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

基本信息

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
项目类别：
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

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

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项目摘要

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.

抽象的住院患者急性肾脏（AKI）损伤的发育可能是灾难性的。通常， AKI患者的医院死亡率估计在20％至25％之间。 Aki延长住院，增加成本，并需要利用其他资源。毒品与大约有四分之一的住院患者患有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至关重要，但它们具有风险。临床医生可以改变可修改的危险因素，但许多患者天生就会增加AKI的风险。确切的分子抗生素诱导的AKI机制尚不清楚，但新兴数据支持氧化应激和线粒体功能障碍。褪黑激素是一种马饮食补充剂，具有核因子红细胞的抗氧化特性 2-相关因子2（NRF2）途径，也可以恢复线粒体生物能学。因此，褪黑激素是肾脏保护的有吸引力的选择。该提案将检验以下假设，即褪黑激素通过 NRF2转录途径的激活以及线粒体功能和生物能学的平衡。到检验该假设，我们提出了一种平行研究机制和效率的翻译策略。第一的，在我们的体外研究中，我们将使人肾近端细胞（RPT）细胞暴露于肾毒性抗生素中存在 /不存在褪黑激素。 RPT细胞将包括对照细胞以及nrf2中断的细胞， KEAP1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）转录组学识别完整和替代性的肾脏保护途径。接下来，我们将注册300 住院的患者开处方万古霉素和哌拉西林 - tazobactam，然后将它们随机分配给褪黑激素 5毫克或匹配的安慰剂。将分析全血的基因表达（NRF2/KEAP1）和血浆评估抗生素和褪黑激素生物分布。此外，传统和新颖的肾脏损伤生物标志物和线粒体应力将被评估。两个目的中描述的研究将提供证据以支持褪黑激素的使用并提供了该机制的证据。