Rapid mineralocorticoid receptor trafficking

Gekle, Michael; Bretschneider, Maria; Meinel, Sandra; Ruhs, Stefanie; Großmann, Claudia

doi:10.1016/j.steroids.2013.10.016

Cited by 25 publications

(37 citation statements)

References 52 publications

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“…Upon aldosterone exposure, MR is shifted to the nucleus consecutively to conformational modification (47). Our results demonstrated that finerenone competes with aldosterone by inhibiting the nuclear accumulation of GFP-hMR and also impedes MR nuclear translocation slightly more efficiently than spironolactone.…”

Section: Discussionmentioning

confidence: 71%

Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1

Amazit

Billan

Kolkhof

et al. 2015

Journal of Biological Chemistry

123

107

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Background: Finerenone is a novel nonsteroidal mineralocorticoid antagonist, currently in clinical phase IIb trials. Results: Finerenone delays mineralocorticoid receptor nuclear import and inhibits its binding and transcriptional coactivator recruitment onto target gene promoters. Conclusion: Finerenone impedes three critical steps of the mineralocorticoid receptor signaling pathway. Significance: Finerenone, which behaves differently from currently available mineralocorticoid antagonists, is potentially a promising molecule to treat cardiorenal diseases.

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Section: Discussionmentioning

confidence: 71%

Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1

Amazit

Billan

Kolkhof

et al. 2015

Journal of Biological Chemistry

123

107

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“…Treatment with the antibiotic geldanamycin (17-AAG) in vitro accelerated MR degradation in epithelial cells by inhibiting the function of its chaperone Hsp90 (Figure 3, Table 2) (161). Modulators of MR trafficking have been discussed but are not yet available (162).…”

Section: New Mineralocorticoid Receptor Antagonistsmentioning

confidence: 99%

Mineralocorticoids in the Heart and Vasculature: New Insights for Old Hormones

Lother

Moser

Bode

et al. 2015

Annu. Rev. Pharmacol. Toxicol.

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The mineralocorticoid aldosterone is a key regulator of water and electrolyte homeostasis. Numerous recent developments have advanced the field of mineralocorticoid pharmacology—namely, clinical trials have shown the beneficial effects of aldosterone antagonists in chronic heart failure and post-myocardial infarction treatment. Experimental studies using cell type-specific gene targeting of the mineralocorticoid receptor (MR) gene in mice have revealed the importance of extrarenal aldosterone signaling in cardiac myocytes, endothelial cells, vascular smooth cells, and macrophages. In addition, several molecular pathways involving signal transduction via the classical MR as well as the G protein-coupled receptor GPER mediate the diverse spectrum of effects of aldosterone on cells. This knowledge has initiated the development of new pharmacological ligands to specifically interfere with targets on different levels of aldosterone signaling. For example, aldosterone synthase inhibitors such as LCI699 and the novel nonsteroidal MR antagonist BAY 94-8862 have been tested in clinical trials. Interference with the interaction between MR and its coregulators seems to be a promising strategy toward the development of selective MR modulators.

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“…Mineralocorticoids are, at least partially, effective by binding to the mineralocorticoid receptor, which acts as a ligand-dependent transcription factor regulating gene expression [9,34,36,46,48,87,88,89]. The receptor is similar to the glucocorticoid receptor and may be activated by glucocorticoids [90].…”

Section: Mechanisms Involved In Mineralocorticoid Effectsmentioning

confidence: 99%

“…At least in part due to extracellular volume expansion, mineralocorticoids enhance cardiac output and blood pressure [7,8]. However, the mineralocorticoid receptor [9,10,11] is expressed in a wide variety of tissues [10]. The mineralocorticoid receptor binds aldosterone, cortisol and corticosterone with similar affinity [10,12] but the inactivation of glucocorticoids by 11β-hydroxysteroid dehydrogenase 2 (HSD2) in aldosterone-target cells confers some aldosterone specificity in those cells [10,12,13].…”

Section: Introductionmentioning

confidence: 99%

On the Pleotropic Actions of Mineralocorticoids

Läng

2014

Nephron Physiol

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Classical effects of mineralocorticoids include stimulation of Na⁺ reabsorption and K⁺ secretion in the kidney and other epithelia including colon and several glands. Moreover, mineralocorticoids enhance the excretion of Mg²⁺ and renal tubular H⁺ secretion. The renal salt retention following mineralocorticoid excess leads to extracellular volume expansion and hypertension. The increase of blood pressure following mineralocorticoid excess is, however, not only the result of volume expansion but may result from stiff endothelial cell syndrome impairing the release of vasodilating nitric oxide. Beyond that, mineralocorticoids are involved in the regulation of a wide variety of further functions, including cardiac fibrosis, platelet activation, neuronal function and survival, inflammation as well as vascular and tissue fibrosis and calcification. Those functions are briefly discussed in this short introduction to the special issue. Beyond that, further contributions of this special issue amplify on mineralocorticoid-induced sodium appetite and renal salt retention, the role of mineralocorticoids in the regulation of acid-base balance, the involvement of aldosterone and its receptors in major depression, the mineralocorticoid stimulation of inflammation and tissue fibrosis and the effect of aldosterone on osteoinductive signaling and vascular calcification. Clearly, still much is to be learned about the various ramifications of mineralocorticoid-sensitive physiology and pathophysiology.

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Rapid mineralocorticoid receptor trafficking

Cited by 25 publications

References 52 publications

Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1

Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1

Mineralocorticoids in the Heart and Vasculature: New Insights for Old Hormones

On the Pleotropic Actions of Mineralocorticoids

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