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J. Biol. Chem., Vol. 276, Issue 30, 28484-28492, July 27, 2001
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-Hydroxysteroid
Dehydrogenase Type 2*
,
From the Department of Clinical Research, Division of Nephrology
and Hypertension, University of Berne, 3010 Berne, Switzerland
11
-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.
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.
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