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

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Serval ID
serval:BIB_5AF33F0048C4
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mineralocorticoid receptor degradation is promoted by Hsp90 inhibition and the ubiquitin-protein ligase CHIP.
Journal
American Journal of Physiology. Renal Physiology
Author(s)
Faresse N., Ruffieux-Daidie D., Salamin M., Gomez-Sanchez C.E., Staub O.
ISSN
1522-1466 (Electronic)
ISSN-L
1522-1466
Publication state
Published
Issued date
12/2010
Peer-reviewed
Oui
Volume
299
Number
6
Pages
F1462-F1472
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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.
Keywords
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
Create date
11/03/2011 14:37
Last modification date
20/08/2019 15:13
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