Mechanisms of Mitochondrial Metabolic Dysfunction in Chronic Kidney Disease

慢性肾脏病线粒体代谢功能障碍的机制

基本信息

批准号：
10862480
负责人：
sarah huen
金额：
$ 15万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10862480
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A Acetyl Coenzyme A Acute Acute Renal Failure with Renal Papillary Necrosis Adult Animals Automobile Driving Bacterial Model Biogenesis Breeding Cell Separation Cells Chronic Kidney Failure Clinical Complex Creatinine Data Depressed mood Development Disease Progression Electron Transport End stage renal failure Enterobacteria phage P1 Cre recombinase Enzymes Event Exhibits Fasting Fibrosis Gene Dosage Gene Expression Goals Health Homeostasis Hospitals Hour Human Inflammation Injury Injury to Kidney Ischemia Ketones Kidney Kidney Diseases Kidney Transplantation Knock-out Knockout Mice Lipopolysaccharides Liver Metabolic Metabolic Pathway Metabolic dysfunction Metabolism Mitochondria Modeling Molecular Mus Organ Outcome Oxidative Phosphorylation PPAR gamma Pathogenicity Patients Phase Plasma Predisposition Prevalence Production Proteome Proteomics Publishing Recovery Reperfusion Injury Respiration Risk Role Testing Therapeutic Intervention Time Tubular formation United States Waiting Lists cohort conditional knockout epidemiologic data experimental study fatty acid oxidation genetic approach global health ischemic injury ketogenesis ketogentic kidney biopsy kidney fibrosis metabolomics mitochondrial dysfunction mouse model novel overexpression pharmacologic prevent renal ischemia response to injury septic transcriptomics

项目摘要

PROJECT SUMMARY Chronic kidney disease (CKD) is a growing global health problem with a recent estimated global prevalence of over 700 million cases, with over 37 million in the United States. Even after clinical recovery from one episode of acute kidney injury (AKI), patients who survive AKI after hospital discharge have an 8.8-fold increased risk of developing CKD and a 3.3-fold increased risk for developing end stage renal disease. Mitochondrial dysfunction is a key contributor to the progression of AKI to CKD, also known as the “AKI-to-CKD” transition. The long-term goal of this application is to define the molecular mechanisms of proximal tubular mitochondrial metabolic dysfunction, leading to dysregulated fatty acid oxidation and CKD. We have identified mitochondrial Hydroxymethylglutaryl-CoA synthase 2 (HMGCS2), the rate limiting enzyme for ketogenesis, to be expressed in the kidney in an inducible fashion. Using liver- and kidney-specific Hmgcs2 deletion mouse models, we found that renal HMGCS2 likely acts locally, without contributing to circulating ketones. After LPS challenge, renal HMGCS2 is induced after the initial kidney injury has resolved, suggesting a potential role in late recovery after septic AKI. Kidney-specific Hmgcs2 knockout mice do not exhibit any difference in the early kidney injury response to LPS. However, two months after recovering from acute septic AKI, mice lacking renal Hmgcs2 show increased levels of kidney injury and fibrosis markers compared to wild-type animals. In ischemic kidney injury, kidney HMGCS2 is suppressed both during the early AKI period and in the late fibrotic phase. Mice lacking renal Hmgcs2 develop more acute tubular injury and late fibrosis after ischemic kidney injury. Twenty-four hours after ischemic injury, kidneys lacking Hmgcs2 exhibit decreased expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (Ppargc1a) which encodes PGC1a, a master regulator of mitochondrial biogenesis, oxidative phosphorylation, and fatty acid oxidation. Using a novel mouse model capable of isolating proximal tubule-specific mitochondria, we found that proximal tubular mitochondria lacking HMGCS2 have depressed mitochondrial respiration. Transcriptomic data from kidney biopsies show that HMGCS2 is suppressed across multiple CKD patient cohorts. Thus, renal mitochondrial HMGCS2 deficiency may not only be a marker of kidney disease but could also be pathogenic. Together these data led to the hypothesis that activation of renal ketogenesis is a protective metabolic pathway limiting the development of CKD by promoting mitochondrial homeostasis and maintaining mitochondrial function and fatty acid oxidation. In Aim 1, we examine the mechanism by which renal HMGCS2 deficiency promotes the AKI-to-CKD transition in ischemic and septic AKI. We will explore the extent to which PGC1a suppression promotes CKD progression in the context of HMGCS2 deficiency. In Aim 2, we dissect the role of renal HMGCS2 in maintaining mitochondrial function by analyzing proximal tubular-specific mitochondria. In Aim 3, we differentiate the effect of endogenous liver-derived or exogenous circulating ketones compared to intra-renal ketone production in AKI and CKD.

