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: 8325925
• 负责人: Deanna L Kroetz
• 金额: $ 36.88万
• 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/8325925
• 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）：可溶性环氧水解酶（SEH）是一种双功能II期代谢酶，可催化异生物元素和内生元环氧化物的水解。异生元环氧化物的SEH代谢通常会导致其排毒和加速消除，而内向生物环氧化物的代谢通常与环氧生物学特性的衰减有关。 SEH的内源性底物是不饱和的脂肪酸环氧化物，包括上氧化三烯酸（EET），它们是细胞色素P450（CYP）的主要产物 - 催化的花生四烯酸代谢，一种必需脂肪酸的养分。最近，通过SEH将EET的Eets水解为其相应的二羟基钠酸酸，最近已成为控制EET的生物学作用的关键因素，包括血管活性，抗炎性和抗凋亡作用。我们实验室的最新初步数据表明，SEH活性的化学或遗传破坏可预防顺铂治疗引起的急性肾脏损伤。具体而言，SEH抑制作用的保护作用与炎症减少和凋亡的显着衰减有关。该提案的重点是了解SEH活性中断提供的重期保护的机理基础。提出了三个具体目标来检验抑制SEH防止急性肾脏损伤的总体假设。第一个目标将确定在急性肾损伤模型中SEH抑制作用的肾脏保护作用所涉及的信号传导途径。 NF-？B和PPAR的作用？将检查信号传导，特别是关于SEH抑制在急性肾脏损伤中的抗炎作用。还将研究SEH抑制对固有线粒体凋亡途径的影响。针对第二个目标提出的研究将使我们的发现在急性肾损伤的顺铂模型中扩展到涉及不同肾脏损伤和信号通路的其他模型。 SEH抑制的肾脏保护特性将在单侧输尿管连接模型和缺血/再灌注中研究。最后，第三个目标将直接测试EET使用培养的肾上皮细胞预防药物或缺血诱导的肾细胞损伤的能力。还将使用具有组织特异性过表达的小鼠菌株或CYP加氧酶和SEH的小鼠菌株和SEH的小鼠菌株测试血管与管状形成的脂肪酸环氧化物的相对贡献。化学和遗传工具调节SEH活性和EET产生的结合提供了关键的框架，以推动我们对与SEH抑制相关的重妇保护的初步观察。这些研究的长期目标是制定用于预防和治疗急性肾脏损伤的SEH治疗调节策略。 SEH抑制作用的抗炎和抗凋亡作用的一般性质将使我们的发现与影响其他器官的疾病更广泛地相关。 公共卫生相关性：急性肾脏损伤是一种复杂的综合征，在20％至30％的重症患者中发生，并且与死亡率增加，住院，医疗保健资源的使用以及成本有关。尽管在动物模型中进行了数十年的研究，但预防急性肾脏损伤的有效策略尚未进入诊所。本应用中提出的研究将探索一种防止急性肾脏损伤的新途径，该途径利用了具有较丰富的肾脂肪酸环氧，在炎症和凋亡中既有作用。