Cyclin-dependent Kinase Inhibitor in Acute Renal Failure

急性肾衰竭中的细胞周期蛋白依赖性激酶抑制剂

• 批准号: 8477648
• 负责人: PETER M. PRICE
• 金额: $ 22.95万
• 依托单位: BIOMEDICAL RESEARCH FDN/CENTRAL ARKANSAS
• 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8477648
• 关键词: Cyclin; dependent; Kinase; Inhibitor; Acute

Our long-term objective is to prevent and/or treat acute renal failure. We showed that activation of the gene for the p21 cyclin-dependent kinase (cdk) inhibitor ameliorated renal failure after cisplatin administration and renal ischemia/reperfusion. After these injuries, comparing p21(+/+) with p21(-/-) mice, there was significantly less cellular damage, including both necrosis and apoptosis, less functional kidney failure, and less mortality in the p21(+/+) population. The mechanism was directly dependent on the role of p21 as a regulator of the cell cycle. We now find that induction of p21 using an adenoviral vector before cisplatin exposure completely protected mouse kidney proximal tubule cells in vitro from cytotoxicity. Similarly, pretreatment of kidney cells with different pharmacologic cdk2 inhibitors or with a histone deacetylase (HDAC) inhibitor known to induce p21 was also protective. We extended these findings by showing that a cdk2 inhibitory drug, with a spectrum of activity similar to p21, also protected kidney function and cell morphology in vivo from cisplatin-induced renal injury. We hypothesize that cdk2 inhibitors protect kidney cells from cisplatin-induced toxicity by inhibiting cell death pathways activated by cisplatin exposure. Furthermore, we hypothesize that cdk2 inhibitors will be useful to prevent and treat acute renal failure. We have developed aims that will determine the mechanism of cdk inhibitor protection in vitro and in vivo and provide initial steps to utilize cdk inhibitors to ameliorate cisplatin-induced renal failure. Our first specific aim is to determine the mechanism of cdk inhibitor protection. We will confirm that cdk inhibitor protection is dependent on repressing cdk2 activity. We will determine cdk2 localization and the localization of cdk2-p21 interaction. We will determine the cell death pathway(s) inhibited by cdk2 inhibitors, and for each death pathway inhibited by cdk2 inhibitors, determine whether it is activated by cisplatin. Our second specific aim is to determine conditions and mechanisms of protection by cdk2 inhibitors in vivo. We will determine whether cdk2 knock-out mice are protected from cisplatin nephrotoxicity, and whether the samefragment of p21 that protects in vitro also protects in vivo. We will confirm purvalanol in vivo protection and refine the conditions for its action.

我们的长期目标是预防和/或治疗急性肾衰竭。我们发现， p21细胞周期蛋白依赖性激酶（cdk）抑制剂基因改善顺铂治疗后的肾衰竭 给药和肾缺血/再灌注。在这些损伤后，比较p21（+/+）和p21（-/-）小鼠， 细胞损伤明显减少，包括坏死和凋亡， p21（+/+）人群中的失败率和死亡率较低。该机制直接依赖于 p21作为细胞周期的调节因子。我们现在发现，使用腺病毒载体诱导p21之前， 顺铂暴露完全保护体外小鼠肾近端小管细胞免受细胞毒性。 类似地，用不同的药理学cdk 2抑制剂或用组蛋白 已知诱导p21的脱乙酰酶（HDAC）抑制剂也具有保护作用。我们将这些发现扩展为 表明具有与p21相似的活性谱的CDK 2抑制药物也保护肾功能 以及顺铂诱导的肾损伤的体内细胞形态。我们假设cdk 2抑制剂可以保护 通过抑制顺铂暴露激活的细胞死亡途径，使肾细胞免受顺铂诱导的毒性。 此外，我们推测cdk 2抑制剂将有助于预防和治疗急性肾功能衰竭。我们 已经开发了确定体外和体内CDK抑制剂保护机制的目标， 提供了利用CDK抑制剂改善顺铂诱导的肾衰竭的初始步骤。 我们的第一个具体目标是确定cdk抑制剂的保护机制。我们将确认， CDK抑制剂保护依赖于抑制CDK 2活性。我们将确定cdk 2的本地化， cdk 2-p21相互作用的定位。我们将确定由cdk 2抑制的细胞死亡途径 抑制剂，并且对于被cdk 2抑制剂抑制的每种死亡途径，确定其是否被 顺铂 我们的第二个具体目标是确定cdk 2抑制剂的保护条件和机制。 in vivo.我们将确定cdk 2基因敲除小鼠是否受到顺铂肾毒性的保护， p21的相同片段在体外是否也能在体内起保护作用。我们将确认Purvalanol 体内保护和完善其行动的条件。