Reference - Detail
|Author||Iida T, Makino Y, Okamoto K, Yoshikawa N, Makino I, Nakamura T, Tanaka H.|
|Title||Functional modulation of the mineralocorticoid receptor by cis-diamminedichloroplatinum (II).|
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.
|MeSH||Animals Biological Transport / drug effects COS Cells Cisplatin / pharmacology* Cross-Linking Reagents / pharmacology* DNA Adducts / metabolism DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Gene Expression / drug effects In Vitro Techniques Oxidation-Reduction Reactive Oxygen Species / metabolism Receptors, Mineralocorticoid / genetics* Receptors, Mineralocorticoid / metabolism* Renin-Angiotensin System / physiology Sodium / metabolism Transcription, Genetic / drug effects Transfection|
|WOS Category||UROLOGY & NEPHROLOGY|
|Human and Animal Cells|