Impairment of Mineralocorticoid Receptor
(MR)-dependent Biological Response by Oxidative Stress and
Aging
CORRELATION WITH POST-TRANSLATIONAL MODIFICATION OF MR AND
DECREASED ADP-RIBOSYLATABLE LEVEL OF ELONGATION FACTOR 2 IN KIDNEY
CELLS*
Graciela
Piwien-Pilipuk
,
Antonio
Ayala§,
Alberto
Machado§, and
Mario D.
Galigniana¶
From the Departamento de Química
Biológica, Facultad de Ciencias Exactas y Naturales, Universidad
de Buenos Aires, Ciudad Universitaria, 1428 Buenos Aires, Argentina
and the § Departamento de Bioquímica,
Bromatología y Toxicología, Facultad de Farmacia,
Universidad de Sevilla, 41012 Sevilla, Spain
Acute and chronic treatments of mice with the
glutathione-depleting agent,
L-buthionine-(SR)-sulfoximine (BSO),
impaired the mineralocorticoid receptor (MR)-dependent
biological response by inhibiting aldosterone binding. This
steroid-binding inhibition was fully reversed when reducing agents were
added to kidney cytosol obtained from mice treated for 5 h, but it
was only partially reversed in cytosol obtained from mice treated for
10 days. Although the oligomeric structure of the MR-hsp90
heterocomplex was always unaffected, a decreased amount of MR protein
was evidenced after the long term treatment. Such a deleterious effect
was correlated with a post-translational modification of MR, as
demonstrated by an increased level of receptor carbonylation. In
addition, a failure at the elongation/termination step was also
observed during the receptor translation process in a reticulocyte
lysate system. Thus, a high polyribosomes/monomers ratio and both
increased proteolysis and decreased ADP-ribosylatable concentration of
elongation factor 2 (EF-2) were shown. Importantly, similar
observations were also performed in vivo after depletion of
glutathione. Notwithstanding the EF-2 functional disruption, not all
renal proteins were equally affected as the MR. Interestingly, both
EF-2 and MR expressed in old mice were similarly affected as in
L-buthionine-(SR)-sulfoximine-treated young
mice. We therefore propose that a dramatic depletion of glutathione in
kidney cells mimics the cumulative effect of aging which, at the end,
may lead to a renal mineralocorticoid dysfunction.
*
This work was supported by grants from Consejo Nacional de
Investigaciones Científicas y Técnicas de la
República Argentina and Ministerio de Sanidad y Consumo de
España Grant FIS 96-1442.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: 1301 Medical
Science Research Bldg. III, Dept. of Pharmacology, the University of
Michigan Medical School, Ann Arbor, MI 48109. Tel.: 734-764-5414; Fax:
734-763-4450; E-mail: mgali@umich.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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