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.

抽象的 住院患者发生急性肾损伤（AKI）可能是灾难性的。 据估计，AKI 患者的医院死亡率为 20% 至 25%。 住院治疗会增加费用，并需要使用额外的资源。 大约四分之一的住院患者出现 AKI，其中大约一半的病例与 虽然广谱抗生素对于治疗感染至关重要，但临床医生可以改变它们。 危险因素是可改变的，但许多患者本身就有 AKI 风险增加。 抗生素诱发 AKI 的机制尚不清楚，但新出现的数据支持氧化应激和线粒体 褪黑激素是一种激素膳食补充剂，通过核因子红细胞具有抗氧化特性。 2 相关因子 2 (NRF2) 途径，也可以恢复线粒体生物能，因此，褪黑激素是一种。 肾脏保护的有吸引力的选择。 该提案将检验褪黑激素通过以下方式降低抗生素相关 AKI 风险的假设： NRF2 转录途径的激活以及线粒体功能和生物能量学的平衡。 检验这一假设，我们提出了一种并行研究机制和功效的转化策略。 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中 RPT 细胞的存在/不存在将包括对照细胞以及 NRF2 和 NRF2 被破坏的细胞。 KEAP1 功能分析将包括 1) 线粒体/细胞健康的目标生物标志物和 2) 接下来，我们将招募 300 名患者进行转录组学研究，以确定补充性和替代性肾脏保护途径。 住院患者服用万古霉素和哌拉西林-他唑巴坦，并按 1:1 随机分配至褪黑激素 将分析 5 mg 或匹配的安慰剂的全血的基因表达 (NRF2/KEAP1) 和血浆。 进一步评估抗生素和褪黑激素的生物分布，以及肾损伤的传统和新型生物标志物。 将评估线粒体应激，这两个目标中描述的研究将提供支持证据。 褪黑激素的使用并提供其机制的证据。