Takeda M, Kobayashi M, Shirato I, Osaki T, Endou H
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan.
Arch Toxicol. 1997;71(10):612-21. doi: 10.1007/s002040050434.
Cisplatin is known to induce serious renal damage including acute renal failure, the major site of renal injury appears to be localized to the third segment of the proximal tubule (S3). Apoptosis occurs during a variety of acute injuries to tubule cell. The purpose of this study was to determine whether cisplatin induces apoptosis of immortalized mouse S3 cells, and to define the intracellular pathways leading to cell death. S3 cells exposed to cisplatin exhibited biochemical, morphological, and flow cytometric changes characteristic of apoptosis associated with slight necrosis. Cisplatin-induced apoptosis could be inhibited by overexpression of crmA, a cowpox virus gene, of which the product is known to suppress activities of the interleukin-1 beta converting enzyme (ICE) family proteases. On the other hand, overexpression of bcl-2, an antiapoptotic oncogene, rendered S3 cells partially resistant to cisplatin. These results indicate that cisplatin-induced proximal tubule damage is associated with apoptosis, which is positively modulated by the ICE family of proteases and negatively by the product of bcl-2.
已知顺铂会导致严重的肾损伤，包括急性肾衰竭，肾损伤的主要部位似乎局限于近端小管的第三段（S3）。在各种肾小管细胞急性损伤过程中都会发生凋亡。本研究的目的是确定顺铂是否会诱导永生化小鼠S3细胞凋亡，并确定导致细胞死亡的细胞内途径。暴露于顺铂的S3细胞表现出与轻微坏死相关的凋亡特征性生化、形态和流式细胞术变化。顺铂诱导的凋亡可被牛痘病毒基因crmA的过表达抑制，已知该基因产物可抑制白细胞介素-1β转化酶（ICE）家族蛋白酶的活性。另一方面，抗凋亡癌基因bcl-2的过表达使S3细胞对顺铂产生部分抗性。这些结果表明，顺铂诱导的近端小管损伤与凋亡有关，凋亡受到ICE家族蛋白酶的正向调节和bcl-2产物的负向调节。
