Role of branched-chain amino acid catabolism in the proximal tubule

支链氨基酸分解代谢在近曲小管中的作用

基本信息

批准号：
10657039
负责人：
Sian Piret
金额：
$ 35.09万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
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：
2023-03-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657039
关键词：
Acute Renal Failure with Renal Papillary Necrosis Address Affect Automobile Driving Autophagocytosis Biology Branched-Chain Amino Acids Catabolism Cells Chronic Kidney Failure Citric Acid Cycle Clinical Compensation Complex Development Drug Design Enzymes FRAP1 gene Family Fatty Acids Fibrosis Genes Genetic Transcription Glycolysis Goals Grant Human In Vitro Injury Isoleucine Kidney Leucine Link Metabolic Metabolic Pathway Metabolism Mitochondria Morbidity - disease rate Mus Outcome Oxidative Phosphorylation Oxygen Consumption Pathogenesis Pathway interactions Patients Pilot Projects Process Production Recovery Regulation Reporting Research Respiration Risk Factors Role Severities Signal Transduction Testing Therapeutic Transcriptional Regulation Up-Regulation Valine Zinc Fingers anaerobic glycolysis design fatty acid oxidation field study gene repression improved injured injury and repair knock-down member mortality mouse model nephrotoxicity new therapeutic target novel novel therapeutics overexpression oxidation protective effect public health relevance restoration small molecule transcription factor

项目摘要

Acute kidney injury (AKI) causes significant morbidity and mortality, both of itself and as a major risk factor for development of chronic kidney disease (CKD). The proximal tubule (PT) is the primary target of AKI, triggering profound changes in PT cellular metabolism that contribute to injury. Whilst uninjured PT cells utilize fatty acid oxidation (FAO), TCA cycle and oxidative phosphorylation to generate ATP, in injury, these processes are severely downregulated, with inadequate compensation from glycolysis. Experimental upregulation of FAO can partially rescue AKI, but these strategies have so far not translated to clinical use. Furthermore, loss of the key FAO regulator PPARa does not result in PT injury at baseline, suggesting that other important PT metabolic pathways remain to be described. Branched chain amino acids (BCAA; valine, leucine, isoleucine) are catabolized by the kidney to generate TCA cycle intermediates. We recently reported that genes encoding BCAA catabolic enzymes are strongly downregulated in mouse models of AKI and CKD, and in human CKD, likely driven by transcriptional repression by Krüppel-like factor 6 (KLF6). In vitro, this led to decreased ATP production, whilst activation of BCAA catabolism increased mitochondrial respiration. However, the significance of downregulated BCAA catabolism in AKI or CKD has not been explored. Potential effects of loss of BCAA catabolism may include loss of ATP production, and toxic or detrimental accumulation of uncatabolized BCAA. In particular, leucine is a potent activator of mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signaling, which may downregulate FAO, but this has not been demonstrated in kidney. This proposal will address these current gaps in the field by testing our central hypothesis that transcriptional suppression of PT BCAA catabolism in nephrotoxic AKI is detrimental via loss of ATP production, activation of mTORC1 signaling, and suppression of FAO. This hypothesis will be tested in two specific aims, to: 1) elucidate the mechanism by which disrupted BCAA catabolism alters FAO through mTORC1 activation; and 2) determine the contribution of BCAA catabolism to the severity of AKI and transition to fibrosis. These studies will enhance understanding of the significance of BCAA catabolism in the kidney, which is highly active yet currently unexplored. Furthermore, the link between BCAA catabolism and the critical cellular pathways of mTORC1 signaling and FAO, all of which are potentially druggable, will allow design of improved therapeutics for AKI. The long-term goal is to comprehensively define PT metabolic alterations in nephrotoxic and non-nephrotoxic AKI.

急性肾损伤 (AKI) 本身会导致显着的发病率和死亡率，并且是肾损伤的主要危险因素慢性肾脏病 (CKD) 的发展是 AKI 的主要靶点。 PT 细胞代谢的深刻变化导致损伤，而未损伤的 PT 细胞则利用脂肪酸。氧化（FAO）、TCA循环和氧化磷酸化生成ATP，在损伤时，这些过程是严重下调，糖酵解补偿不足。FAO 的实验上调可以。部分挽救 AKI，但这些策略迄今尚未转化为临床使用，此外，还失去了关键。基线时，FAO 调节剂 PPARa 不会导致 PT 损伤，这表明其他重要的 PT 代谢支链氨基酸（BCAA；缬氨酸、亮氨酸、异亮氨酸）是我们最近报道了编码 BCAA 的基因。在 AKI 和 CKD 小鼠模型以及人类 CKD 模型中，分解代谢酶可能被强烈下调由 Krüppel 样因子 6 (KLF6) 的转录抑制驱动，在体外，这会导致 ATP 产生减少，然而，BCAA 分解代谢的激活增加了线粒体呼吸。尚未探讨 AKI 或 CKD 中 BCAA 分解代谢下调的潜在影响。分解代谢可能包括 ATP 产生的损失以及未分解代谢的支链氨基酸的有毒或不健康的积累。特别是，亮氨酸是雷帕霉素 (mTOR) 复合物 1 (mTORC1) 机制靶标的有效激活剂信号，这可能会下调FAO，但这尚未在肾脏中得到证实。通过测试我们的中心假设来解决该领域当前的空白，即 PT 的转录抑制肾毒性 AKI 中的 BCAA 分解代谢通过 ATP 产生的丧失、mTORC1 信号传导的激活而造成痛苦，这一假设将在两个具体目标上进行检验，以：1）通过以下方式阐明其机制：破坏 BCAA 分解代谢，通过 mTORC1 激活改变 FAO；2) 确定 BCAA 分解代谢与 AKI 严重程度以及向纤维化转变的关系这些研究将加深对这些研究的了解。 BCAA 分解代谢在肾脏中的重要性，其高度活跃但目前尚未探索。 BCAA 分解代谢与 mTORC1 信号传导和 FAO 的关键细胞途径之间的联系，所有这些具有潜在的可药物性，将有助于设计改进的 AKI 疗法。全面定义肾毒性和非肾毒性 AKI 中的 PT 代谢改变。