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

在顺铂诱导的急性肾功能衰竭(ARF)中，受损的肾小管细胞经历DNA修复或细胞凋亡性死亡。我们假设，受损的肾小管细胞将使细胞周期停止在G1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因子在CDDP诱导的ARF肾脏中是否增加。我们还研究了DNA修复标志物的表达，并评价了细胞周期调节和DNA修复标志物的表达是否与ARF的严重程度有关。在顺铂诱导的ARF模型中，p21、p27、细胞周期蛋白D_1和增殖细胞核抗原在第3天出现过度表达，而增殖细胞核抗原表达的增加与BrdU掺入的增加无关，提示增殖细胞核抗原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。在第二次注射顺铂前14天预先给予顺铂，可减轻肾功能下降和肾小管损伤。这种减弱与p21和增殖细胞核抗原的升高有关。预先给予亚砷酸钠可增强p27和增殖细胞核抗原的表达，抑制细胞周期蛋白D_1的表达，继而使ARF的功能和形态减弱。应用IGF-1还可增加p21和增殖细胞核抗原的表达，减轻细胞周期蛋白D_1的升高和肾功能的下降。综上所述，p21、p27和增殖细胞核抗原的表达增加，细胞周期蛋白D_1的表达减少与CDDP诱导的ARF的减轻有关，提示细胞周期调控和DNA修复在CDDP诱导的ARF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.