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Functional modulation of the mineralocorticoid receptor by cis-diamminedichloroplatinum (II)
1Second Department of Internal Medicine, Asahikawa Medical College, Midorigaoka, Asahikawa, Japan.
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.