Mineralocorticoid receptor degradation is promoted by Hsp90 inhibition and the ubiquitin-protein ligase CHIP.

Détails

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Etat: Supprimée
Version: de l'auteur⸱e
ID Serval
serval:BIB_5AF33F0048C4
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Mineralocorticoid receptor degradation is promoted by Hsp90 inhibition and the ubiquitin-protein ligase CHIP.
Périodique
American Journal of Physiology. Renal Physiology
Auteur⸱e⸱s
Faresse N., Ruffieux-Daidie D., Salamin M., Gomez-Sanchez C.E., Staub O.
ISSN
1522-1466 (Electronic)
ISSN-L
1522-1466
Statut éditorial
Publié
Date de publication
12/2010
Peer-reviewed
Oui
Volume
299
Numéro
6
Pages
F1462-F1472
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
The mineralocorticoid receptor (MR) plays a crucial role in the regulation of Na(+) balance and blood pressure, as evidenced by gain of function mutations in the MR of hypertensive families. In the kidney, aldosterone binds to the MR, induces its nuclear translocation, and promotes a transcriptional program leading to increased transepithelial Na(+) transport via the epithelial Na(+) channel. In the unliganded state, MR is localized in the cytosol and part of a multiprotein complex, including heat shock protein 90 (Hsp90), which keeps it ligand-binding competent. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin antibiotic that binds to Hsp90 and alters its function. We investigated whether 17-AAG affects the stability and transcriptional activity of MR and consequently Na(+) reabsorption by renal cells. 17-AAG treatment lead to reduction of MR protein level in epithelial cells in vitro and in vivo, thereby interfering with aldosterone-dependent transcription. Moreover, 17-AAG inhibited aldosterone-induced Na(+) transport, possibly by interfering with MR availability for the ligand. Finally, we identified the ubiquitin-protein ligase, COOH terminus of Hsp70-interacting protein, as a novel partner of the cytosolic MR, which is responsible for its polyubiquitylation and proteasomal degradation in presence of 17-AAG. In conclusion, 17-AAG may represent a novel pharmacological tool to interfere with Na(+) reabsorption and hypertension.
Mots-clé
Aldosterone/pharmacology, Animals, Benzoquinones/pharmacology, Female, HSP70 Heat-Shock Proteins/metabolism, HSP90 Heat-Shock Proteins/antagonists & inhibitors, Kidney Tubules, Collecting/metabolism, Lactams, Macrocyclic/pharmacology, Leupeptins/pharmacology, Mice, Mice, Inbred C57BL, Receptors, Mineralocorticoid/drug effects, Receptors, Mineralocorticoid/metabolism, Sodium/metabolism, Transcriptional Activation/drug effects, Ubiquitin-Protein Ligases/antagonists & inhibitors, Ubiquitin-Protein Ligases/metabolism
Pubmed
Web of science
Création de la notice
11/03/2011 13:37
Dernière modification de la notice
20/10/2020 14:41
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