Cardiac dysfunction after ischemic AKI in mice

小鼠缺血性 AKI 后的心脏功能障碍

基本信息

批准号：
10403537
负责人：
Sarah g Faubel
金额：
$ 59.25万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-10 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10403537
关键词：
Acetyl Coenzyme A Acute Acute Renal Failure with Renal Papillary Necrosis Affect Amino Acids Antioxidants Basic Science Cardiac Characteristics Citric Acid Cycle Clinical Consumption Data Dialysis patients Dialysis procedure Distant Echocardiography Electron Spin Resonance Spectroscopy Energy Metabolism Essential Amino Acids Functional disorder Glutamine Glutathione Glycolysis Goals Grant Heart Heart failure Impairment Injury Injury to Kidney Kidney Link Mediating Mediator of activation protein Metabolic Metabolism Mind Mitochondria Mus Myocardial dysfunction Nephrology Nonesterified Fatty Acids Organ Oxidative Phosphorylation Pathway interactions Patient Care Patients Phosphorylation Plasma Production Publishing Reactive Oxygen Species Reporting Resolution Respiration Stress Superoxides Supplementation Syndrome Systemic disease Testing Tissues Up-Regulation aerobic glycolysis base clinically relevant epidemiologic data glucose metabolism heart function improved in vivo inhibitor mortality mouse model novel prevent wasting

项目摘要

Abstract The overall goal of this proposal is to determine the mechanisms by which acute kidney injury (AKI) leads to acute cardiac dysfunction. Clinically, AKI-mediated cardiac dysfunction is known as cardiorenal syndrome type 3 (CRS3). The mechanisms underpinning CRS3 are not well understood and few plausible mediators of CRS3 have been identified. We recently demonstrated that ischemic AKI causes cardiac dysfunction in mice which was associated with a 50% reduction in cardiac ATP levels. Thus, cardiac energy metabolism and production is impaired during AKI and is a fundamental characteristic of CRS3. To identify mediators of CRS3, we examined plasma and cardiac metabolites. We expected to identify increased levels of circulating metabolites that might affect cardiac energy metabolism. Rather, we found that numerous metabolites necessary to maintain cardiac energy production and anti-oxidant defense were deficient in the plasma and heart after AKI, including over a dozen amino acids and the anti-oxidant glutathione. During cardiac stress, amino acids are essential substrates for ATP production. Glutamine is particularly important since it can be metabolized to substrates for both ATP and glutathione synthesis. Glutathione is the most abundant anti-oxidant in the heart and is critical to maintain normal energy production since excess reactive oxygen species (ROS) impairs mitochondrial function and inhibits oxidative phosphorylation (OXPHOS). OXPHOS occurs within mitochondria and is normally the major mechanism of cardiac ATP production. Our preliminary data demonstrate that during AKI: 1) cardiac mitochondrial function and OXPHOS are impaired, 2) cardiac superoxide (O2●-, an ROS) is significantly increased, 3) glutamine significantly increases cardiac ATP and reduces O2●-. Based on these data, our overall hypothesis is that the deficiency of energy substrates and glutathione precursors during AKI results in increased reactive oxygen species, reduced OXPHOS, reduced ATP production, and cardiac dysfunction. We have 3 Aims. Aim 1: Determine the effect of AKI on cardiac energy metabolism via metabolic flux analysis. Aim 2: Determine the mechanisms by which glutamine improves cardiac ATP production after AKI, in vivo, with the hypothesis that glutamine will reduce cardiac O2●-, increase ATP production, and improve mitochondrial and cardiac function. Aim 3: Determine the substrates of glutamine metabolism that improve cardiac ATP production after AKI, ex vivo, with the hypothesis that metabolism to glutathione is the primary mechanism of glutamine benefit. Since the complications of AKI have long been considered to be due to the accumulation of metabolic wastes and other substances that may be removed by dialysis for patient benefit, our overall hypothesis that substrate deficiency is a mechanisms of harm is a paradigm shift that challenges one of the most fundamental notions in nephrology and will have wide ranging implications regarding the care of patients with AKI, particularly regarding dialysis.

抽象的该提案的总体目标是确定急性肾损伤 (AKI) 导致的机制急性心功能不全临床上将AKI介导的心功能不全称为心肾综合征型。 3 (CRS3)。 CRS3 的基础机制尚不清楚，而且 CRS3 的合理介质也很少。我们最近发现，缺血性 AKI 会导致小鼠心脏功能障碍。与心脏 ATP 水平降低 50% 相关，从而降低心脏能量代谢和产生。 AKI 期间受损，并且是 CRS3 的基本特征为了识别 CRS3 的介质，我们。我们期望检测血浆和心脏代谢物的水平升高。相反，我们发现许多代谢物是影响心脏能量代谢所必需的。 AKI 后血浆和心脏中缺乏维持心脏能量产生和抗氧化防御的能力，包括十多种氨基酸和抗氧化谷胱甘肽在心脏应激期间，氨基酸是重要的。谷氨酰胺是 ATP 产生的必需底物，因为它可以代谢为 ATP 的必需底物。 ATP 和谷胱甘肽合成的底物谷胱甘肽是心脏中最丰富的抗氧化剂。对于维持正常的能量生产至关重要，因为过量的活性氧 (ROS) 会损害线粒体功能并抑制线粒体内发生的氧化磷酸化 (OXPHOS)。通常是心脏 ATP 产生的主要机制。我们的初步数据表明，在这一过程中。 AKI：1) 心脏线粒体功能和 OXPHOS 受损，2) 心脏超氧化物（O2●-，一种 ROS）显着增加，3) 谷氨酰胺显着增加心脏 ATP 并减少 O2●- 基于这些。根据数据，我们的总体假设是 AKI 期间能量底物和谷胱甘肽前体的缺乏导致活性氧增加、OXPHOS 减少、ATP 生成减少、心脏功能下降我们有 3 个目标目标 1：通过代谢确定 AKI 对心脏能量代谢的影响。目标 2：确定谷氨酰胺改善心脏 ATP 产生的机制。 AKI，体内，假设谷氨酰胺会减少心脏 O2●-，增加 ATP 生成，并改善目标 3：确定改善谷氨酰胺代谢的底物。 AKI 后心脏 ATP 的离体产生，假设代谢为谷胱甘肽是主要的谷氨酰胺获益的机制长期以来一直被认为是 AKI 的并发症所致。代谢废物和其他物质的积累可以通过透析去除以造福于患者，我们的总体假设是底物缺乏是一种危害机制，这是一个挑战的范式转变肾脏病学最基本的概念之一，将对护理产生广泛的影响 AKI 患者，尤其是透析患者。