Cardiac dysfunction after ischemic AKI in mice

小鼠缺血性 AKI 后的心脏功能障碍

• 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
• 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

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脏损伤（AKI）导致的机制 急性心脏功能障碍。在临床上，AKI介导的心脏功能障碍称为心脏综合征类型 3（CRS3）。 CRS3支撑的机制尚不清楚，很少有CRS3的合理介质 已经确定了。我们最近证明，缺血性AKI在小鼠中引起心脏功能障碍 与心脏ATP水平降低50％有关。那是心脏能源代谢和生产 在AKI期间受到损害，并且是CRS3的基本特征。为了识别CRS3的调解人，我们 检查了血浆和心脏代谢物。我们期望确定循环代谢物的水平增加 这可能会影响心脏能量代谢。相反，我们发现需要许多代谢物 维持心脏能量产生和抗氧化剂防御在AKI之后的血浆和心脏不足， 包括超过十二个氨基酸和抗氧化剂谷胱甘肽。在心脏应激期间，氨基酸为 ATP生产的基本基材。谷氨酰胺尤其重要，因为它可以代谢为 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 并且对于维持正常能源的产生至关重要，因为过量的活性氧（ROS）会损害 线粒体功能并抑制氧化磷酸化（OXPHOS）。 oxphos发生在线粒体内 通常是心脏ATP产生的主要机制。我们的初步数据表明，在 AKI：1）心脏线粒体功能和OXPHOS受损，2）心脏超氧化物（O2● - ，ROS）为 显着增加，3）谷氨酰胺显着增加了心脏ATP并减少了O2● - 。基于这些 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 导致活性氧的增加，OXPHOS减少，ATP的产生减少和心脏 功能障碍。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 通量分析。 AIM 2：确定谷氨酰胺改善心脏ATP产生的机制 Aki，in Vivo，假设谷氨酰胺会减少心脏O2● - 增加ATP的产生并改善 线粒体和心脏功能。目标3：确定谷氨酰胺代谢的底物，以改善 AKI后的心脏ATP产生，即在体内，并假设代谢为谷胱甘肽是主要的 谷氨酰胺益处的机理。由于AKI的并发症长期以来一直被认为是由于 代谢废物和其他物质的积累，可以通过透析去除以获得患者的益处， 我们的总体假设是底物缺乏是一种伤害机制，是一种范式转变，挑战 肾脏科中最基本的注释之一，对护理的影响很大 AKI患者，特别是关于透析的患者。