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The prevention of acute renal failure through the intervention in the DNA repair system.

通过干预 DNA 修复系统预防急性肾衰竭。

基本信息

批准号：
15590846
负责人：
HISHIDA Akira
金额：
$ 2.24万
依托单位：
HAMAMATSU UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590846/
关键词：
p21 p27 cyclineD1 cyclinB1 cisplatin acute renal failure p21 antisense GADD45 p27 サイクリンB_1 サイクリンD_1 GADD153

项目摘要

In this study, we evaluated the expressions and the roles of proteins involved in cell cycle regulation and DNA repair in cisplatin(CDDP)-induced acute renal failure(ARF). CDDP-induced tubular damage and the increase in serum creatinine (Scr) were observed at day 3 and peaked at day 5. The expressions of cell cycle regulatory proteins(p21, p27, cyclin B1 and cyclin D1) and DNA repair-related proteins(PCNA, GADD 45 and GADD 153) were significantly increased in the outer medulla, reaching peak levels at 3 days after CDDP. Sodium arsenite (SA) attenuated tubular damage and increased Scr at 5 day after CDDP. SA augmented GDDP-induced increment of p27 but suppressed the increased expression of cyclin B1 and cyclin D1. SA-induced attenuation of nephrotoxicity was associated with enhanced expression of PCNA and GADD 153 in damaged tubular cells.The administration of p21 antisense oligodeoxynucleotide(ODN), which was mainly uptaken by cortical proximal tubule(PT) cells, induced a decrease inn the number of p21-positive PT cells in the cortex and aggravated cortical PT damage, but did not affect these in the outer stripe of outer medulla. The antisense also did not alter Scr level at day 5.Our findings indicated that (1) proteins related to cell cycle regulation and DNA repair are induced in CDDP nephrotoxicity, (2) the SA-induced attenuation of CDDP nephrotoxicity is associated with increased expression of p27 and decreased expression of cyclin B1 and cyclin D1, they all induce cell cycle arrest at G1/S and G2/M, and (3) enhanced expression of DNA repair-related proteins is also associated with attenuation of CDDP-nephrotoxicity.

本研究旨在探讨顺铂（CDDP）诱导的急性肾功能衰竭（ARF）中细胞周期调控和DNA修复相关蛋白的表达及其作用。CDDP诱导的肾小管损伤和血清肌酐（Scr）的增加在第3天观察到，并在第5天达到峰值。外髓细胞周期调控蛋白（p21、p27、cyclin B1和cyclin D1）和DNA修复相关蛋白（PCNA、GADD 45和GADD 153）的表达明显增加，在CDDP后3d达高峰。亚砷酸钠（SA）可减轻CDDP后第5天肾小管损伤，升高Scr。SA可增强GDDP诱导的p27表达的增加，但抑制cyclin B1和cyclin D1表达的增加。结果表明，SA减轻肾毒性与肾小管上皮细胞PCNA和GADD 153表达增强有关，而p21反义寡核苷酸（ODN）主要被皮质近曲小管（PT）细胞摄取，可使皮质PT细胞数量减少，加重皮质PT损伤，但对外髓外条PT细胞无影响。结果表明：（1）在顺铂肾毒性中，与细胞周期调控和DNA修复相关的蛋白质被诱导表达;（2）SA对顺铂肾毒性的减轻与p27表达增加，cyclin B1和cyclin D1表达减少有关，它们均诱导细胞周期阻滞在G1/S和G2/M期，（3）DNA修复相关蛋白表达的增强也与CDDP肾毒性的减弱有关。