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修复的蛋白质在顺铂(CDDP)诱导的急性肾功能衰竭(ARF)中的表达和作用。外髓细胞周期调控蛋白(p21、p27、细胞周期蛋白B1和细胞周期蛋白D1)和DNA修复相关蛋白(增殖细胞核抗原、Gadd45和Gadd153)的表达显著增加，在CDDP后3d达到高峰。顺铂后5d，亚砷酸钠(SA)可减轻肾小管损伤，增加Scr。SA可增强GDDP诱导的p27表达增加，但抑制细胞周期蛋白B1和细胞周期蛋白D1的表达。SA诱导的肾毒性减弱与肾小管损伤细胞中增殖细胞核抗原和GADD153的表达增加有关。给予p21反义寡核苷酸(ODN)后，皮质近端小管(PT)细胞摄取的p21阳性细胞数量减少，皮质PT损伤加重，但对外髓外条的影响不明显。结果表明：(1)顺铂肾毒性诱导了与细胞周期调控和DNA修复相关的蛋白表达；(2)SA诱导的顺铂肾毒性减弱与p27表达增加、细胞周期蛋白B1和细胞周期蛋白D1表达降低有关，均导致细胞周期停滞于G1/S和G2/M期；(3)DNA修复相关蛋白表达增强也与顺铂肾毒性减弱有关。

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.