项目概要慢性肾病（CKD）是一个日益严重的全球健康问题，最近估计全球患病率超过 7 亿例，其中美国超过 3700 万例，即使在一次发作后临床恢复。急性肾损伤 (AKI) 的患者，出院后 AKI 幸存的患者发生急性肾损伤 (AKI) 的风险增加 8.8 倍罹患 CKD 且罹患终末期肾病的风险增加 3.3 倍。是 AKI 进展为 CKD（也称为“AKI 至 CKD”长期转变）的关键因素。该应用的目标是定义近端管状线粒体代谢的分子机制功能障碍，导致脂肪酸氧化失调和 CKD。羟甲基戊二酰辅酶 A 合酶 2 (HMGCS2)，生酮作用的限速酶，表达于使用肝脏和肾脏特异性 Hmgcs2 缺失小鼠模型，我们发现 HMGCS2 可能在局部发挥作用，而不会促进循环酮体。 HMGCS2 在最初的肾损伤解决后被诱导，这表明在肾损伤后的后期恢复中具有潜在作用。脓毒症 AKI 的肾脏特异性 Hmgcs2 敲除小鼠在早期肾损伤方面没有表现出任何差异。然而，从急性脓毒症 AKI 中恢复两个月后，缺乏肾脏 Hmgcs2 的小鼠表现出对 LPS 的反应。与野生型动物相比，肾损伤和纤维化标志物水平升高。肾脏 HMGCS2 在 AKI 早期和纤维化晚期均受到抑制。缺血性肾损伤二十四小时后，Hmgcs2 出现更严重的肾小管损伤和晚期纤维化。缺血性损伤，缺乏 Hmgcs2 的肾脏表现出过氧化物酶体增殖物激活表达降低受体 γ 辅激活因子 1 α (Ppargc1a)，编码 PGC1a，线粒体的主要调节因子使用能够分离的新型小鼠模型进行生物发生、氧化磷酸化和脂肪酸氧化。近端肾小管特异性线粒体，我们发现缺乏 HMGCS2 的近端肾小管线粒体具有肾活检的转录组数据显示 HMGCS2 抑制线粒体呼吸。因此，肾线粒体 HMGCS2 缺陷可能不仅是在多个 CKD 患者群体中受到抑制。是肾脏疾病的一个标志，但也可能是致病的。这些数据综合起来得出这样的假设：生酮激活是一种保护性代谢途径，通过促进线粒体稳态和维持线粒体功能以及脂肪酸氧化在目标 1 中，我们研究了线粒体稳态和维持线粒体功能以及脂肪酸氧化。肾 HMGCS2 缺乏促进缺血性和脓毒症患者 AKI 向 CKD 转变的机制我们将探讨 PGC1a 抑制在多大程度上促进 CKD 进展。在目标 2 中，我们通过以下方式剖析了肾 HMGCS2 在维持线粒体功能中的作用。分析近端肾小管特异性线粒体在目标 3 中，我们区分了内源性肝源性线粒体的影响。或外源性循环酮与 AKI 和 CKD 中肾内酮产生的比较。