Role of Mitochondrial Health in Acute and Chronic Kidney Disease in Older Adults

摘要 在这个奖项的过去十年里，我们在理解不利的 慢性肾病(CKD)对老年人健康的影响。肾功能稳步下降 年龄，即使在没有任何临床危险因素的情况下，肾功能减退与 无数的心血管和非心血管疾病。除了肾小球损伤，我们还有 了解到肾小管功能障碍、纤维化和损伤可以预测不良的临床结果。这些结果 提示肾小管的健康对于了解肾脏的发育和进展至关重要。 疾病。在影响老年人的肾外疾病中，如心力衰竭或痴呆症，线粒体 功能障碍似乎在发病机制中起着重要作用。像心脏和大脑一样，肾小管依赖于 线粒体能量代谢，以支持器官的基本功能。在这次更新中，我们 假设线粒体健康状况降低是老年人肾脏疾病的主要原因，原因是 线粒体丰度降低和氧化功能障碍，由积累的突变所致 线粒体DNA(MtDNA) 我们的新的初步数据显示，循环中的线粒体DNA、肾内的 线粒体健康和肾脏功能结果。随着对线粒体的新的治疗兴趣的出现，这 该提案还可能导致预防和治疗CKD的新疗法。我们将利用线粒体DNA的创新 用新开发的下一代测序法衡量其拷贝数和质量的评价 突变负荷法。已公布的结果已经将这些措施与整体老龄化联系在一起。我们会申请 这些技术跨越三个翻译目标：前两个目标将在大型、良好- 第三个目标将使用人类肾脏组织。第一个目标是评估 线粒体DNA的数量和质量与心脏手术患者急性肾损伤的风险相关 做手术。第二个目标是评估相同的mtDNA指标与慢性肾脏病发生的相关性。 并伴随着肾衰竭的进展。第三个目标将利用一套经过验证的技术来调查 使用来自患有和不患有肾脏疾病的老年人的存档肾组织的线粒体原位健康：我们 将比较线粒体生物发生、线粒体数量、氧化磷酸化能力、 和超微结构表现，然后评估它们与组织病理学和临床状态的关系。 这些目标将把线粒体的新兴肾脏生物学转化为老年人的人类肾脏疾病 成年人。阳性结果将：1)提高mtDNA的数量和质量，作为潜在的治疗靶点 肾脏疾病；2)开发评估肾脏组织线粒体的创新方法；以及3) 为未来针对线粒体的治疗方法的临床试验选择患者提供信息。

ABSTRACT Over the past decade of this award, we have made substantial progress toward understanding the adverse impact of chronic kidney disease (CKD) on the health of older adults. Kidney function declines steadily with age, even in the absence of any clinical risk factors, and reduced kidney function is strongly associated with myriad cardiovascular and non-cardiovascular morbidities. In addition to glomerular impairments, we have learned that kidney tubule dysfunction, fibrosis, and injury predict adverse clinical outcomes. These results suggest that kidney tubular health is pivotal for understanding the development and progression of kidney disease. In extrarenal conditions affecting older adults such as heart failure or dementia, mitochondrial dysfunction appears to have a major role in pathogenesis. Like the heart and brain, the kidney tubules rely upon mitochondrial energy metabolism to support fundamental functions of the organ. In this renewal, we hypothesize that reduced mitochondrial health is a major cause of kidney disease in older adults, driven by reduced mitochondrial abundance and oxidative dysfunction that results from accumulated mutations in the mitochondrial DNA (mtDNA). Our new preliminary data implicate unexpectedly striking relationships between circulating mtDNA, intrarenal mitochondrial health, and functional renal outcomes. With emerging therapeutic interest in mitochondria, this proposal could also lead to novel therapies to prevent and treat CKD. We will leverage innovations in mtDNA assessment to measure its quantity by copy number and its quality by newly developed next-gen sequencing methods for mutation burden. Published results already link these measures to overall aging. We will apply these techniques across three translational Aims: the first two Aims will be conducted in large, well- characterized cohorts and the third Aim will use human kidney tissue. The first Aim will evaluate whether mtDNA quantity and quality are associated with risk for acute kidney injury in persons undergoing cardiac surgery. The second Aim will evaluate associations of the same mtDNA measures with development of CKD and with progression to kidney failure. The third Aim will utilize a suite of validated techniques to investigate mitochondrial health in situ using archived kidney tissue from older adults with and without kidney disease: we will compare measures of mitochondrial biogenesis, mitochondrial quantity, oxidative phosphorylation capacity, and ultrastructural appearance, and then evaluate their associations with histopathology and clinical status. These Aims will translate the emerging renal biology of mitochondria into human kidney disease in older adults. Positive results would: 1) advance mtDNA quantity and quality as potential therapeutic targets for kidney diseases; 2) develop innovative methods for the assessment of mitochondria in kidney tissue; and 3) inform selection of patients for future clinical trials of therapies targeted to the mitochondria.