Mechanistic evaluation of melatonin as a protectant against antibiotic associated kidney injury

褪黑激素作为抗生素相关性肾损伤保护剂的机制评估

• 批准号: 10343032
• 负责人: Luigi Brunetti
• 金额: $ 43.96万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343032
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Antibiotics; Antioxidants; Apoptotic; Biodistribution; Bioenergetics; CASP3 gene; Cells; Clinical; Clinical Trials; Creatinine; Data; Development; Dose; Drug Combinations; Early identification; Enrollment; Equilibrium; Evaluation; Event; Exposure to; Gene Expression Profiling; Genetic Transcription; Health; Healthcare; Hormonal; Hospital Mortality; Hospitalization; Human; In Vitro; Incidence; Infection; Injury to Kidney; Institution; Interferons; Interleukin-1; Interleukin-18; Intervention; Kidney; Literature; Mediating; Melatonin; Membrane Potentials; Mitochondria; Mitochondrial DNA; Molecular; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Piperacillin-Tazobactam; Placebos; Plasma; Prevention; Property; Prospective Studies; Protons; Proximal Kidney Tubules; Randomized; Randomized Controlled Trials; Reporting; Resources; Risk; Risk Factors; Role; Serum; Signal Transduction; Sleep; Stress; TNF gene; Testing; Time; Vancomycin; Whole Blood; clinical decision-making; cost; cytochrome c; dietary supplements; exposed human population; hypnotic; in vivo; mitochondrial dysfunction; mitochondrial membrane; modifiable risk; nephrotoxicity; novel; novel marker; nuclear factor-erythroid 2; post gamma-globulins; pre-clinical; preservation; prevent; prospective; response; restoration; sedative; sleep quality; targeted biomarker; transcriptomics; translational approach; urinary; zolpidem

ABSTRACT The development of acute kidney (AKI) injury in hospitalized patients may be catastrophic. In general, the in- hospital mortality rate for patients with AKI has been estimated between 20% to 25%. AKI prolongs hospitalization, increases costs, and requires the utilization of additional resources. Drugs are implicated in roughly one-quarter of hospitalized patients who develop AKI, and roughly half of the cases are related to antibiotics. While broad spectrum antibiotics are essential to treat infections, they carry risk. Clinicians can alter modifiable risk factors, but many patients are inherently at an increased risk of AKI. The exact molecular mechanisms of antibiotic induced AKI are unclear, but emerging data supports oxidative stress and mitochondrial dysfunction. Melatonin, a hormonal dietary supplement, has antioxidant properties via the nuclear factor erythroid 2–related factor 2 (NRF2) pathway and can also restore mitochondrial bioenergetics. As such, melatonin is an attractive option for kidney protection. This proposal will test the hypothesis that melatonin reduces the risk of antibiotic-associated AKI through activation of the NRF2 transcriptional pathway and balancing of mitochondrial function and bioenergetics. To test this hypothesis, we propose a translational strategy to investigate mechanism and efficacy in parallel. First, in our in vitro studies, we will expose human renal proximal tubule (RPT) cells to nephrotoxic antibiotics in the presence /absence of melatonin. RPT cells will include control cells as well as those with disrupted NRF2 and KEAP1 function. Analyses will include 1) targeted biomarkers of mitochondrial/cellular health and 2) transcriptomics to identify complementary and alternative reno-protective pathways. Next, we will enroll 300 hospitalized patients prescribed vancomycin and piperacillin-tazobactam and randomize them 1:1 to melatonin 5 mg or matched placebo. Whole blood will be analyzed for gene expression (NRF2/KEAP1) and plasma to evaluate antibiotic and melatonin biodistribution. Further, traditional and novel biomarkers of kidney injury and mitochondrial stress will be assessed. The studies described in the two aims will provide evidence to support the use of melatonin and provide evidence of the mechanism.

摘要 住院患者发生急性肾损伤(AKI)可能是灾难性的。总体而言，在- AKI患者的住院死亡率估计在20%至25%之间。Aki加长 住院，增加了成本，需要利用额外的资源。毒品被牵连到 大约四分之一的住院患者发展为AKI，大约一半的病例与 抗生素。虽然广谱抗生素对于治疗感染是必不可少的，但它们也有风险。临床医生可以改变 风险因素是可以改变的，但许多患者天生就有更高的AKI风险。确切的分子 抗生素诱导AKI的机制尚不清楚，但新的数据支持氧化应激和线粒体 功能障碍。褪黑激素是一种荷尔蒙膳食补充剂，通过核因子红系具有抗氧化特性。 2相关因子2(NRF2)途径，并可恢复线粒体生物能量学。因此，褪黑素是一种 有吸引力的肾脏保护选择。 这项提议将检验褪黑素通过以下途径降低抗生素相关性AKI风险的假设 激活NRF2转录途径，平衡线粒体功能和生物能量学。至 为了检验这一假设，我们提出了一种并行研究机制和有效性的翻译策略。第一, 在我们的体外研究中，我们将人肾近端小管(RPT)细胞暴露于肾毒性抗生素 有/没有褪黑素。RPT细胞将包括对照细胞以及具有中断的NRF2和 Keap1函数。分析将包括1)线粒体/细胞健康的靶向生物标记物和2) 转录学，以确定互补的和替代的肾脏保护途径。接下来，我们将招收300人 住院患者开万古霉素和哌拉西林-他唑巴坦，随机1：1服用褪黑素 5毫克或匹配的安慰剂。全血将分析基因表达(NRF2/Keap1)，血浆将分析 评估抗生素和褪黑素的生物分布。此外，肾脏损伤的传统和新的生物标志物和 将对线粒体应激进行评估。这两个目标中描述的研究将提供证据支持 并为褪黑素的使用机制提供了证据。