Genetic variation of the mineralocorticoid receptor gene (MR, NR3C2) is associated with a conceptual endophenotype of “CRF-hypoactivity”

Kumsta, Robert; Kliegel, David; DeRijk, Roel H.; Kloet, E. Ronald de

doi:10.1016/j.psyneuen.2018.09.036

Cited by 12 publications

(5 citation statements)

References 47 publications

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“…74 Interestingly, the G-allele containing haplotypes that are associated with higher aldosterone levels has been associated with features of atypical depression. 76 This is in line with our observation of the overlap between hyperaldosteronism and this subtype of depression. However, whether these differences are causally related to aldosterone levels or whether aldosterone levels are an epiphenomenon needs to be further explored.…”

Section: Network Model Of Aldosterone Effectsupporting

confidence: 90%

“…The C‐A haplotype, which is the second most frequent (approximately 40%) is a gain of function haplotype and is associated with higher optimism and a lower risk of depression in females, but no effect in males 74 . Interestingly, the G‐allele containing haplotypes that are associated with higher aldosterone levels has been associated with features of atypical depression 76 . This is in line with our observation of the overlap between hyperaldosteronism and this subtype of depression.…”

Section: Network Model Of Aldosterone Effectsupporting

confidence: 89%

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A viewpoint on aldosterone andBMIrelated brain morphology in relation to treatment outcome in patients with major depression

Murck

Lehr

Ježová

2022

J Neuroendocrinology

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An abundance of knowledge has been collected describing the involvement of neuroendocrine parameters in major depression. The hypothalamic–pituitary–adrenocortical (HPA) axis regulating cortisol release has been extensively studied; however, attempts to target the HPA axis pharmacologically to treat major depression have failed. This review focuses on the importance of the adrenocortical stress hormone aldosterone, which is released by adrenocorticotropic hormone and angiotensin, and the mineralocorticoid receptor (MR) in depression. Depressed patients, in particular those with atypical depression, have signs of central hyperactivation of the aldosterone sensitive MR, potentially as a consequence of a reactive aldosterone release induced by low blood pressure and as a result of low sensitivity of peripheral MR. This is reflected in reduced heart rate variability, increased salt appetite and sleep changes in this group of patients. In addition, enlarged brain ventricles, compressed corpus callosum and changes of the choroid plexus are associated with increased aldosterone (in relation to cortisol). Furthermore, subjects with these features often show obesity. These characteristics are related to a worse antidepressant treatment outcome. Alterations in choroid plexus function as a consequence of increased aldosterone levels, autonomic dysregulation, metabolic changes and/or inflammation may be involved. The characterization of this regulatory system is in its early days but may identify new targets for therapeutic interventions.

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Section: Network Model Of Aldosterone Effectsupporting

confidence: 90%

Section: Network Model Of Aldosterone Effectsupporting

confidence: 89%

A viewpoint on aldosterone andBMIrelated brain morphology in relation to treatment outcome in patients with major depression

Murck

Lehr

Ježová

2022

J Neuroendocrinology

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“…Although the rs5522 mutation is not considered to be a pathological variant, it has been shown to play a role in sporadic pseudohypoaldosteronism [ 26 ], hypertension comorbidity in androgen-deprivation therapy [ 29 ] and neurological processes such as memory [ 30 ] and stress-related disorders [ 31 , 32 , 33 ]. It is likely that this single polymorphism leads to a slight modulation of MR function, inducing disease only when it co-occurs with certain environmental factors.…”

Section: Discussionmentioning

confidence: 99%

Genetic Profiling of Glucocorticoid (NR3C1) and Mineralocorticoid (NR3C2) Receptor Polymorphisms before Starting Therapy with Androgen Receptor Inhibitors: A Study of a Patient Who Developed Toxic Myocarditis after Enzalutamide Treatment

2022

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Enzalutamide is a nonsteroidal inhibitor of the androgen receptor (AR) signaling pathway and is used to treat patients with metastatic castration-resistant prostate cancer. However, the risk of cardiovascular-related hospitalization in patients with no contraindications for the use of enzalutamide is about 1–2%. To date, the underlying molecular basis of this has not been established. The androgen receptor, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are nuclear receptors that share structural similarities and have closely related DNA-binding sites and coregulators. In non-epithelial cells, a fine balance of the activities of these receptors is essential to ensure correct cellular function. In this study, we present a molecular characterization of these nuclear receptors in a prostate cancer patient who developed congestive heart failure after enzalutamide treatment. White cell RNAseq revealed a homozygous rs5522 MR polymorphism and both the rs143711342 and rs56149945 GR polymorphisms, carried in different alleles. No different specific splice isoforms were detected. Recent research suggests that AR inhibition by enzalutamide makes available a coregulator that specifically interacts with the rs5522-mutated MR, increasing its activity and producing adverse effects on cardiovascular health. We suggest an evaluation of the MR rs5522 polymorphism before starting therapy with AR inhibitors.

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“…For instance, hippocampal CA2 neurons with abundant expression of MR express high basal levels of FKBP5 with little GR activity, while much GR activation is observed following MR blockade or genetic deletion [ 20 ]. One would predict, therefore, that high MR expression because of genetic polymorphisms [ 21 ] or epigenetically induced by positive (early) life experience [ 22 ] would result in increased basal FKBP5 production, which raises the threshold for GR activation in response to an acute stressor. Thus, if co-localized, under basal conditions the degree of MR activation may determine via FKBP5 the tone of GR functionality.…”

Section: Fine-tuning Mr/gr Balance With Fkbp5mentioning

confidence: 99%

Brain mineralocorticoid and glucocorticoid receptor balance in neuroendocrine regulation and stress-related psychiatric etiopathologies

Kloet

2022

Current Opinion in Endocrine and Metabolic Research

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Genetic variation of the mineralocorticoid receptor gene (MR, NR3C2) is associated with a conceptual endophenotype of “CRF-hypoactivity”

Cited by 12 publications

References 47 publications

A viewpoint on aldosterone andBMIrelated brain morphology in relation to treatment outcome in patients with major depression

A viewpoint on aldosterone andBMIrelated brain morphology in relation to treatment outcome in patients with major depression

Genetic Profiling of Glucocorticoid (NR3C1) and Mineralocorticoid (NR3C2) Receptor Polymorphisms before Starting Therapy with Androgen Receptor Inhibitors: A Study of a Patient Who Developed Toxic Myocarditis after Enzalutamide Treatment

Brain mineralocorticoid and glucocorticoid receptor balance in neuroendocrine regulation and stress-related psychiatric etiopathologies

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