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

肾毒性是顺铂的主要剂量限制性毒性，它是许多固体药物的有效一线治疗方法。 恶性肿瘤。顺铂致肾损害的机制还不完全清楚，也没有有效的治疗方法。 管理策略目前是可用的。内源性大麻素(EC)系统，已初步被 主要集中在中枢神经系统，在包括肾脏在内的周围器官中也扮演着重要的角色。 特征最好的内皮细胞是烷基酰胺(AEA)和2-花生四烯基甘油(2-AG)。生物合成 AEA的作用是通过至少三种不同的途径使N-花生四烯酰磷脂酰乙醇胺发生水解反应 生物合成路线。2-氨基二酸甘油是由二酰基甘油脂肪酶产生的，它能水解含有2-花生四烯酰基的2-甘油 二酰甘油(DAG)生成2-AG。在产生后，ECs与当地的大麻素受体(CB1和CB1)结合 CB2)以自分泌或旁分泌的方式。已有研究表明EC系统参与不同肾脏的功能。 疾病，包括顺铂诱导的肾毒性(CIN)，以及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。 ECS代谢酶在肾脏损害中的作用。解决这一重大差距很重要，而且迫切需要 探讨ECS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显著升高，而2-AG无明显变化，并抑制CB1受体 减轻顺铂所致的肾功能障碍，提示内源性大麻素系统通过CB1 受体促进顺铂引起的肾损伤。我们最初的目的是测试FAAH抑制，这是 结果AEA水平升高，会加重CIN。令人惊讶的是，CIN在 FAAHKO小鼠，表明AEA水平的增加实际上对CIN具有保护作用。AEA的提升 FAAH抑制后的水平也可导致AEA-FAAH衍生的花生四烯酸(AA)水平降低和 AEA-COX2衍生的前列腺素水平增加。我们的初步数据显示， FAAH抑制剂被底物选择性COX2抑制剂LM4131逆转(抑制AEA-COX2，而不是AA-COX2 COX2)，但不是补充AA，也不是通过阻断CB受体。根据上述信息， 需要检验的假设是，FAAH抑制通过AEA-COX2衍生保护肾脏免受CIN的影响 助剂。为了检验这些假说，我们提出了以下目标。目标1：确定抑制是否 保护肾脏免受CIN的侵袭。研究将使用遗传学和药理学以及系统性 以及针对肾脏的FAAH抑制方法。目的2：确定AEA-COX2是否源于 前列腺素是FAAH抑制后肾保护作用的下游信号通路 CIN。目的：确定抑制FAAH不会干扰顺铂的抗肿瘤作用。这个 这些拟议研究的结果将表明，抑制FAAH是一种新的治疗策略 CIN的预防和治疗。

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.