Renal Oxygenation in the Pathophysiology of Kidney Disease

肾病病理生理学中的肾氧合

• 批准号: 8967093
• 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/8967093
• 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 Progression; Disease model; End stage renal failure; Energy Metabolism; Environment; Event; Functional disorder; Future; Gene Targeting; Generations; Genetic Transcription; Goals; Health; Healthcare; Homeostasis; Human; Hypertrophy; Hypoxia; Hypoxia Inducible Factor; Incidence; Infarction; Injury; 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; Physiology; Population; Production; Reactive Oxygen Species; Regulation; Renal function; Research Personnel; Research Proposals; Rodent; Rodent Model; Role; Sodium; Sodium Chloride; Staging; Stress; Study models; Superoxides; Thick; Tissues; Tubular formation; United States; Validation; Veterans; Work; base; cost; genetic approach; hemodynamics; hypertensive heart disease; 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; 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）： 在慢性肾脏病（CKD）中，肾内缺氧已被确定为疾病进展的主要原因。因此，必须了解在健康和疾病中调节肾脏氧合的途径。在最早阶段，功能性氧气供需不匹配会造成缺氧环境。肾单位耗氧量高而不增加供氧量是导致氧供需失配的最早的病理生理变化。降低肾单位耗氧量可改善肾功能和形态。该提案旨在研究肾次全切除术（一种 CKD 啮齿动物模型）早期阶段耗氧量的调节因素。该策略和总体目标是在不可逆的结构变化发生之前研究病程早期的关键病理生理事件及其调节，并确定可以预防或减缓 CKD 进展的新治疗靶点。肾脏中的大部分能量是由线粒体的氧化磷酸化提供的。初步数据表明，早期肾次全切除术中线粒体功能和形态发生了一些变化，表明存在线粒体应激。缺氧诱导因子 (HIF) 转录复合物是氧稳态的主要氧传感器/调节器，可诱导多个影响氧输送和消耗的靶基因。它还对线粒体功能有一些有益的影响。 AMP 激活蛋白激酶 (AMPK) 是另一种重要的能量传感器，可在 ATP 剥夺条件下调节细胞代谢适应，并且越来越多地被认为是肾脏病理生理学的主要参与者。 HIF 和 AMPK 也正在成为钠转运的调节剂，而钠转运是肾单位耗氧的主要驱动因素。根据初步数据，总体假设是早期次全肾缺氧，由于肾单位耗氧量增加，导致线粒体功能障碍和ROS生成，导致组织损伤和肾功能障碍。由于 AMPK 激活受到抑制而导致细胞应激适应异常，从而使这种情况持续存在。 HIF-1 诱导通过影响肾血流动力学、盐转运和细胞效应（包括改善线粒体形态和功能以及恢复 AMPK 激活）来降低氧消耗和增加氧供应，从而改善肾氧合。具体目标是确定 HIF-1 激活改善早期 CKD 肾氧合的亚细胞、细胞和血流动力学机制，并通过检查其在早期 CKD 肾小管转运和代谢中的作用来确定 AMPK 通路在肾功能和氧合中的重要性。这些研究不仅将为疾病进展的早期机制提供重要而新颖的见解，并确定可早期采用以预防疾病进展的通常过程的治疗策略，而且基础广泛的方法也将为未来关于 HIF 和 AMPK 在细胞和亚细胞水平的能量代谢和运输调节中协调作用的特定机制途径的建议提供跳板。鉴于线粒体功能障碍在各种病理生理条件下的普遍影响以及 HIF 和 AMPK 在多个器官中几乎无处不在的细胞表达，从这些研究中获得的理解将超越所研究的模型。