Inhibition of fatty acid amide hydrolase as a novel strategy to prevent nephrotoxicity of cisplatin.

抑制脂肪酸酰胺水解酶作为预防顺铂肾毒性的新策略。

• 批准号: 10684803
• 负责人: Ningjun Li
• 金额: $ 17.43万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10684803
• 关键词: 2-arachidonylglycerol; Address; Agonist; Anabolism; Applications Grants; Arachidonic Acids; Attenuated; Binding; Breast; CNR2 gene; Cannabidiol; Cells; Central Nervous System; Cisplatin; Clinical; Coxibs; Data; Diglycerides; Dose Limiting; Endocannabinoids; Enzyme Inhibition; Enzymes; FAAH inhibitor; Fatty Acids; Genetic; Head and Neck Cancer; Hydrolysis; Injury to Kidney; Intervention; Investigation; Kidney; Kidney Diseases; Knockout Mice; Ligands; Lung; Malignant Neoplasms; Metabolic; Monoacylglycerol Lipases; Mus; N-arachidonylphosphatidylethanolamine; Organ; Ovarian; PTGS2 gene; Patients; Peripheral; Play; Prevention strategy; Probability; Production; Reporting; Role; Route; Serine Hydrolase; Signal Pathway; Solid; Supplementation; Testing; Therapeutic; Toxic effect; Tubular formation; anandamide; antagonist; anticancer treatment; autocrine; cannabinoid receptor; endogenous cannabinoid system; enzyme biosynthesis; fatty acid amide hydrolase; kidney dysfunction; lipoprotein lipase; nephrotoxicity; novel; novel strategies; novel therapeutic intervention; novel therapeutics; paracrine; pharmacologic; prevent; receptor; renal damage; systemic intervention; targeted delivery; therapeutic target; tissue injury; tumor

Nephrotoxicity is a primary dose-limiting toxicity for cisplatin, a potent first-line therapy for many solid malignancies. The mechanistic basis for cisplatin-induced kidney damage is not fully understood and no efficient management strategies are currently available. The endocannabinoid (EC) system, which has been initially focused on the central nervous system, also plays important roles in the peripheral organs, including the kidneys. The most well-characterized ECs are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The biosynthesis of AEA is through the hydrolysis of N-arachidonoyl-phosphatidyl-ethanolamines via at least three distinct biosynthetic routes. The 2-AG is produced by diacylglycerol lipases, which hydrolyze 2-arachidonoyl-containing diacylglycerols (DAG) to generate 2-AG. After production, ECs bind to the local cannabinoid receptors (CB1 and CB2) in an autocrine or paracrine manner. It has been shown that EC system participates in different kidney diseases, including cisplatin-induced nephrotoxicity (CIN), and that interventions of CB receptors are promising therapeutic strategies. Surprisingly, majority of studies focus on CB receptors, and little is known about roles of ECs metabolic enzymes in kidney damages. It is important to address this significant gap and imperative to investigate the role of ECs enzymes in kidney diseases. A recent study showed that in cisplatin-treated mice, AEA was significantly increased while 2-AG had no change in the kidneys and that inhibition of CB1 receptors attenuated the cisplatin-induced renal dysfunction, suggesting that endocannabinoid system through CB1 receptors promotes cisplatin-induced kidney injury. We initially intended to test whether FAAH inhibition, which results in increased levels of AEA, would aggravate the CIN. Surprisingly, CIN was dramatically attenuated in FAAH KO mice, suggesting that the increased levels of AEA is actually protective in CIN. The elevation of AEA levels after FAAH inhibition could also result in reduced levels of AEA-FAAH-derived arachidonic acid (AA) and increased levels of AEA-COX2-derived prostamides. Our preliminary data demonstrated that the protection by FAAH inhibitor was reversed by the substrate-selective COX2 inhibitor LM4131 (inhibits AEA-COX2, not AA- COX2), but not by the supplementation of AA, nor the blocking CB receptors. Based on the above information, the hypothesis to be tested is that FAAH inhibition protects the kidneys against CIN via AEA-COX2-derived prostamides. The following Aims are proposed to test the hypotheses. Aim 1: To determine whether inhibition of FAAH protects the kidneys against CIN. Studies will use genetic and pharmacological as well as both systemic and kidney-targeted approaches for FAAH inhibition. Aim 2: to determine whether AEA-COX2-derived prostamides are the downstream signaling pathway responsible for the renoprotection after FAAH inhibition in CIN. Aim 3: To establish that inhibition of FAAH will not interfere with the antitumor actions of cisplatin. The findings from these proposed studies will suggest that inhibition of FAAH is new therapeutic strategy for the prevention and treatment of CIN.

肾毒性是顺铂的主要剂量限制性毒性，顺铂是许多实体瘤的有效一线治疗。 恶性肿瘤。顺铂诱导肾损害的机制基础尚未完全了解， 目前，管理战略已经出台。内源性大麻素（EC）系统，最初被 集中于中枢神经系统，也在包括肾脏在内的外周器官中发挥重要作用。 最好表征的EC是花生四烯酸酰胺（AEA）和2-花生四烯酸甘油（2-AG）。生物合成 AEA的水解是通过N-花生四烯酸-磷脂酰-乙醇胺经由至少三种不同的 生物合成路线2-AG由二酰基甘油脂肪酶产生，其水解含2-花生四烯酸的 二酰基甘油（DAG）以产生2-AG。产生后，EC与局部大麻素受体（CB 1和CB 2）结合。 CB 2）以自分泌或旁分泌的方式。研究表明EC系统参与不同肾脏的病理过程 疾病，包括顺铂诱导的肾毒性（CIN），CB受体的干预是有希望的 治疗策略令人惊讶的是，大多数研究都集中在CB受体上，而对CB受体的作用知之甚少。 内皮细胞代谢酶在肾损伤中的作用。必须解决这一重大差距， 研究内皮细胞酶在肾脏疾病中的作用。最近的一项研究表明，在顺铂治疗的小鼠中， AEA显著增加，而2-AG在肾脏和CB 1受体抑制方面无变化 减轻顺铂引起的肾功能不全，提示内源性大麻素系统通过CB 1 受体促进顺铂诱导的肾损伤。我们最初打算测试FAAH抑制， 导致AEA水平升高，会加重CIN。令人惊讶的是，CIN显著减弱， FAAH KO小鼠，表明AEA水平的增加实际上在CIN中具有保护作用。AEA的升高 FAAH抑制后的水平也可导致AEA-FAAH衍生的花生四烯酸（AA）和 AEA-COX 2衍生的前列腺酰胺水平升高。我们的初步数据表明， FAAH抑制剂被底物选择性COX 2抑制剂LM 4131逆转（抑制AEA-COX 2，而不是AA-COX 2）。 COX 2），但不是通过补充AA，也不是通过阻断CB受体。根据上述信息， 待检验的假设是FAAH抑制通过AEA-COX 2衍生的 前列腺酰胺提出了以下目的来检验假设。目的1：确定抑制是否 FAAH保护肾脏免受CIN的侵害。研究将使用遗传学和药理学以及全身性 和用于FAAH抑制的肾靶向方法。目的2：确定AEA-COX 2-衍生物是否 前列腺酰胺是下游信号通路，负责FAAH抑制后的肾保护作用。 中国。目的3：确定FAAH的抑制不会干扰顺铂的抗肿瘤作用。的 这些研究的结果表明，抑制FAAH是新的治疗策略， CIN的预防和治疗。