Functional modulation of the mineralocorticoid receptor by cis-diamminedichloroplatinum (II).

Abstract:

BACKGROUND:Renal salt wasting and hypotension are some of the frequent complications in patients treated with cis-diamminedichloroplatinum (II) (cDDP), and it is suggested that cDDP produces an abnormality in the renin-angiotensin system. However, not only the underlying mechanism but also prophylactic treatment of this cDDP toxicity remains unknown. In the present study, we investigated the molecular mechanism of this cDDP-induced disturbance of renal sodium handling with focusing on the effect of cDDP on mineralocorticoid receptor (MR) function. METHODS:The effect of cDDP was studied on nuclear translocation, DNA binding activity, and transactivation function of the MR. RESULTS:In a transient transfection assay, cDDP suppressed MR-dependent reporter gene expression. This cDDP-mediated repression of MR function, at least in part, is suggested to be due to the generation of reactive oxygen species and a subsequent decrease in ligand-dependent nuclear translocation and suppression of the interaction with DNA of the MR. This redox-dependent repression of MR function both in vitro and in vivo was reversed by treatment with reducing reagents. Moreover, cDDP, most possibly via formation of DNA adducts, inhibited MR-DNA interaction in a redox-independent fashion. CONCLUSIONS:MR function is impaired by cDDP at multiple levels, via redox-dependent and -independent mechanisms.

journal_name

Kidney Int

journal_title

Kidney international

authors

Iida T,Makino Y,Okamoto K,Yoshikawa N,Makino I,Nakamura T,Tanaka H

doi

10.1046/j.1523-1755.2000.00307.x

subject

Has Abstract

pub_date

2000-10-01 00:00:00

pages

1450-60

issue

4

eissn

0085-2538

issn

1523-1755

pii

S0085-2538(15)47244-8

journal_volume

58

pub_type

杂志文章
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