Mechanisms of Renoprotection by Soluble Epoxide Hydrolase Inhibition

可溶性环氧化物水解酶抑制的肾脏保护机制

• 批准号: 8539676
• 负责人: Deanna L Kroetz
• 金额: $ 36.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8539676
• 关键词: Acids; Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Arachidonic Acids; Area; Attenuated; Biological; Blood Vessels; Chemicals; Cisplatin; Clinic; Complex; Critical Illness; Cytochrome P450; Data; Disease; Drug Metabolic Detoxication; Endotoxins; Enzymes; Epithelial Cells; Epoxide hydrolase; Epoxy Compounds; Essential Fatty Acids; Fatty Acids; Genetic; Goals; Healthcare; Hepatic; Hospitalization; Hydrolysis; Inflammation; Inflammatory; Injury; Ischemia; Kidney; Knowledge; Laboratories; Ligation; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Morbidity - disease rate; Mouse Strains; Mus; Nature; Nutrient; Organ; PPAR alpha; Pathologic Processes; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phase; Prevention; Prevention strategy; Production; Property; Regulation; Relative (related person); Reperfusion Therapy; Research; Resources; Role; Signal Pathway; Signal Transduction; Syndrome; Testing; Therapeutic; Tissues; Tubular formation; Unsaturated Fatty Acids; Ureter; Xenobiotic Metabolism; Xenobiotics; attenuation; base; cell injury; chemical genetics; cost; defined contribution; fatty acid metabolism; interest; kidney cell; mortality; novel; overexpression; protective effect; public health relevance; renal ischemia; therapeutic target; tool

DESCRIPTION (provided by applicant): Soluble epoxide hydrolase (sEH) is a dual function Phase II metabolic enzyme that catalyzes the hydrolysis of both xenobiotic and endobiotic epoxides. sEH metabolism of xenobiotic epoxides often results in their detoxification and accelerated elimination, whereas that of endobiotic epoxides is generally associated with attenuation of epoxide biological properties. Endogenous substrates of sEH are unsaturated fatty acid epoxides, including epoxyeicosatrienoic acids (EETs), which are major products of cytochrome P450 (CYP)-catalyzed metabolism of arachidonic acid, an essential fatty acid nutrient. The hydrolysis of EETs to their corresponding dihydroxyeicosatrienoic acids by sEH has recently emerged as a key factor controlling the biological effects of EETs, including vasoactive, anti- inflammatory and anti-apoptotic effects. Recent preliminary data from our laboratory shows that chemical or genetic disruption of sEH activity protects against acute kidney injury induced by cisplatin treatment. Specifically, the protective effects of sEH inhibition are associated with decreased inflammation and a dramatic attenuation of apoptosis. The focus of this proposal is to understand the mechanistic basis for the renoprotection afforded by disruption of sEH activity. Three specific aims are proposed to test the overall hypothesis that inhibition of sEH protects against acute kidney injury. The first aim will identify the signaling pathways involved in the renoprotective effect of sEH inhibition in a cisplatin model of acute kidney injury. The role of NF-?B and PPAR? signaling will be examined, particularly with respect to the anti-inflammatory effects of sEH inhibition in acute kidney injury. The effect of sEH inhibition on the intrinsic mitochondrial apoptotic pathway will also be investigated. Studies proposed for the second aim will extend our findings in a cisplatin model of acute kidney injury to additional models which involve different renal insults and signaling pathways. The renoprotective properties of sEH inhibition will be studied in both a unilateral ureter ligation model and in ischemia/reperfusion. Finally, the third aim will directly test the ability of EETs to protect against drug- or ischemia-induced renal cell injury, using cultured renal epithelial cells. The relative contribution of vascular versus tubular formed fatty acid epoxides in renoprotection will also be tested, using mouse strains with tissue specific overexpression or disruption of CYP epoxygenases and sEH. A combination of chemical and genetic tools to modulate sEH activity and EET production provide the critical framework to advance our preliminary observation of renoprotection associated with sEH inhibition. A long term goal of these studies is to develop strategies for the therapeutic modulation of sEH for the prevention and treatment of acute kidney injury. The general nature of the anti-inflammatory and anti-apoptotic effects of sEH inhibition will make our findings more broadly relevant to diseases affecting other organs as well. PUBLIC HEALTH RELEVANCE: Acute kidney injury is a complex syndrome occurring in 20% to 30% of critically ill patients, and is associated with increased mortality, hospitalization, use of healthcare resources, and costs. Despite decades of research in animal models, effective strategies for prevention of acute kidney injury have yet to make it to the clinic. The studies proposed in this application will explore a novel pathway for protection against acute kidney injury which exploits an abundant renal fatty acid epoxide with established roles in inflammation and apoptosis.

描述（由申请人提供）：可溶性环氧化物水解酶（sEH）是一种双功能II期代谢酶，催化异生质和内生环氧化物的水解。外源性环氧化物的sEH代谢通常导致其解毒和加速消除，而内源性环氧化物的sEH代谢通常与环氧化物生物学性质的衰减有关。sEH的内源性底物是不饱和脂肪酸环氧化物，包括环氧二十碳三烯酸（E13），其是细胞色素P450（E13）催化的花生四烯酸（必需脂肪酸营养素）代谢的主要产物。最近，通过sEH将雌二醇水解成其相应的二羟基二十碳三烯酸已成为控制雌二醇生物效应的关键因素，包括血管活性、抗炎和抗凋亡效应。我们实验室最近的初步数据显示，sEH活性的化学或遗传破坏可防止顺铂治疗诱导的急性肾损伤。具体而言，sEH抑制的保护作用与炎症减少和细胞凋亡的显著减弱相关。该建议的重点是了解破坏sEH活性所提供的肾保护的机制基础。提出了三个具体目标来检验抑制sEH防止急性肾损伤的总体假设。第一个目标是确定在急性肾损伤的顺铂模型中sEH抑制的肾保护作用所涉及的信号通路。NF-？B和PPAR？将检查信号传导，特别是关于sEH抑制在急性肾损伤中的抗炎作用。还将研究sEH抑制对内在线粒体凋亡途径的影响。为第二个目标提出的研究将把我们在顺铂急性肾损伤模型中的发现扩展到涉及不同肾损伤和信号通路的其他模型。将在单侧输尿管结扎模型和缺血/再灌注模型中研究sEH抑制的肾保护特性。最后，第三个目标将使用培养的肾上皮细胞直接测试Eclase保护免受药物或缺血诱导的肾细胞损伤的能力。还将使用组织特异性过表达或破坏α-环氧合酶和sEH的小鼠品系，测试血管与肾小管形成的脂肪酸环氧化物在肾保护中的相对贡献。调节sEH活性和EET产生的化学和遗传工具的组合提供了关键框架，以推进我们对与sEH抑制相关的肾保护的初步观察。这些研究的长期目标是开发用于预防和治疗急性肾损伤的sEH的治疗性调节的策略。sEH抑制的抗炎和抗凋亡作用的一般性质将使我们的发现更广泛地与影响其他器官的疾病相关。 公共卫生相关性：急性肾损伤是一种复杂的综合征，发生在20%至30%的重症患者中，与死亡率、住院率、医疗资源使用和成本增加相关。尽管在动物模型上进行了数十年的研究，但预防急性肾损伤的有效策略尚未进入临床。本申请中提出的研究将探索一种新的保护急性肾损伤的途径，该途径利用了丰富的肾脂肪酸环氧化物，其在炎症和细胞凋亡中具有既定的作用。