CYCLIN DEPENDENT KINASE INHIBITOR IN ACUTE RENAL FAILURE

细胞周期蛋白依赖性激酶抑制剂治疗急性肾衰竭

• 批准号: 6177901
• 负责人: PETER M. PRICE
• 金额: $ 17.54万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6177901
• 关键词: acute renal failure; apoptosis; cell cycle; cis platinum compound; cyclin dependent kinase; enzyme induction /repression; enzyme inhibitors; gene deletion mutation; genetic promoter element; kidney cell; laboratory mouse; proliferating cell nuclear antigen; tissue /cell culture; tumor suppressor genes

This application is directed towards the study of p21, a cyclin- dependent kinase inhibitor in acute renal failure. The Principal Investigator has found that in three different types of acute renal injury, namely, ischemia reperfusion, cisplatin administration, and ureteral obstruction, there is rapid and profound induction in renal tubules of p21, a cyclin-dependent kinase inhibitor, which has pleiotropic effects on cell fate, including cell-cycle interruption, induction of cellular senescence, termination differentiation and inhibition of regeneration. The Principal Investigator provides evidence that p21 may serve a protective role in acute renal failure. This view is based on studies using a p21 null mouse subjected to cisplatin nephrotoxicity. The wild type p21 mouse as compared to the p21 null mouse demonstrated markedly reduced necrosis and apoptosis, less histologic injury and greater preservation of renal function in conjunction with less mortality from acute renal failure. In the wild type mouse, proximal tubular necrosis mainly involved the S3 segment whereas in the p21 null mouse, such necrosis had extended through all segments. The induction of p21 is observed not only in the cisplatin model, but also in ischemia reperfusion injury as well as urinary tract obstruction. In the cisplatin model, there is also intense induction of p53, a finding that is not observed in the other models. Since p53 is known to include p21, the principal investigator hypothesizes that renal injury per se, and in some instances, complemented by induction of p53 as occurs in cisplatin nephropathy, represents an adaptive response to renal injury. This induction of p21 has a protective effect in renal injury since it prevents the progression of cells from the G1 phase to the S phase. That prevention of progression from G1 to S allow reparative responses to occur such that the entry of cells with damaged DNA into the S phase does not occur. In the latter circumstance, when there is an absence of p21 the entry of cells into the S phase leads to the induction of necrosis and apoptosis because of unrepaired and damaged DNA. The cell death resulting from such DNA injury in turn leads to a commensurate proliferative response. Thus, p21, in essence, prevents both the proliferation and cell death which is more manifest in the p21 null mouse.

本申请涉及p21的研究，p21是一种细胞周期蛋白， 急性肾功能衰竭的治疗 校长 研究人员发现，在三种不同类型的急性肾衰竭中， 损伤，即缺血再灌注，顺铂给药，和 输尿管梗阻时，肾内有快速而深刻的感应， p21的小管，一种细胞周期蛋白依赖性激酶抑制剂， 对细胞命运的多效性作用，包括细胞周期中断， 诱导细胞衰老、终止分化和 抑制再生。 主要研究者提供 有证据表明p21可能在急性肾衰竭中起保护作用。 这一观点是基于使用p21无效小鼠的研究， 顺铂肾毒性 野生型p21小鼠与 p21基因敲除小鼠表现出明显减少的坏死和凋亡， 减少组织损伤，更好地保护肾功能， 同时急性肾衰竭的死亡率较低。 在野外 型小鼠，近端肾小管坏死主要累及S3段 而在p21基因敲除小鼠中，这种坏死已经扩展到所有的细胞， 片段 不仅在顺铂中观察到p21的诱导， 模型，而且在缺血再灌注损伤以及泌尿道 梗阻在顺铂模型中，也存在强烈的 p53，这是在其他模型中未观察到的结果。 因为p53是 已知包括p21，主要研究者假设肾 损伤本身，在某些情况下，通过诱导p53 如发生在顺铂肾病中，代表了对 肾损伤 p21的这种诱导在肾损伤中具有保护作用。 损伤，因为它阻止细胞从G1期进展到 S阶段。 阻止从G1到S的进展， 修复性反应的发生，使得受损细胞的进入， DNA进入S期不会发生。 在后一种情况下，当 如果没有p21，细胞进入S期， 由于未修复和细胞凋亡， 受损的DNA 这种DNA损伤导致的细胞死亡反过来 导致相应的增殖反应。因此，p21，本质上， 阻止增殖和细胞死亡， 在p21 null小鼠中。