Renal Oxygenation in the Pathophysiology of Kidney Disease

肾病病理生理学中的肾氧合

• 批准号: 9280806
• 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 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280806
• 关键词: 5' -AMP-activated protein kinase; Adult; Affect; Animals; Area; Attenuated; Biogenesis; Catalytic Domain; Cell Respiration; Cells; Cellular Stress; Chronic; Chronic Kidney Failure; Clinical; Complex; Consumption; Data; Development; Diabetes Mellitus; Disease; Disease Pathway; Disease Progression; Disease model; End stage renal failure; Energy Metabolism; Environment; Event; Functional disorder; Future; Gene Targeting; Generations; Goals; Health; Healthcare; Heart Diseases; Homeostasis; Human; Hypertension; Hypertrophy; Hypoxia; Hypoxia Inducible Factor; Impairment; Incidence; Infarction; Injury; Interruption; Investigation; Kidney; Kidney Diseases; Limb structure; Metabolic; Metabolic stress; Metabolism; Mitochondria; Molecular; Morbidity - disease rate; Morphology; Nephrectomy; Nephrons; Organ; Oxidative Phosphorylation; Oxygen; Oxygen Consumption; Pathway interactions; Pharmacology; Physiology; Population; Production; Protein Kinase; Reactive Oxygen Species; Regulation; Renal function; Research Personnel; Research Proposals; Rodent; Rodent Model; Role; Sodium; Sodium Chloride; Stress; Study models; Superoxides; Thick; Tissues; Tubular formation; United States; Validation; Veterans; Work; base; cost; genetic approach; hemodynamics; hypoxia inducible factor 1; improved; improved outcome; insight; mitochondrial dysfunction; mortality; new therapeutic target; novel; prevent; public health relevance; response; restoration; sensor; success; targeted treatment; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): In chronic kidney disease (CKD), intrarenal hypoxia has been identified as a major contributor to disease progression. Hence, it is imperative to understand the pathways that regulate kidney oxygenation in health and disease. At the earliest stages, a functional oxygen supply-demand mismatch creates a hypoxic environment. High nephron oxygen consumption without an increase in oxygen supply is the earliest pathophysiological change that leads to oxygen supply-demand mismatch. Lowering nephron oxygen consumption improves kidney function and morphology. This proposal is aimed at investigating the regulators of oxygen consumption at the earliest stages in subtotal nephrectomy, a rodent model of CKD. The strategy and overall objective is to investigate key pathophysiological events and their regulation early in the course of disease before irreversible structural changes set in and to identify novel therapeutic targets which can prevent or slow the progression of CKD. The majority of the energy in the kidney is provided by oxidative phosphorylation by the mitochondria. Preliminary data demonstrates several alterations in mitochondrial function and morphology in early subtotal nephrectomy indicating mitochondrial stress. Hypoxia inducible factor (HIF) transcription complex is a primary oxygen sensor/regulator of oxygen homeostasis and induces several target genes that impact oxygen delivery and consumption. It also has several beneficial effects on mitochondrial function. AMP-activated protein kinase (AMPK) is another important energy sensor that regulates cellular metabolic adaptations under ATP-deprived conditions and is increasingly being identified as a major player in renal pathophysiology. HIF and AMPK are also emerging as regulators of sodium transport, which is a primary driver of nephron oxygen consumption. Based on the preliminary data, the overall hypothesis is that hypoxia in early subtotal kidney, due to increased nephron oxygen consumption, leads to mitochondrial dysfunction and ROS generation, resulting in tissue injury and renal dysfunction. This is perpetuated by abnormal cellular stress adaptation due to suppressed AMPK activation. HIF-1 induction improves renal oxygenation by lowering oxygen consumption and increasing oxygen supply via effects on renal hemodynamics, salt transport and cellular effects including improvements in mitochondrial morphology and function and restoration of AMPK activation. The specific aims are to determine the subcellular, cellular and hemodynamic mechanisms whereby HIF-1 activation improves renal oxygenation in early CKD and to determine the significance of the AMPK pathway in renal function and oxygenation by examining its role in tubular transport and metabolism in early CKD. These investigations will not only 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, but the broad-based approach will also serve as a spring-board for future proposals on specific mechanistic pathways underlying the coordinated actions of HIF and AMPK in the regulation of energy metabolism and transport at a cellular and subcellular level. The understanding obtained from these investigations will be valuable beyond the model studied given the universal implications of mitochondrial dysfunction in various pathophysiological conditions and the nearly ubiquitous cellular expression of HIF and AMPK in several organs.

描述（由申请人提供）：