clinically beneficial in the management of heart failure and blood pressure for decades. However, the role of cortisol-dependent MR activation in the physiological setting is less well defined. Like other steroid hormone receptors, the MR also regulates non-DNA-binding pathways including MAPK pathways and G protein coupled receptors to provide diversity to MR signaling. Whether nonDNA binding pathways are more relevant for MR activation in non-epithelial, versus epithelial, tissues remain unclear. This review will focus on molecular regulation of ligand-dependent MR activation and the physiology and pathophysiology of MR actions in the heart with a focus on the cardiomyocyte and provide a discussion of relevant genomic and non-genomic MR pathways and potential new transcriptional partners for the MR and their relevance for health and disease. Understanding MR actions in the heart will provide new insights into cell-selective mechanisms that underpin the therapeutic benefits of MRAs, and are a critical step towards developing next-generation tissue selective MR modulators with improved safety profiles.

2001 ◽  
Vol 361 (1) ◽  
pp. 97-103 ◽  
Author(s):  
Guy VERRIJDT ◽  
Annemie HAELENS ◽  
Erik SCHOENMAKERS ◽  
Wilfried ROMBAUTS ◽  
Frank CLAESSENS

We performed a comparative analysis of the effect of high-mobility group box protein 1 (HMGB1) on DNA binding by the DNA-binding domains (DBDs) of the androgen, glucocorticoid, progesterone and mineralocorticoid receptors. The affinity of the DBDs of the different receptors for the tyrosine aminotransferase glucocorticoid response element, a classical high-affinity binding element, was augmented up to 7-fold by HMGB1. We found no major differences in the effects of HMGB1 on DNA binding between the different steroid hormone receptors. In transient transfection assays, however, HMGB1 significantly enhances the activity of the glucocorticoid and progesterone receptors but not the androgen or mineralocorticoid receptor. We also investigated the effect of HMGB1 on the binding of the androgen receptor DBD to a subclass of directly repeated response elements that is recognized exclusively by the androgen receptor and not by the glucocorticoid, progesterone or mineralocorticoid receptor. Surprisingly, a deletion of 26 amino acid residues from the C-terminal extension of the androgen receptor DBD does not influence DNA binding but destroys its sensitivity to HMGB1. Deletion of the corresponding fragment in the DBDs of the glucocorticoid, progesterone and mineralocorticoid receptor destroyed their DNA binding. This 26-residue fragment is therefore essential for the influence of HMGB1 on DNA recognition by all steroid hormone receptors that were tested. However, it is dispensable for DNA binding by the androgen receptor.


eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Christopher A Natale ◽  
Elizabeth K Duperret ◽  
Junqian Zhang ◽  
Rochelle Sadeghi ◽  
Ankit Dahal ◽  
...  

The association between pregnancy and altered cutaneous pigmentation has been documented for over two millennia, suggesting that sex hormones play a role in regulating epidermal melanocyte (MC) homeostasis. Here we show that physiologic estrogen (17β-estradiol) and progesterone reciprocally regulate melanin synthesis. This is intriguing given that we also show that normal primary human MCs lack classical estrogen or progesterone receptors (ER or PR). Utilizing both genetic and pharmacologic approaches, we establish that sex steroid effects on human pigment synthesis are mediated by the membrane-bound, steroid hormone receptors G protein-coupled estrogen receptor (GPER), and progestin and adipoQ receptor 7 (PAQR7). Activity of these receptors was activated or inhibited by synthetic estrogen or progesterone analogs that do not bind to ER or PR. As safe and effective treatment options for skin pigmentation disorders are limited, these specific GPER and PAQR7 ligands may represent a novel class of therapeutics.


Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 2953-2962 ◽  
Author(s):  
Edward J. Filardo ◽  
Peter Thomas

Using cDNA cloning strategies commonly employed for G protein-coupled receptors (GPCR), GPCR-30 (GPR30), was isolated from mammalian cells before knowledge of its cognate ligand. GPR30 is evolutionarily conserved throughout the vertebrates. A broad literature suggests that GPR30 is a Gs-coupled heptahelical transmembrane receptor that promotes specific binding of naturally occurring and man-made estrogens but not cortisol, progesterone, or testosterone. Its “pregenomic” signaling actions are manifested by plasma membrane-associated actions familiar to GPCR, namely, stimulation of adenylyl cyclase and Gβγ-subunit protein-dependent release of membrane-tethered heparan bound epidermal growth factor. These facts regarding its mechanism of action have led to the formal renaming of this receptor to its current functional designate, G protein-coupled estrogen receptor (ER) (GPER)-1. Further insight regarding its biochemical action and physiological functions in vertebrates is derived from receptor knockdown studies and the use of selective agonists/antagonists that discriminate GPER-1 from the nuclear steroid hormone receptors, ERα and ERβ. GPER-1-selective agents have linked GPER-1 to physiological and pathological events regulated by estrogen action, including, but not limited to, the central nervous, immune, renal, reproductive, and cardiovascular systems. Moreover, immunohistochemical studies have shown a positive association between GPER-1 expression and progression of female reproductive cancer, a relationship that is diametrically opposed from ER. Unlike ER knockout mice, GPER-1 knockout mice are fertile and show no overt reproductive anomalies. However, they do exhibit thymic atrophy, impaired glucose tolerance, and altered bone growth. Here, we discuss the role of GPER-1 in female reproductive cancers as well as renal and vascular physiology.


2021 ◽  
Vol 135 (16) ◽  
pp. 1945-1980
Author(s):  
William S. Powell

Abstract Eicosanoids comprise a group of oxidation products of arachidonic and 5,8,11,14,17-eicosapentaenoic acids formed by oxygenases and downstream enzymes. The two major pathways for eicosanoid formation are initiated by the actions of 5-lipoxygenase (5-LO), leading to leukotrienes (LTs) and 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), and cyclooxygenase (COX), leading to prostaglandins (PGs) and thromboxane (TX). A third group (specialized pro-resolving mediators; SPMs), including lipoxin A4 (LXA4) and resolvins (Rvs), are formed by the combined actions of different oxygenases. The actions of the above eicosanoids are mediated by approximately 20 G protein-coupled receptors, resulting in a variety of both detrimental and beneficial effects on airway smooth muscle and inflammatory cells that are strongly implicated in asthma pathophysiology. Drugs targeting proinflammatory eicosanoid receptors, including CysLT1, the receptor for LTD4 (montelukast) and TP, the receptor for TXA2 (seratrodast) are currently in use, whereas antagonists of a number of other receptors, including DP2 (PGD2), BLT1 (LTB4), and OXE (5-oxo-ETE) are under investigation. Agonists targeting anti-inflammatory/pro-resolving eicosanoid receptors such as EP2/4 (PGE2), IP (PGI2), ALX/FPR2 (LXA4), and Chemerin1 (RvE1/2) are also being examined. This review summarizes the contributions of eicosanoid receptors to the pathophysiology of asthma and the potential therapeutic benefits of drugs that target these receptors. Because of the multifactorial nature of asthma and the diverse pathways affected by eicosanoid receptors, it will be important to identify subgroups of asthmatics that are likely to respond to any given therapy.


1993 ◽  
Vol 45 (4) ◽  
pp. 205-215 ◽  
Author(s):  
Marie-Thérèse Bocquel ◽  
Jingwei Ji ◽  
Timo Ylikomi ◽  
Brigitte Benhamou ◽  
Agnès Vergezac ◽  
...  

Chemosphere ◽  
1987 ◽  
Vol 16 (8-9) ◽  
pp. 1681-1686
Author(s):  
Lorenz Poellinger ◽  
Anna Wilhelmsson ◽  
Scott Cuthill ◽  
Johan Lund ◽  
Peter Söderkvist ◽  
...  

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