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: 10399538
• 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/10399538
• 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; 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）与慢性肾脏疾病（CKD）相互促进，导致