Renal Oxygenation in the Pathophysiology of Kidney Disease

描述（由申请人提供）： 在慢性肾脏疾病（CKD）中，肾内缺氧已被确定为疾病进展的主要因素。因此，必须了解在健康和疾病中调节肾脏氧合的途径。在最早的阶段，功能性氧供需不匹配会造成缺氧环境。高肾单位氧消耗而不增加氧供应是导致氧供需不匹配的最早病理生理变化。降低肾单位耗氧量可改善肾功能和形态。这项建议的目的是调查的监管机构的氧气消耗在最早阶段的肾大部切除术，慢性肾脏病的啮齿动物模型。该策略和总体目标是在不可逆的结构变化发生之前，在疾病过程的早期研究关键的病理生理学事件及其调节，并确定可以预防或减缓CKD进展的新型治疗靶点。肾脏中的大部分能量由线粒体的氧化磷酸化提供。初步数据表明，在早期肾大部切除术线粒体功能和形态的几个变化，表明线粒体应激。缺氧诱导因子（Hypoxia inducible factor，HIF）转录复合物是氧稳态的主要氧传感器/调节器，并诱导影响氧输送和消耗的几个靶基因。它对线粒体功能也有一些有益的影响。AMP活化蛋白激酶（AMPK）是另一种重要的能量传感器，在ATP缺乏的条件下调节细胞代谢适应，并越来越多地被确定为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，钠转运是肾单位氧消耗的主要驱动力。基于初步数据，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产生，导致组织损伤和肾功能障碍。由于AMPK激活受到抑制，导致细胞应激适应异常，从而使其持续存在。HIF-1诱导通过降低氧消耗和增加氧供应来改善肾氧合，这是经由对肾血流动力学、盐转运和细胞效应的影响，包括线粒体形态和功能的改善以及AMPK活化的恢复。具体的目的是确定亚细胞，细胞和血液动力学机制，从而HIF-1激活改善早期CKD的肾氧合，并通过检查其在早期CKD的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意义。这些研究不仅将为疾病进展的早期机制提供重要和新颖的见解，并确定可以早期采用的治疗策略，以预防疾病进展的通常过程，但基础广泛的方法也将成为一个春天-委员会的未来建议的具体机制途径的基础上协调行动的HIF和AMPK的调节能量代谢和运输在一个细胞和亚细胞水平。从这些调查中获得的理解将是有价值的超越模型研究的线粒体功能障碍的普遍影响，在各种病理生理条件下和几乎无处不在的细胞表达的HIF和AMPK在几个器官。

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.