30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor activation and specificity-conferring mechanisms: a brief history

Funder, John W.

doi:10.1530/joe-17-0119

Cited by 36 publications

(42 citation statements)

References 21 publications

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“…Despite these similar affinities, MR is more sensitive to aldosterone than to glucocorticoids (6,7). This is mainly because of an imperfect accommodation of glucocorticoids within the ligand-binding pocket of MR, which forms unstable complexes that are less productive (8); however, given that plasma levels of cortisol are 100-to 1000-fold higher than those of aldosterone, it has been suggested that MR may be fully and permanently bound by glucocorticoids (9). Epithelial tissues, classic MR targets, express the 11b-hydroxysteroid dehydrogenase type 2 enzyme (11bHSD2), which converts glucocorticoids into their 11-dehydroderivatives; cortisol into cortisone, and corticosterone into 11-dehydrocorticosterone, that are almost unable to activate MRs, which allows selective access and specific activation of MRs by aldosterone (10,11).…”

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confidence: 99%

“…Moreover, it has been reported that, despite 11bHSD2 action, cortisol is not fully metabolized and is still present at a concentration at least 10 times higher than that of aldosterone (12,13), which suggests that MR signaling in epithelial cells might be activated by both hormones. Finally, 11bHSD2 is not expressed in nonepithelial MR target tissues, such as the heart, brain, and adipose tissues, thus removing the selective protection of MRs from glucocorticoids (9).…”

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confidence: 99%

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Corticosteroid receptors adopt distinct cyclical transcriptional signatures

et al. 2018

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Mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) are two closely related hormone-activated transcription factors that regulate major pathophysiologic functions. High homology between these receptors accounts for the crossbinding of their corresponding ligands, MR being activated by both aldosterone and cortisol and GR essentially activated by cortisol. Their coexpression and ability to bind similar DNA motifs highlight the need to investigate their respective contributions to overall corticosteroid signaling. Here, we decipher the transcriptional regulatory mechanisms that underlie selective effects of MRs and GRs on shared genomic targets in a human renal cellular model. Kinetic, serial, and sequential chromatin immunoprecipitation approaches were performed on the period circadian protein 1 ( PER1) target gene, providing evidence that both receptors dynamically and cyclically interact at the same target promoter in a specific and distinct transcriptional signature. During this process, both receptors regulate PER1 gene by binding as homo- or heterodimers to the same promoter region. Our results suggest a novel level of MR-GR target gene regulation, which should be considered for a better and integrated understanding of corticosteroid-related pathophysiology.-Le Billan, F., Amazit, L., Bleakley, K., Xue, Q.-Y., Pussard, E., Lhadj, C., Kolkhof, P., Viengchareun, S., Fagart, J., Lombès, M. Corticosteroid receptors adopt distinct cyclical transcriptional signatures.

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Corticosteroid receptors adopt distinct cyclical transcriptional signatures

et al. 2018

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“…This mechanism is not supported by in vivo evidence in the cardiovascular, immune, and central nervous systems. Indeed, the preponderance of evidence suggests little or no 11β-HSD2 activity in the heart, inflammatory cells, and regions of the central nervous system; yet there is extensive evidence to support MR binding in these organs [10]. In addition, in vivo competition studies in adrenalectomized animals show high MR selectivity in these organs.…”

Section: Mr Activation/antagonism and Specificity-conferring Mechanismsmentioning

confidence: 99%

“…A model that provides an explanation for glucocorticoid-mediated MR signaling in the setting of a protected MR (presence of 11β-HSD2) is the concept that the activity of the enzyme 11β-HSD2 results in a decrease in the NAD/NADH ratio (owing to generation of NADH) which alters the redox state, resulting in blocking activity of MR. There is direct evidence for redox stress/state regulating the activation of other nuclear transactivating factors, and it is likely that similar changes in redox state are operant for cortisol [10]. There are undoubtedly other aspects such as conformation of the ligand-binding interactions and co-regulator recruitment that may contribute to between-ligand (cortisol vs. aldosterone) differentiation in signaling [7,12].…”

Section: Mr Activation/antagonism and Specificity-conferring Mechanismsmentioning

confidence: 99%

The Role of the Mineralocorticoid Receptor in Inflammation: Focus on Kidney and Vasculature

et al. 2017

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Background: The remarkable success of clinical trials in mineralocorticoid receptor (MR) inhibition in heart failure has driven research on the physiological and pathological role(s) of nonepithelial MR expression. MR is widely expressed in the cardiovascular system and is a major determinant of endothelial function, smooth muscle tone, vascular remodeling, fibrosis, and blood pressure. An important new dimension is the appreciation of the role MR plays in immune cells and target organ damage in the heart, kidney and vasculature, and in the development of insulin resistance. Summary: The mechanism for MR activation in tissue injury continues to evolve with the evidence to date suggesting that activation of MR results in a complex repertoire of effects involving both macrophages and T cells. MR is an important transcriptional regulator of macrophage phenotype and function. Another important feature of MR activation is that it can occur even with normal or low aldosterone levels in pathological conditions. Tissue-specific conditional models of MR expression in myeloid cells, endothelial cells, smooth muscle cells and cardiomyocytes have been very informative and have firmly demonstrated a critical role of MR as a key pathophysiologic variable in cardiac hypertrophy, transition to heart failure, adipose inflammation, and atherosclerosis. Finally, the central nervous system activation of MR in permeable regions of the blood-brain barrier may play a role in peripheral inflammation. Key Message: Ongoing clinical trials will help clarify the role of MR blockade in conditions, such as atherosclerosis and chronic kidney disease.

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“…As has been previously noted, all really great lies are half true (Funder 1979); in this instance, both laboratories jumped to what appeared to be the obvious conclusion rather than consciously fabricating fake news. In a brief historical review of pre-receptor specificity-conferring mechanisms in epithelia, John Funder documents the context-dependent bivalent (agonist, antagonist) role of cortisol in MR, an unanticipated inverse agonist action of spironolactone on MR, and points to the sorts of studies that the next generation might consider to refine these concepts and set them in their appropriate physiological space (Funder 2017).…”

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confidence: 99%