Renal Oxygenation and Mitochondrial Function in the in the Pathophysiology of Kidney Disease

急性肾损伤(AKI)和慢性肾脏病(CKD)相互促进，导致 患者的预后不佳。这在退伍军人群体中是一个重要的问题，在他们中，这两种疾病的发生率 AKI和CKD增加。此外，这两种情况都与严重的共病有关，包括 糖尿病、HTN和心血管疾病，死亡率高。AKI后，患者面临更高的风险 进展为慢性肾脏病。同时，慢性肾脏病使患者易患急性KI，并经常阻碍患者的康复。 尽管有几项临床研究确认了这些有害的相互作用，但潜在的机制仍然 难以捉摸。这一建议直接解决了对慢性肾脏病发病机制的认识差距。 对AKI的康复产生负面影响，并建议为此推进新的治疗方法 这是影响退伍军人健康的重要问题。 通常，肾近端小管支持线粒体氧化推动的高水平转运。 磷酸化(OXPHOS)，糖酵解能力有限。然而，初步数据表明， 肾大部切除术中近端肾小管代谢的显著改变及糖酵解增加 CKD模型。先前的数据暗示了AMP-Kinase(AMPK)途径活性降低的作用，这是一种 细胞内的中心能量感受器和代谢调节器。此外，肾小管新陈代谢的改变和 AKI后也可见线粒体功能受损。肾小管新陈代谢和转运是如何演变的 Aki以及这些因素中先前存在的变化如何影响肾小管恢复尚不清楚，将予以解决 在这份提案中。该项目的具体目标包括研究AMPK在近端肾小管中的作用 CKD和AKI中的重新编程以及先前存在的肾小管代谢和转运变化如何影响 从AKI中恢复。拟议的工作将利用评估管材的新方法来完成 新陈代谢结合当代分子方法和经典的生理技术，如 肾微穿刺术对近端肾小管运输及其与肾小管的相关性的机械研究 慢性肾脏病AKI患者康复过程中的代谢(氧化和糖酵解)。验证其他文件中的相关调查结果 还将评估损伤模型和与临床疾病的翻译相关性。 这些研究将为疾病的早期机制提供重要和新颖的见解。 进展和确定可以及早采用的治疗策略，以防止通常的病程 进步。从这些调查中获得的理解将比所研究的模型更有价值。 鉴于细胞代谢和线粒体功能障碍在各种疾病中的普遍意义 几个器官的病理生理状况。重要的是，高度的临床相关性和直接相关性 退伍军人的健康状况对拟议的研究产生了重大影响。

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.