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

细胞凋亡在顺铂诱导的急性肾功能衰竭中的作用。

基本信息

批准号：
10670993
负责人：
HISHIDA Akira
金额：
$ 1.6万
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：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670993/
关键词：
apoptosis cisplatin acute renal failure p21 p53 cell cycle DNA repair BC12

项目摘要

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.

众所周知，肾毒性急性肾功能衰竭可诱导细胞凋亡。然而，细胞凋亡在急性肾功能衰竭发生发展中的作用尚未得到研究。在这项研究中，通过给予二甲基硫脲或甘氨酸，或通过使用其他肾毒性物质（醋酸双氧铀）预处理来改善顺铂诱导的肾小管损伤之前和之后，评估了顺铂诱导的急性肾衰竭中细胞凋亡的程度，据报道所有这些都可以减轻肾小管细胞损伤。肾小管损伤评分与TUNEL法检测的凋亡细胞数呈显著正相关。急性肾功能衰竭早期TUNEL阳性细胞的增加与增殖细胞核抗原（PCNA）、p53和p21（细胞周期蛋白依赖性激酶抑制剂）的增加有关。PCNA的增加与BrdU掺入的增加无关，BrdU掺入是细胞增殖的标志物，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DNA修复的增强。这些结果可能表明，凋亡细胞死亡在顺铂诱导的急性肾功能衰竭肾小管损伤的发展中起重要作用，并可能表明顺铂损伤的肾小管细胞诱导p53介导的p21过表达，并将细胞周期停止在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，未被修复的细胞可能发生凋亡并导致肾小管损伤。