IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Journal of Pharmacology and Experimental Therapeutics Pub Date : 2025-02-01 Epub Date: 2024-11-22 DOI:10.1124/jpet.124.002282
Chaoling Chen, Weili Wang, Justin L Poklis, Pin-Lan Li, Aron H Lichtman, David A Gewirtz, Ningjun Li
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摘要

脂肪酸酰胺水解酶(FAAH)是降解内源性大麻酰胺的主要酶。通过药物或遗传操作抑制脂肪酸酰胺水解酶,可以有效减轻大脑、结肠、心脏和肾脏等多个器官的炎症反应。将 FAAH 抑制剂注入肾髓质可产生利尿和利钠作用。此外,FAAH 基因敲除小鼠对肾缺血/再灌注后损伤和顺铂诱导的急性肾损伤(AKI)均有保护作用,但机制不同。本研究测试了药物抑制 FAAH 活性可减轻顺铂诱导的 AKI 的假设,从而探索潜在的肾脏保护机制。雄性野生型 C57BL/6J 在腹腔注射顺铂(25 毫克/千克)前 72、48、24 和 2 小时以及注射后 24 和 48 小时分别口服 FAAH 抑制剂(PF-04457845,5 毫克/千克)或载体(10% PEG200+5% 吐温 80+ 生理盐水)。小鼠在顺铂治疗 72 小时后安乐死。与药物治疗的小鼠相比,PF-04457845治疗的小鼠显示出顺铂诱导的血浆肌酐、血尿素氮水平、肾损伤生物标志物(中性粒细胞明胶酶相关脂褐素和肾损伤分子-1)和肾小管损伤均有所下降。口服 PF-04457845 对顺铂诱导的肾毒性的保护作用与内源性大麻酰胺的增强以及 DNA 损伤反应生物标志物 p53 和 p21 水平的降低有关。我们的研究表明,PF-04457845 能有效缓解顺铂诱导的小鼠肾毒性,这凸显了口服 FAAH 抑制剂作为预防顺铂肾毒性新策略的潜力。意义声明:口服脂肪酸酰胺水解酶(FAAH)抑制剂 PF-04457845 可减少顺铂诱导的 DNA 损伤反应、肾小管损伤和肾功能障碍。抑制脂肪酸酰胺水解酶是预防顺铂诱导的肾毒性的一种有效方法。
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Mitigation of cisplatin-induced acute kidney injury through oral administration of fatty acid amide hydrolase inhibitor PF-04457845.

Fatty acid amide hydrolase (FAAH) serves as the primary enzyme responsible for degrading the endocannabinoid anandamide. Inhibition of FAAH, either through pharmacological means or genetic manipulation, can effectively reduce inflammation in various organs, including the brain, colon, heart, and kidneys. Infusion of a FAAH inhibitor into the kidney medulla induces diuretic and natriuretic effects. Moreover, FAAH knockout mice show protection against both post renal ischemia/reperfusion injury and cisplatin-induced acute kidney injury (AKI), although through distinct mechanisms. This study tested the hypothesis that pharmacological inhibition of FAAH activity mitigates cisplatin-induced AKI, thus, exploring potential renoprotective mechanism. Male wild-type C57BL/6J were administered an oral gavage of a FAAH inhibitor (PF-04457845, 5 mg/kg) or vehicle (10% PEG200+5% Tween 80+normal saline) at 72, 48, 24, and 2 hours before and 24 and 48 hours after a single intraperitoneal injection of cisplatin (25 mg/kg). Mice were euthanized 72 hours after cisplatin treatment. Compared with vehicle-treated mice, PF-04457845-treated mice showed a decrease of cisplatin-induced plasma creatinine, blood urea nitrogen levels, kidney injury biomarkers (neutrophil gelatinase-associated lipocalin and kidney injury molecule-1) and renal tubular damage. The renal protection from oral gavage of PF-04457845 against cisplatin-induced nephrotoxicity was associated with an enhanced endocannabinoid anandamide tone and reduced levels of DNA damage response biomarkers p53 and p21. Our work demonstrated that PF-04457845 effectively alleviates cisplatin-induced nephrotoxicity in mice, underscoring the potential of oral administration of a FAAH inhibitor as a novel strategy to prevent cisplatin nephrotoxicity. SIGNIFICANCE STATEMENT: Oral administration of the fatty acid amide hydrolase (FAAH) inhibitor, PF-04457845, reduced cisplatin-induced DNA damage response, tubular damage, and kidney dysfunction. Inhibition of FAAH represents a promising approach to prevent cisplatin-induced nephrotoxicity.

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来源期刊
CiteScore
6.90
自引率
0.00%
发文量
115
审稿时长
1 months
期刊介绍: A leading research journal in the field of pharmacology published since 1909, JPET provides broad coverage of all aspects of the interactions of chemicals with biological systems, including autonomic, behavioral, cardiovascular, cellular, clinical, developmental, gastrointestinal, immuno-, neuro-, pulmonary, and renal pharmacology, as well as analgesics, drug abuse, metabolism and disposition, chemotherapy, and toxicology.
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