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: 10620166
• 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/10620166
• 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; 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; Physiological; Predisposition; Proliferating; Proximal Kidney Tubules; Pyruvate; Recovery; Recovery of Function; Regulation; Research; Respiration; Role; Stress; 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; pharmacologic; prevent; progression risk; 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.

急性肾脏损伤（AKI）和慢性肾脏疾病（CKD）相互加强，导致 患者的结果不佳。这是在退伍军人人口中的重要问题 AKI和CKD增加了。此外，这两种情况都与重大合并症有关 糖尿病，HTN和心血管疾病以及高死亡率。 AKI之后，患者的风险增加 进展到CKD。同时，CKD容易使患者患有AKI，并经常阻碍其恢复。 尽管有几项临床研究确定了这些有害相互作用，但潜在的机制仍然存在 难以捉摸。该建议直接解决了了解CKD的机制的差距 对AKI的恢复产生负面影响，并建议为此提高新型治疗剂 影响退伍军人人口健康的重要问题。 通常，肾脏近端小管支撑着线粒体氧化燃料的高水平运输 磷酸化（OXPHOS）具有有限的糖酵解能力。但是，初步数据证明了 近端肾脏切除术的近端肾小管代谢的显着改变 CKD的模型。先前的数据暗示了AMP-激酶（AMPK）途径减少活性的作用，这是一个 中央能量传感器和细胞代谢的调节剂。另外，肾小管代谢和 在AKI之后也可以看到线粒体功能受损。管状新陈代谢和运输如何发展 AKI以及这些因素的预先存在的变化如何影响管状恢复，并将解决 在此提案中。该项目的具体目的包括研究AMPK在近端管状中的作用 在CKD和AKI中重新编程，以及管状代谢和运输影响的预先存在变化 从AKI恢复。提出的工作将利用新颖的方法来评估管状 代谢结合当代分子方法和经典的生理技术（例如 肾脏微型函数可提供机械洞察近端管状转运的见解及其与管状的相关性 从CKD中的AKI恢复的代谢（氧化和糖酵解）。其他相关发现的验证 还将评估损伤模型和与临床疾病的转化相关性。 这些调查将为疾病的早期机制提供重要和新颖的见解 进步并确定可以尽早采用的治疗策略来预防通常的疾病过程 进展。从这些调查中获得的理解将在研究模型之外有价值 考虑到各种细胞代谢和线粒体功能障碍的普遍影响 几个器官的病理生理状况。重要的是，与 退伍军人人口的健康对拟议的研究产生了重大影响。