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

• 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
• 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

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.

项目总结 慢性肾脏疾病(CKD)是一个日益严重的全球健康问题，最近估计全球发病率为 超过7亿例，其中3700万例在美国。即使在临床从一次发作中恢复之后 对于急性肾损伤(AKI)，出院后在AKI中存活的患者患AKI的风险增加8.8倍 发展为慢性肾脏病，发展为终末期肾病的风险增加3.3倍。线粒体功能障碍 是AKI向CKD发展的关键贡献者，也称为“AKI到CKD”的转变。长期的 本应用的目的是确定近端小管线粒体代谢的分子机制。 功能障碍，导致脂肪酸氧化失调和慢性肾脏病。我们已经确定了线粒体 酮类合成限速酶羟甲基戊二酰辅酶A合成酶2(HMGCS2)在 以一种可诱导的方式移植肾脏。使用肝脏和肾脏特异的HMGCS2缺失小鼠模型，我们发现 肾脏HMGCS2可能在局部起作用，而不是促进循环酮。在内毒素激发后，肾脏 HMGCS2是在最初的肾损伤缓解后诱导的，这表明HMGCS2在以后的恢复中可能起着作用 败血症AKI。肾脏特异性HMGCS2基因敲除小鼠在早期肾脏损伤中没有表现出任何差异 对内毒素的反应。然而，在急性败血症AKI康复两个月后，缺乏肾脏HMGCS2的小鼠表现出 与野生型动物相比，肾脏损伤和纤维化标志物水平增加。在缺血性肾损伤中， 肾脏HMGCS2在AKI早期和纤维化晚期均受到抑制。肾功能缺乏的小鼠 HMGCS2在缺血肾损伤后发生更多的急性肾小管损伤和晚期纤维化。二十四小时后 缺血损伤，缺乏HMGCS2的肾脏表现为过氧化体增殖物激活的表达减少 Ppargc1a，编码线粒体的主要调节因子PGC1a 生物发生、氧化磷酸化和脂肪酸氧化。使用一种新的能够隔离的小鼠模型 近端小管特异性线粒体，我们发现缺少HMGCS2的近端小管线粒体有 线粒体呼吸受抑制。肾脏活检的转录数据显示，HMGCS2是 在多个CKD患者队列中被抑制。因此，肾脏线粒体HMGCS2缺乏症不仅可能 是肾脏疾病的标志，但也可能是致病的。这些数据加在一起导致了这样的假设 肾酮体生成的激活是一种保护性代谢途径，促进了CKD的发展 维持线粒体动态平衡和维持线粒体功能及脂肪酸氧化。在目标1中，我们检查 肾脏HMGCS2缺乏促进缺血和脓毒症AKI向CKD转变的机制 阿琪。我们将探索PGC1a抑制在多大程度上促进CKD的进展 HMGCS2缺乏。在目标2中，我们剖析了肾脏HMGCS2在维持线粒体功能中的作用。 分析近端小管特异性线粒体。在目标3中，我们区分内源性肝源的作用 在AKI和CKD中，外源性循环酮与肾内酮产生的比较。