Renal Oxygenation and Mitochondrial Function in the in the Pathophysiology of Kidney Disease

肾脏疾病病理生理学中的肾氧合和线粒体功能

• 批准号: 10252475
• 负责人: Prabhleen Singh
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10252475
• 关键词: Acetyl Coenzyme A; Acute Renal Failure with Renal Papillary Necrosis; Address; Adult; American; Biomass; Cardiovascular Diseases; Caring; Cell Proliferation; Cells; Cellular Stress; Chronic Kidney Failure; Clinical; Clinical Research; Coupled; Data; Death Rate; Dependence; Development; Diabetes Mellitus; Disease; Disease Progression; Early Intervention; Energy Metabolism; Enzymes; Fibrosis; Functional disorder; Gatekeeping; Genetic; Glucose; Glycolysis; Goals; Health; Heart Diseases; Hypertension; Hypoxia; Hypoxia Inducible Factor; Impairment; Incidence; Injury; Injury to Kidney; Investigation; Kidney; Kidney Diseases; Kidney Failure; Knowledge; Lead; Link; Malignant neoplasm of prostate; Measures; Metabolic; Metabolism; Methodology; Methods; Micropuncture; Mitochondria; Modeling; Molecular; Nephrectomy; Organ; Outcome; Oxidative Phosphorylation; PDH kinase; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Physiological; Proximal Kidney Tubules; Pyruvate; Recovery; Recovery of Function; Regulation; Research; Respiration; Risk; Role; Stress; Structure; Study models; Techniques; Therapeutic; Time; Tubular formation; Up-Regulation; Validation; Veterans; Work; adenylate kinase; clinically relevant; comorbidity; improved; injury recovery; insight; malignant breast neoplasm; metabolomics; military veteran; mitochondrial dysfunction; mortality; novel; novel therapeutics; prevent; pyruvate dehydrogenase; repaired; sensor; transcriptomics; treatment strategy

Acute kidney injury (AKI) and chronic kidney disease (CKD) mutually reinforce each other leading to poor outcomes in patients. This is a significant issue in the Veteran population in whom the incidences of both AKI and CKD are increased. Moreover, both conditions are associated with significant comorbidities including diabetes, HTN and cardiovascular disease and high mortality. After AKI, patients are at increased risk of progression to CKD. Meanwhile, CKD predisposes patients to AKI and frequently impedes recovery from it. Despite several clinical studies identifying these harmful interactions, the underlying mechanisms remain elusive. This proposal directly addresses the gap in knowledge of the mechanisms by which CKD negatively impacts recovery from AKI and proposes to advance novel therapeutics for this important problem effecting the health of the Veteran population. Typically, kidney proximal tubules support high levels of transport fueled by mitochondrial oxidative phosphorylation (OXPHOS) with limited glycolytic capacity. However, preliminary data demonstrates significant alterations in proximal tubular metabolism with increased glycolysis in the subtotal nephrectomy model of CKD. Prior data implicate a role for diminished activity of AMP-Kinase (AMPK) pathway, which is a central energy sensor and regulator of metabolism in cells. Additionally, alterations in tubular metabolism and impaired mitochondrial function are also seen after AKI. How tubular metabolism and transport evolve after AKI and how pre-existing changes in these factors impact tubular recovery is not known and will be addressed in this proposal. The specific aims of the project include investigating the role of AMPK in proximal tubular reprogramming in CKD and AKI and how pre-existing changes in tubular metabolism and transport impact recovery from AKI. The proposed work will be accomplished utilizing novel methodologies to assess tubular metabolism combined with contemporary molecular methods and classical, physiological techniques such as renal micropuncture to provide mechanistic insights into proximal tubular transport and its relevance to tubular metabolism (oxidative and glycolytic) in recovery from AKI in CKD. Validation of pertinent findings in other injury models and translational relevance to clinical disease will also be assessed. These investigations will provide important and novel insights into the early mechanisms of disease progression and identify treatment strategies that can be employed early to prevent the usual course of disease progression. The understanding obtained from these investigations will be valuable beyond the model studied given the universal implications of cellular metabolism and mitochondrial dysfunction in various pathophysiological conditions in several organs. Importantly, the high clinical relevance and direct relevance to the health of the Veteran population lend significant impact to the proposed research.

急性肾损伤（AKI）和慢性肾病（CKD）相互强化，导致 患者的不良结局。这是退伍军人群体中的一个重要问题， AKI和CKD增加。此外，这两种情况都与显著的合并症相关，包括 糖尿病、高血压和心血管疾病以及高死亡率。AKI后，患者的风险增加， 进展为CKD。同时，CKD使患者易患AKI，并经常阻碍其康复。 尽管一些临床研究确定了这些有害的相互作用，但其潜在机制仍然存在 难以捉摸。该提案直接解决了CKD的机制知识方面的差距， 对AKI的恢复产生负面影响，并提出了针对这一点的新疗法 影响退伍军人健康的重要问题。 通常，肾近端小管支持由线粒体氧化应激提供燃料的高水平转运。 糖酵解能力有限的磷酸化（OXPHOS）。然而，初步数据显示， 肾次全切除术中近端肾小管代谢的显著改变伴糖酵解增加 CKD模型先前的数据暗示了AMP-激酶（AMPK）途径活性降低的作用，这是一种免疫抑制剂。 细胞内的能量传感器和代谢调节器。此外，肾小管代谢的改变和 在AKI后还观察到受损的线粒体功能。肾小管的代谢和运输是如何演变的 AKI以及这些因素的既存变化如何影响肾小管恢复尚不清楚，将予以解决 在这个提议中。该项目的具体目标包括研究AMPK在近端肾小管上皮细胞中的作用。 CKD和AKI中的重编程以及肾小管代谢和转运的既存变化如何影响 从AKI中恢复。拟议的工作将利用新的方法来完成，以评估管状 代谢结合当代分子方法和经典的生理技术， 肾微穿刺提供近端肾小管转运机制及其与肾小管 代谢（氧化和糖酵解）在CKD患者AKI恢复中的作用。验证其他领域的相关调查结果 还将评估损伤模型和与临床疾病的翻译相关性。 这些研究将为疾病的早期机制提供重要而新颖的见解 进展，并确定可以早期采用的治疗策略，以防止疾病的正常过程 进展从这些调查中获得的理解将是有价值的超越模型研究 考虑到细胞代谢和线粒体功能障碍在各种疾病中的普遍意义， 几个器官的病理生理状况。重要的是，高临床相关性和直接相关性， 退伍军人群体的健康状况对拟议的研究产生了重大影响。