RENAL PROTECTION BY DOCOSAHEXAENOIC ACID

急性肾衰竭每年夺去 25,000 人的生命。 该项目探索二十二碳六烯酸（DHA）在治疗缺血性急性肾衰竭中的应用。 DHA 是一种 22 个碳、具有 6 个双键的 omega-3 脂肪酸。 我们目前的建议是基于 DHA 的两个显着功效。 首先，我们发现二十二碳六烯酸 (DHA) 可预防小鼠模型中的缺血/再灌注损伤。 所有对照动物在夹闭双侧肾动脉 30 分钟后 72 小时内死于急性肾功能衰竭，但接受 DHA 治疗的动物中只有 15% 死亡。 其次，我们发现 DHA 在体外抑制巨噬细胞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，导致缺血后的肾损伤。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基因、细胞因子、趋化因子和 iNOS 基因。 在本提案中，我们将探索 DHA 作为急性肾衰竭的潜在疗法，并检验 DHA 通过抑制转录因子 IRF-1 来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。 我们将测试 DHA 通过抑制 IRF-1 作用来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 plus/plus 对照小鼠对肾缺血的敏感性。 我们还将使用IRF-1反义疗法来治疗缺血性急性肾衰竭。 其他人已经开发了针对IRF-1的硫代磷酸酯反义寡核苷酸，而肾脏由于近曲小管吸收聚阴离子（例如反义寡核苷酸）的倾向，是反义治疗的理想靶点。

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.