权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The role of p21, a cell cycle regulation factor, in the development of cisplatin-induced acute renal failure

细胞周期调节因子 p21 在顺铂诱导的急性肾功能衰竭发展中的作用

基本信息

批准号：
13671106
负责人：
HISHIDA Akira
金额：
$ 2.3万
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：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

In CDDP-induced acute renal failure(ARF), the damaged tubular cells undergo DNA repair or apoptotic cell death. We hypothesized that damaged tubular cells would stop the cell cycle at G1 and accelerate DNA repair. In this study, we evaluated whether the cyclins and cyclin dependent kinase inhibitors, which are cell cycle regulation factors, are increased in CDDP-induced ARF kidneys. We also studied the expression of DNA repair markers and evaluated whether the expression of se markers of cell cycle regulations and DNA repair are related to the severity of ARF. In CDDP-induced ARF, the overexpressions of p21, p27, cyclin D_1 and PCNA were observed on day 3. The increase in PCNA was not associated with the increase in BrdU incorporation, suggesting that the increase in PCNA positive cells might reflect the increased DNA repair rather than the increased cell proliferation. The pretreatment with CDDP 14 days prior to the second CDDP injection attenuated the decline of kidney function and tubular damage in CDDP-induced ARF. This attenuation was associated with the increases in p21 and PCNA. The preadministration of sodium arsenite augmented the expression of p27 and PCNA and suppressed the expression of cyclin D_1, which were followed by the functional and morphological attenuation of the degree of ARF. The administration of IGF-1 also increased the expression of p21 and PCNA and attenuated the increase in cyclin D_1 and the decline of renal function. In summary, the increases in p21, p27 and PCNA and the decrease in cyclin D_1 were associated with the attenuation of CDDP-induced ARF, suggesting an important role of cell cycle regulation and DNA repair in the development of CDDP-induced ARF.

在CDDP诱导的急性肾功能衰竭（ARF）中，受损的肾小管细胞进行DNA修复或凋亡细胞死亡。我们假设受损的肾小管细胞会在G1期停止细胞周期，并加速DNA修复。在这项研究中，我们评估是否细胞周期蛋白和细胞周期蛋白依赖性激酶抑制剂，这是细胞周期调节因子，增加CDDP诱导的ARF肾脏。我们还研究了DNA修复标志物的表达，并评估了细胞周期调控和DNA修复标志物的表达是否与ARF的严重程度有关。CDDP诱导的ARF中，p21、p27、cyclin D_1和PCNA在第3天出现过度表达。PCNA的增加与BrdU掺入的增加无关，提示PCNA阳性细胞的增加可能反映了DNA修复的增加而不是细胞增殖的增加。在第二次注射CDDP前14天给予CDDP预处理可减轻CDDP诱导的ARF的肾功能下降和肾小管损伤。这种衰减与p21和PCNA的增加有关。亚砷酸钠预处理可使p27、PCNA表达增强，cyclin D_1表达降低，使ARF的功能和形态学程度减轻。IGF-1还可增加p21和PCNA的表达，减轻cyclin D_1的升高和肾功能的下降。结论：CDDP诱导ARF的发生发展与细胞周期调控和DNA修复有关，CDDP诱导ARF的发生发展与p21、p27和PCNA的表达增加和cyclin D_1的表达减少有关。