The induction of cell cycle regulatory and DNA repair proteins in cisplatin-induced acute renal failure
The induction of cell cycle regulatory and DNA repair proteins in cisplatin-induced acute renal failure
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DOI：
10.1016/j.taap.2004.04.003
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发表时间：
2004-10-15
影响因子：
3.8
通讯作者：
Hishida, A
中科院分区：
文献类型：
--
作者：
Zhou, H;Kato, A;Hishida, A
本研究旨在探讨顺铂（cisplatin，CDDP）诱导的急性肾功能衰竭（acute renal failure，ART）中细胞周期调控和DNA修复相关蛋白的表达及其作用。CDDP（6 mg/kg，iv）可引起肾小管损伤，血清肌酐（Scr）和外髓外条TUNEL阳性细胞数增加，并在CDDP后5 d达到高峰。CDDP后外髓细胞周期蛋白依赖性激酶抑制因子（p21和p27）、细胞周期蛋白B 1、细胞周期蛋白D1、PCNA、GADD 45和GADD 153的表达均明显增加，并于CDDP后3d达高峰。p27和PCNA在同一细胞核内表达增加。亚砷酸钠（SA），一种重金属，减轻肾小管损伤和增加Scr和TUNEL阳性细胞在CDDP后5天。SA可增强CDDP诱导的p27表达，但抑制CDDP诱导的cyclin B1和cyclin D1表达。SA诱导的肾毒性衰减与受损肾小管细胞中增殖细胞核抗原（PCNA）和生长停滞和DNA损伤（GADD）153的表达增强有关。结果表明：（1）顺铂肾毒性中细胞周期调控和DNA修复相关蛋白被诱导表达;（2）水杨酸减轻顺铂肾毒性与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。(C)2004年爱思唯尔公司All rights reserved.
The purpose of this study was to evaluate the expressions and the roles of proteins involved in cell cycle regulation and DNA repair in cis-diamminedichloroplatinum (II) (cisplatin or CDDP)-induced acute renal failure (ART). Treatment with CDDP (6 mg/kg, iv) induced tubular damage and increased serum creatinine (Scr) and the number of TUNEL-positive cells in the outer stripe of the outer medulla in rats, which reached peak levels at 5 days after CDDP. The expressions of cyclin-dependent kinase inhibitors (p21 and p27), cyclin B 1, cyclin D 1, PCNA, GADD 45, and GADD 153 were significantly increased in the outer medulla, reaching peak levels at 3 days after CDDP. Increments of p27 and PCNA were observed in the same nuclei. Sodium arsenite (SA), a heavy metal, attenuated tubular damage and increased Scr- and TUNEL-positive cells at 5 days after CDDP. SA augmented CDDP-induced increment of p27 but suppressed the increased expression of cyclin B1 and cyclin D1 at 3 days after CDDP. SA-induced attenuation of nephrotoxicity was associated with enhanced expression of proliferating cell nuclear antigen (PCNA) and growth-arrest and DNA damage (GADD) 153 in damaged tubular cells. 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. (C) 2004 Elsevier Inc. All rights reserved.