Mechanisms of selective glycolytic inhibition in ischemic kidney proximal tubles

缺血肾近曲小管选择性糖酵解抑制机制

• 批准号: 8534448
• 负责人: BABU Joseph PADANILAM
• 金额: $ 15万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-14 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534448
• 关键词: ATP Synthesis Pathway; Accounting; Acute Kidney Tubular Necrosis; Acute Renal Failure with Renal Papillary Necrosis; Address; Apoptosis Regulator; Apoptotic; Autophagocytosis; Biochemical; Biological Assay; Cell Death; Cell Death Inhibition; Cell Survival; Cells; Clinical; Data; Disease; Down-Regulation; Energy Metabolism; Enzymes; Event; Experimental Models; Fructose; Functional disorder; Genetic; Glucose; Glucose-6-Phosphate; Glyceraldehyde 3-Phosphate; Glyceraldehyde-3-Phosphate Dehydrogenases; Glycolysis; Health Care Costs; Human; Hypoxia; Injury; Intervention; Kidney; Link; Mediating; Metabolic; Methods; Molecular; Morbidity - disease rate; NADP; Necrosis; Nephrons; Organ; PARP inhibition; Pathogenesis; Pathway interactions; Pentosephosphate Pathway; Perfusion; Poly(ADP-ribose) Polymerases; Production; Pyruvate; Regulation; Renal Tissue; Reperfusion Injury; Reporting; Resort; Respiration; Role; Stress; Syndrome; Testing; abstracting; anaerobic glycolysis; base; fructose-6-phosphate; glycerate 1,3-biphosphate; in vivo; in vivo Model; innovation; mortality; novel; novel therapeutics; renal ischemia; response; success

Abstract Following ischemic renal injury (IRI), selective proximal straight tubule (PST) injury occurs in in vivo experimental models. Previous reports indicated that selective glycolytic inhibition and the consequent ATP depletion is the initiating cause that triggers all the subsequent events leading to PST injury and cell death to instigate renal dysfunction; however, the exact mechanism by which glycolysis is inhibited is not elucidated. Our recent report demonstrates that poly (ADP-ribose) Polymerase-1 (PARP-1) mediated inhibition of the key glycolytic enzyme, glyceraldehyde-3- phosphate dehydrogenase (GAPDH), can induce downregulation of glycolysis and ATP depletion in IRI. However, GAPDH inhibition by PARP-1 only partially accounted for ATP depletion, suggesting that synergetic inhibition at additional glycolytic steps may occur. The current proposal is based on new preliminary data indicating a novel paradigm that links p53 target TIGAR (Tp53 inducible glycolysis and apoptosis regulator) to metabolic regulation of the rate limiting glycolytic enzyme Phosphofructokinase (PFK) to induce ATP depletion and PST injury post-IRI. The objective of the proposal is to define the role and the mechanisms by which TIGAR regulate glycolytic energy metabolism in ischemic renal PST and determine whether synergistic inhibition of TIGAR and PARP- 1 protects from glycolytic inhibition and ATP depletion in the setting of IRI. The central hypothesis is that modulation of the activity of the key glycolytic enzymes, PFK and GAPDH by TIGAR and PARP-1 respectively, leads to downregulation of glycolysis and anaerobic ATP production in ischemic PSTs. Based on our strong preliminary data, the validity of the hypothesis will be tested by pursuing the following three specific aims: 1) determine the mechanism by which TIGAR activation in renal PSTs inhibits anaerobic energy production post-IRI; 2) determine if the level of ischemic stress switch TIGAR response towards ROS scavenging and autophagy versus glycolytic inhibition and cell death pathways post-IRI and 3) determine if synergetic inhibition of TIGAR and PARP activation completely protects PST from ischemic/hypoxic injury in in vivo models. Successful completion of the proposed studies, will establish a new paradigm on the role of PARP-1 and TIGAR as the primary mechanism that initiates glycolytic inhibition, ATP depletion and PST injury in IRI. The studies are innovative as a role for PARP-1 and TIGAR in glycolytic inhibition in a pathological condition such as ischemia/reperfusion injury has not been previously addressed in any organ. Results from the study may provide novel therapeutic opportunities to intervene in PARP-1 and TIGAR functions to modulate PST injury at its onset and may be extrapolated to intervene in the pathogenesis of human AKI.

抽象的 在体内发生以下缺血性肾损伤（IRI），在体内发生选择性近端直立小管（PST）损伤 实验模型。先前的报告表明，选择性糖酵解抑制和 因此，ATP耗竭是启动原因，它触发了所有后续事件，导致 PST损伤和细胞死亡以激发肾功能障碍；但是，确切的机制 糖酵解抑制不阐明。我们最近的报告表明poly（ADP-核糖） 聚合酶-1（PARP-1）介导了对关键糖酵解酶，甘油醛-3--的抑制作用 磷酸盐脱氢酶（GAPDH）可以诱导糖酵解和ATP耗竭的下调 艾里。但是，PARP-1抑制GAPDH仅部分解释了ATP耗竭，这表明 可能会在其他糖酵解步骤中进行协同抑制。当前的提议基于 新的初步数据，指示链接p53目标tigar的新型范式（TP53诱导 糖酵解和凋亡调节剂）以限制糖酵解酶的代谢调节 IRI后IRI诱导ATP耗竭和PST损伤。目的 建议是定义蒂加尔调节糖酵解能的作用和机制 缺血性肾脏PST中的代谢，并确定对Tigar和PARP的协同抑制 1在IRI的情况下保护免受糖酵解抑制和ATP耗竭。中心假设 是对蒂加尔（Tigar）和 PARP-1分别导致缺血性糖酵解和厌氧ATP的下调 PST。根据我们强大的初步数据，将通过追求假设的有效性来检验 以下三个特定目的：1）确定肾脏中蒂加尔激活的机制 PST在IRI后抑制厌氧能源生产； 2）确定缺血性应力转换水平是否 Tigar对ROS清除和自噬与糖酵解抑制和细胞死亡的反应 IRI之后的途径和3）确定Tigar和PARP激活的协同抑制是否完全 保护PST免受体内模型中缺血/低氧损伤。成功完成拟议的 研究将建立关于PARP-1和TIGAR作为主要机制的作用的新范式 这引发了IRI中的糖酵解抑制，ATP耗竭和PST损伤。研究是创新的 PARP-1和TIGAR在糖酵解抑制中的作用，例如 以前在任何器官中都没有解决缺血/再灌注损伤。研究结果 可以提供新颖的治疗机会来干预PARP-1和TIGAR功能以调节 PST发作时的损伤，可以推断以干预人AKI的发病机理。