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.

项目摘要慢性肾脏疾病（CKD）是日益增长的全球健康问题，最近估计的全球流行率超过7亿个案件，在美国超过3700万。即使从一集中恢复临床后急性肾脏损伤（AKI），住院后AKI生存的患者增加了8.8倍开发CKD，并增加3.3倍的终端肾脏疾病风险。线粒体功能障碍是AKI向CKD的发展的关键因素，也称为“ Aki-to-CKD”过渡。长期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，导致脂肪酸氧化和CKD失调。我们已经确定了线粒体羟甲基戊二核-COA合酶2（HMGCS2），酮发生的速率限制酶，在以酮的形成中表达使用肝和肾脏特异性HMGCS2缺失鼠标模型，我们发现该肾脏HMGCS2可能在本地起作用，而不会导致循环酮。在LPS挑战之后，肾脏在最初的肾脏损伤解决后诱导HMGCS2，这表明在化粪池Aki。肾脏特异性的HMGCS2敲除小鼠在早期肾脏受伤中没有任何差异对LPS的响应。但是，从急性化粪池AKI中恢复两个月后，缺乏肾脏HMGCS2的小鼠显示与野生型动物相比，肾脏损伤和纤维化标记水平增加。在缺血性肾脏损伤中，在AKI初期和晚期纤维化阶段，肾脏HMGCS2都受到抑制。缺乏肾脏的小鼠 HMGCS2在缺血性肾脏损伤后产生更多的急性结节损伤和晚期纤维化。二十四小时后缺血性损伤，缺乏HMGCS2的肾脏表现出降低过氧化物体增生剂激活的表达编码PGC1A的受体伽马共振剂-1α（PPARGC1A），线粒体的主调节剂PGC1A 生物发生，氧化磷酸化和脂肪酸氧化。使用能够隔离的新型鼠标模型近端管特异性线粒体，我们发现缺乏HMGCS2的邻近块茎线粒体具有线粒体呼吸抑郁。来自肾脏活检的转录组数据表明HMGCS2是在多个CKD患者队列中被抑制。那就是肾脏线粒体HMGCS2缺陷不仅可能成为肾脏疾病的标志，但也可能是致病性的。这些数据一起导致了以下假设肾脏生酮发生的激活是一种受保护的代谢途径，通过促进CKD的发展限制了CKD的发展线粒体稳态并维持线粒体功能和脂肪酸氧化。在AIM 1中，我们检查肾脏HMGCS2缺乏促进缺血和化粪池中AKI-CKD转变的机制 aki。我们将探讨PGC1A抑制在多大程度上促进CKD的进展 HMGCS2缺陷。在AIM 2中，我们剖析了肾脏HMGCS2在维持线粒体功能中的作用分析近端管状特异性线粒体。在AIM 3中，我们区分了内源性肝脏的影响或与AKI和CKD中的肾内酮的产生相比，外源循环酮。