Mineralocorticoid receptor degradation is promoted by Hsp90 inhibition and the ubiquitin-protein ligase CHIP.
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.
Faresse
Nourdine
N
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
Ruffieux-Daidie
Dorothée
D
Salamin
Mélanie
M
Gomez-Sanchez
Celso E
CE
Staub
Olivier
O
D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D007976:Leupeptins; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; C112765:tanespimycin; D012964:Sodium; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde