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

• 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
• 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

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.

急性肾脏损伤（AKI）会引起明显的发病率和死亡率 慢性肾脏疾病（CKD）的发展。近端管（PT）是AKI的主要目标，触发 PT细胞代谢的深刻变化导致损伤。而未受伤的PT细胞利用脂肪酸 氧化（FAO），TCA循环和氧化磷酸化以产生ATP，在损伤中，这些过程是 严重下调，糖酵解的补偿不足。粮农组织的实验上调 部分营救了AKI，但这些策略迄今未转化为临床用途。此外，损失钥匙 FAO调节剂PPARA不会在基线时导致PT损伤，这表明其他重要的PT代谢 途径仍有待描述。分支链氨基酸（BCAA； Valine，Leucine，Isoleucine）为 被肾脏分解以产生TCA循环中间体。我们最近报道了编码BCAA的基因 在AKI和CKD的小鼠模型以及人CKD中，分解代谢酶强烈下调，可能 由Krüppel样因子6（KLF6）的转录表达驱动。在体外，这导致了ATP产生的改善， 而BCAA分解代谢的激活增加了线粒体呼吸。但是，意义的意义 尚未探索AKI或CKD中的BCAA分解代谢下调。损失BCAA的潜在影响 分解代谢可能包括ATP产生的损失以及未代谢BCAA的有毒或有害积累。 特别是，亮氨酸是雷帕霉素（MTOR）复合物1（MTORC1）机械靶标的潜在激活剂 信号传导可能会下调粮农组织，但这在肾脏中尚未证明。该提议将 通过测试我们的中心假设，即PT的转录抑制，解决了现场的这些当前差距 肾毒性AKI中的BCAA分解代谢对ATP产生的损失，MTORC1信号传导的激活，有害 和抑制粮农组织。该假设将以两个具体的目的进行检验，以：1）通过 破坏了BCAA的分解代谢通过MTORC1激活改变了粮农组织； 2）确定 BCAA对AKI的严重程度和向纤维化的过渡。这些研究将增强对 BCAA分解代谢在肾脏中的重要性，这是高度活跃但目前出乎意料的。此外， BCAA分解代谢与MTORC1信号传导和粮农的关键细胞途径之间的联系，所有这些 可能会吸毒，可以设计改进AKI的治疗。长期目标是 全面定义的肾毒性和非氯毒性AKI中的PT代谢改变。