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: 10553644
• 负责人: Luigi Brunetti
• 金额: $ 43.14万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 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 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553644
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Antibiotics; Antioxidants; Apoptotic; Back to Sleep; Biodistribution; Bioenergetics; CASP3 gene; Cells; Clinical; Clinical Trials; Creatinine; Data; Development; Dose; Drug Combinations; Early identification; Enrollment; Evaluation; Event; Exposure to; Gene Expression Profiling; Genetic Transcription; Health; Healthcare; Hormonal; Hospital Mortality; Hospitalization; Human; IL18 gene; In Vitro; Incidence; Infection; Injury to Kidney; Institution; Interferons; Interleukin-1; Intervention; Kidney; Literature; Mediating; Melatonin; Membrane Potentials; Mitochondria; Mitochondrial DNA; Molecular; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Piperacillin; Piperacillin-Tazobactam; Placebos; Plasma; Prevention; Property; Prospective Studies; Protons; Proximal Kidney Tubules; Randomized; Randomized, Controlled Trials; Reporting; Resources; Risk; Risk Factors; Risk Reduction; Role; Serum; Signal Transduction; Stress; TNF gene; Tazobactam; Testing; Time; Vancomycin; Whole Blood; clinical decision-making; cost; cytochrome c; dietary supplements; exposed human population; hypnotic; improved; 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（阿基）可能是灾难性的。一般来说，在- 阿基患者的住院死亡率估计在20%至25%之间。阿基 住院，增加了成本，并且需要利用额外的资源。毒品与 大约四分之一的住院患者发生阿基，大约一半的病例与 抗生素虽然广谱抗生素对治疗感染至关重要，但它们具有风险。临床医生可以改变 这些风险因素是可改变的，但许多患者本身就存在阿基风险增加的情况。的确切分子 抗生素诱导阿基的机制尚不清楚，但新出现的数据支持氧化应激和线粒体损伤。 功能障碍褪黑激素是一种激素类膳食补充剂，通过红细胞核因子具有抗氧化作用 2-相关因子2（NRF 2）途径，还可以恢复线粒体生物能量学。因此，褪黑激素是一种 保护肾脏的最佳选择。 该提案将检验褪黑激素通过以下途径降低糖尿病相关阿基风险的假设： NRF 2转录途径的激活以及线粒体功能和生物能量学的平衡。到 为了验证这一假设，我们提出了一种翻译策略来并行研究机制和功效。第一、 在我们的体外研究中，我们将人肾近曲小管（RPT）细胞暴露于肾毒性抗生素， 存在/不存在褪黑激素。RPT细胞将包括对照细胞以及具有破坏的NRF 2和NRF 3的那些细胞。 KEAP 1功能。分析将包括1）线粒体/细胞健康的靶向生物标志物和2） 转录组学以鉴定互补和替代的肾保护途径。接下来，我们将招收300名 住院患者处方万古霉素和哌拉西林-他唑巴坦，并将其1：1随机分配至褪黑激素组 5 mg或匹配安慰剂。将分析全血的基因表达（NRF 2/KEAP 1）和血浆， 评价抗生素和褪黑激素的生物分布。此外，肾损伤的传统和新的生物标志物和 将评估线粒体应激。两个目标中描述的研究将提供证据支持 并为褪黑激素的作用机制提供证据。