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

摘要 在过去的十年里，我们在了解不利因素方面取得了实质性进展。 慢性肾脏病（CKD）对老年人健康的影响。肾功能逐渐下降， 年龄，即使在没有任何临床风险因素的情况下，肾功能下降与 无数的心血管和非心血管疾病。除了肾小球损伤， 了解到肾小管功能障碍、纤维化和损伤可预测不良临床结局。这些结果 提示肾小管健康对于了解肾脏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， 功能障碍似乎在发病机制中起主要作用。像心脏和大脑一样，肾小管依靠 线粒体的能量代谢，以支持器官的基本功能。在这次更新中，我们 假设线粒体健康下降是老年人肾脏疾病的主要原因， 减少线粒体丰度和氧化功能障碍，这是由于累积的突变， 线粒体DNA（mtDNA）。 我们的新的初步数据暗示了循环mtDNA、肾内mtDNA和线粒体DNA之间意外的惊人关系。 线粒体健康和功能性肾结果。随着对线粒体的治疗兴趣的出现， 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 评估通过拷贝数测量其数量，并通过新开发的下一代测序测量其质量 突变负荷的方法。公布的结果已经将这些措施与整体老化联系起来。我们将应用 这些技术跨越三个翻译目标：前两个目标将在大，好， 第三个目标将使用人肾组织。第一个目标将评估是否 mtDNA的数量和质量与心脏病患者急性肾损伤的风险相关 手术第二个目标将评估相同mtDNA测量与CKD发展的关联 并发展为肾衰竭第三个目标将利用一套经过验证的技术来调查 使用有和没有肾脏疾病的老年人存档的肾脏组织原位研究线粒体健康：我们 将比较线粒体生物发生，线粒体数量，氧化磷酸化能力， 和超微结构的外观，然后评估其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。 成年人了积极的结果将：1）提高mtDNA的数量和质量，作为潜在的治疗靶点， 肾脏疾病; 2）开发用于评估肾脏组织中线粒体的创新方法;以及3） 为将来的线粒体靶向治疗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.