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

在cddp诱导的急性肾功能衰竭（ARF）中，受损的肾小管细胞发生DNA修复或凋亡细胞死亡。我们假设受损的小管细胞会在G1停止细胞周期并加速DNA修复。在这项研究中，我们评估了细胞周期调节因子细胞周期蛋白和细胞周期蛋白依赖性激酶抑制剂是否在cddp诱导的ARF肾脏中增加。我们还研究了DNA修复标记的表达，并评估了细胞周期调节和DNA修复的se标记的表达是否与ARF的严重程度有关。在cddp诱导的ARF中，第3天观察到p21、p27、cyclin D_1和PCNA的过表达。PCNA的增加与BrdU掺入的增加无关，这表明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。第二次注射CDDP前14天用CDDP预处理可减轻cdp所致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。亚砷酸钠预处理可提高p27和PCNA的表达，抑制细胞周期蛋白D_1的表达，ARF在功能和形态上均有一定程度的衰减。IGF-1可使大鼠p21和PCNA表达升高，cyclin D_1升高，肾功能下降。综上所述，p21、p27和PCNA的升高和cyclin D_1的降低与cddp诱导的ARF的衰减有关，提示细胞周期调节和DNA修复在cddp诱导的ARF的发生中起重要作用。

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.