The role of apoptosis in cisplatin-induced acute renal failure.

众所周知，肾毒性急性肾功能衰竭可诱导凋亡细胞死亡。然而，细胞凋亡在急性肾功能衰竭发展中的作用尚未得到研究。本研究对顺铂诱导的急性肾功能衰竭患者，采用二甲硫脲或甘氨酸或其他肾毒性物质（醋酸铀酰）预处理顺铂诱导的肾小管损伤前后的细胞凋亡程度进行了评价，这些均可减轻肾小管细胞损伤。TUNEL法测定的肾小管损伤评分与凋亡细胞死亡数呈显著正相关。急性肾衰竭早期TUNEL阳性细胞的增加与增殖细胞核抗原（PCNA）、p53和p21（一种细胞周期蛋白依赖性激酶抑制剂的抑制剂）的增加有关。PCNA的增加与BrdU结合的增加无关，BrdU结合是细胞增殖的标志，这表明PCNA阳性细胞的增加并不反映细胞增殖的增强，而是反映了DNA修复的增强。这些发现可能提示凋亡细胞死亡在顺铂诱导的急性肾功能衰竭小管损伤的发展中起重要作用，并可能提示顺铂损伤的小管细胞诱导p53介导的p21过表达，使细胞周期停止在G1/S期，为DNA修复提供时间。在顺铂诱导的急性肾功能衰竭中，未修复的细胞可能发生凋亡并导致肾小管损伤。

It is well known that apoptotic cell death is induced in nephrotoxic acute renal failure. However, the roles of apoptosis in the development of acute renal failure have not been studied. In this study the degree of apoptosis in cisplatin-induced acute renal failure was evaluated before and after the modification of cisplatin-induced tubular damage by the administration of dimethylthiourea or glycine, or by the pretreatment with other nephrotoxic substance ( uranyl acetate), all of these were reported to attenuate the tubular cell damage. A significant positive correlation was found between the tubular damage score and the number of apoptotic cell death evaluated by TUNEL method. The increase in TUNEL positive cells in the early phase of acute renal failure was associated with the increases in proliferating cell nuclear antigen (PCNA), p53 and p21 (an inhibitor of cyclin-dependent kinase inhibitor). The increase in PCNA was not associated with the increase in the BrdU incorporation which is a marker of cell proliferation, suggesting that the increase in PCNA positive cells does not reflect the enhanced cell proliferation but reflect the enhanced DNA repair. These findings may suggest that apoptotic cell death play an important role in the development of tubular damage in cisplatin-induced acute renal failure and may indicate that the tubular cells damaged by cisplatin induces the p53-mediated overexpression of p21 and stops the cell cycle at G1/S phase, providing the time for DNA repair. The cells which were not repaired may undergo apoptosis and contribute to tubular damage in cisplatin-induced acute renal failure.