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J. Biol. Chem., Vol. 276, Issue 30, 28484-28492, July 27, 2001
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From the Department of Clinical Research, Division of Nephrology
and Hypertension, University of Berne, 3010 Berne, Switzerland
11
The Intracellular Localization of the
Mineralocorticoid Receptor Is Regulated by 11
-Hydroxysteroid
Dehydrogenase Type 2*
,
-Hydroxysteroid dehydrogenase
(11-HSD) type 2 has been considered to protect the mineralocorticoid
receptor (MR) by converting 11-hydroxyglucocorticoids into their
inactive 11-keto forms, thereby providing specificity to the MR for
aldosterone. To investigate the functional protection of the MR by
11-HSD2, we coexpressed epitope-tagged MR and 11-HSD2 in HEK-293
cells lacking 11-HSD2 activity and analyzed their subcellular
localization by fluorescence microscopy. When expressed alone in the
absence of hormones, the MR was both cytoplasmic and nuclear. However,
when coexpressed with 11-HSD2, the MR displayed a reticular
distribution pattern, suggesting association with 11-HSD2 at the
endoplasmic reticulum membrane. The endoplasmic reticulum membrane
localization of the MR was observed upon coexpression only with
11-HSD2, but not with 11-HSD1 or other steroid-metabolizing
enzymes. Aldosterone induced rapid nuclear translocation of the MR,
whereas moderate cortisol concentrations (10-200 nM)
did not activate the receptor, due to 11-HSD2-dependent
oxidation to cortisone. Compromised 11-HSD2 activity (due to genetic
mutations, the presence of inhibitors, or saturating cortisol
concentrations) led to cortisol-induced nuclear accumulation of the MR.
Surprisingly, the 11-HSD2 product cortisone blocked the
aldosterone-induced MR activation by a strictly 11-HSD2-dependent mechanism. Our results provide
evidence that 11-HSD2, besides inactivating
11-hydroxyglucocorticoids, functionally interacts with the MR and
directly regulates the magnitude of aldosterone-induced MR activation.
*
This work was supported by Swiss National Foundation Grants
31-59511.99 (to A. O.) and 31-61505.00 (to F. J. F.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Clinical
Research, Div. of Nephrology and Hypertension, University of Berne,
Freiburgstr. 15, 3010 Berne, Switzerland. Tel.: 41-31-632-9438; Fax:
41-31-632-9444; E-mail: alex.odermatt@dkf2.unibe.ch.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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