論文 - 詳細
| RRC ID | 39858 |
|---|---|
| 著者 | Iida T, Makino Y, Okamoto K, Yoshikawa N, Makino I, Nakamura T, Tanaka H. |
| タイトル | Functional modulation of the mineralocorticoid receptor by cis-diamminedichloroplatinum (II). |
| ジャーナル | Kidney Int |
| 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. |
| 巻・号 | 58(4) |
| ページ | 1450-60 |
| 公開日 | 2000-10-1 |
| DOI | 10.1046/j.1523-1755.2000.00307.x |
| PII | S0085-2538(15)47244-8 |
| PMID | 11012880 |
| 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 |
| IF | 8.945 |
| 引用数 | 7 |
| WOS 分野 | UROLOGY & NEPHROLOGY |
| リソース情報 | |
| ヒト・動物細胞 | COS-7(RCB0539) |