RENAL PROTECTION BY DOCOSAHEXAENOIC ACID

二十二碳六烯酸的肾脏保护

• 批准号: 6517494
• 负责人: CHRISTOPHER Y. LU
• 金额: $ 24.76万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6517494
• 关键词: acute renal failure; antisense nucleic acid; chemoprevention; enzyme induction /repression; gene expression; gene targeting; genetic promoter element; genetically modified animals; inflammation; laboratory mouse; neutrophil; nitric oxide; nitric oxide synthase; nutrition related tag; omega 3 fatty acid; polymerase chain reaction; renal ischemia /hypoxia; transcription factor

Acute renal failure claims 25,000 lives annually. This project explores the use of docosahexaenoic acid (DHA) in the treatment of ischemic acute renal failure. DHA is a 22 carbon, omega-3 fatty acid with 6 double bonds. Our current proposal is based on two striking effects of DHA. First, we find that docosahexaenoic acid (DHA) prevents damage from ischemia/reperfusion injury in a murine model. All of the control animals died of acute renal failure at 72 hours after clamping both renal arteries for 30 minutes, but only 15 percent of the DHA-treated animals. Second, we find that DHA inhibits activation of the gene for inducible nitric oxide synthase (iNOS) by macrophages in vitro. This enzyme produces large quantities of the cytotoxic molecule nitric oxide which contribute to renal injury after ischemia. Furthermore, we find that DHA inhibits iNOS gene activation by inhibiting the action of the transcription factor IRF-1. IRF-1 is activated by cellular stress and coordinates a stress response. This includes activation of genes for endothelial adhesion molecules which regulate inflammation, for cytokines and chemokines and iNOS. In this proposal, we will explore DHA as a potential therapy of acute renal failure and test the hypothesis that DHA inhibits the maladaptive stress response by inhibiting the transcription factor IRF-1. We will determine if DHA inhibits the inflammatory response to ischemia, and if DHA inhibits maladaptive responses of renal tubule cells to ischemic stress. The latter includes activation of iNOS. We will test the prediction that DHA ameliorates ischemic acute renal failure by inhibiting IRF-1 action. We will compare the susceptibility of IRF-1 knockout mice and plus/plus control mice to renal ischemia. We will also use IRF-1 antisense therapy to treat ischemic acute renal failure. Others have developed phosphorothioate antisense oligonucleotides for IRF-1, and the kidney, by virtue of the propensity of the proximal tubule to absorb polyanions such as antisense oligonucleotides, is an ideal target for antisense therapy.

急性肾衰竭每年夺去25，000人的生命。 本项目探讨使用二十二碳六烯酸（DHA）治疗缺血性急性肾功能衰竭。 DHA是一种含有22个碳原子、6个双键的ω-3脂肪酸。 我们目前的建议是基于DHA的两个显著效果。 首先，我们发现二十二碳六烯酸（DHA）可以预防小鼠模型缺血/再灌注损伤。 所有对照组动物在夹闭双侧肾动脉30分钟后72小时死于急性肾衰竭，但仅15%的DHA治疗组动物死亡。 第二，我们发现DHA在体外抑制巨噬细胞对诱导型一氧化氮合酶（iNOS）基因的激活。 这种酶产生大量的细胞毒性分子一氧化氮，这有助于缺血后的肾损伤。此外，我们发现DHA通过抑制转录因子IRF-1的作用来抑制iNOS基因的激活。 IRF-1被细胞应激激活并协调应激反应。 这包括激活调节炎症的内皮粘附分子、细胞因子和趋化因子以及iNOS的基因。 在这个提议中，我们将探索DHA作为急性肾功能衰竭的潜在治疗方法，并测试DHA通过抑制转录因子IRF-1抑制适应不良应激反应的假设。 我们将确定DHA是否抑制对缺血的炎症反应，以及DHA是否抑制肾小管细胞对缺血应激的适应不良反应。 后者包括iNOS的激活。 我们将检验DHA通过抑制IRF-1作用改善缺血性急性肾衰竭的预测。 我们将比较IRF-1敲除小鼠和+/+对照小鼠对肾缺血的易感性。 我们还将使用IRF-1反义疗法治疗缺血性急性肾功能衰竭。 其他人已经开发了IRF-1的硫代磷酸酯反义寡核苷酸，并且肾脏由于近端小管吸收聚阴离子如反义寡核苷酸的倾向，是反义治疗的理想靶点。

项目成果

Ischemia-reperfusion induces G-CSF gene expression by renal medullary thick ascending limb cells in vivo and in vitro.

• DOI: 10.1152/ajprenal.00379.2002
• 发表时间: 2004-06
• 期刊: American journal of physiology. Renal physiology
• 作者: Ying Zhang;Vanessa K. Woodward;John M. Shelton;James A. Richardson;Xin J Zhou;D. Link;M. Kielar;D. Rohan Jeyarajah;Christopher Y Lu

Syngeneic renal transplantation increases the number of renal dendritic cells in the rat.

同基因肾移植增加了大鼠肾树突状细胞的数量。

• DOI: 10.1016/s0966-3274(99)80002-1
• 发表时间: 1999
• 期刊: Transplant immunology.
• 作者: Penfield,JG;Dawidson,IA;Ar'Rajab,A;Kielar,MA;Jeyarajah,DR;Lu,CY
• 通讯作者: Lu,CY