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

在这项研究中，我们评估了参与细胞周期调节和DNA修复的蛋白在顺铂（CDDP）诱导的急性肾功能衰竭（ARF）中的表达和作用。cddp诱导的肾小管损伤和血清肌酐（Scr）升高在第3天出现，第5天达到峰值。细胞周期调节蛋白（p21、p27、cyclin B1、cyclin D1）和DNA修复相关蛋白（PCNA、GADD 45、GADD 153）在外髓质表达显著升高，并在CDDP后3 d达到峰值。亚砷酸钠（SA）在CDDP后第5天减轻了肾小管损伤并增加了Scr。SA增强了gdp诱导的p27的表达，抑制了cyclin B1和cyclin D1的表达。sa诱导的肾毒性减弱与受损小管细胞中PCNA和GADD 153的表达增强有关。主要由皮质近端小管（PT）细胞摄取的p21反义寡脱氧核苷酸（ODN）可导致皮质中p21阳性的PT细胞数量减少，并加重皮质PT损伤，但对外髓质外条纹细胞无影响。反义也没有改变第5天的Scr水平。结果表明：(1)细胞周期调控和DNA修复相关蛋白在CDDP肾毒性中被诱导；(2)sa诱导的CDDP肾毒性减弱与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； (3) DNA修复相关蛋白表达增强也与CDDP肾毒性减弱有关。

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.