Harnessing hypoxia responses to treat postischemic kidney injury and inflammation

修改后的项目摘要/摘要部分 缺血是人类急性肾损伤(AKI)的主要原因，AKI是住院患者常见的一种疾病，发病率和死亡率都很高。在缺血性AKI中，低氧适应是由低氧诱导因子(HIF)介导的，HIF是一种转录因子，其活性受Pro-羟基酶结构域蛋白1至3(PhD1至PHD3)的负调控。在肾脏IRI之前，通过药物抑制PHD激活HIF可以减轻缺血后肾脏损伤和炎症。细胞代谢从氧化磷酸化向无氧糖酵解的转变已成为PHD/HIF信号通路促进细胞抗缺血能力的关键因素。尽管有这一基本概念，但HIF影响糖酵解以外的不同代谢途径的机制仍不清楚。我们的长期目标是了解低氧代谢适应如何影响缺血后肾脏损伤和修复。我们最近发现了HIF信号在色氨酸代谢中的非典型作用，这一途径产生了几种对组织具有深刻保护作用的生物活性代谢物。其中，犬尿氨酸和犬尿酸已成为发挥细胞保护和抗炎作用的代谢物，但它们在AKI中的作用尚不清楚。本研究的目的是了解HIF-2诱导的色氨酸代谢改变如何影响缺血后肾脏损伤和修复。中心假设是，HIF-2的激活通过改变色氨酸衍生的代谢物犬尿氨酸和犬尿酸来保护缺血后的肾损伤并促进修复。我们的理论基础是，确定HIF-2诱导色氨酸代谢改变提供肾脏保护的机制将在AKI领域创造迫切需要的新的靶向治疗机会。我们的特定目的将检验以下假设：激活HIF-2可保护AKI，并通过系统性增加犬尿氨酸水平促进修复，并以SLC7a5或IDO1依赖的方式在肾脏组织中促进修复。这一目标的完成将定义一个通过色氨酸代谢激活HIF-2的缺血后肾脏损伤和修复的新范式，并将为AKI的实验治疗开辟新的领域。这项拟议的研究是创新的，因为我们在缺血性AKI的背景下研究了低氧信号在色氨酸代谢中的作用，AKI是一种具有令人兴奋的翻译应用的未知代谢轴

Modified Project Summary/Abstract Section Ischemia is a major cause of human acute kidney injury (AKI), a common condition in hospitalized patients with high morbidity and mortality. In ischemic AKI, hypoxic adaptation is mediated by Hypoxia-Inducible-Factors (HIF), transcriptional factors whose activity is negatively regulated by prolyl-hydroxylase domain proteins 1 to 3 (PHD1 to PHD3). HIF activation by pharmacologic PHD inhibition prior to renal IRI attenuates postischemic kidney injury and inflammation. The shift of cell metabolism from oxidative phosphorylation to anaerobic glycolysis has emerged as a critical factor by which PHD/HIF signaling promotes resilience to ischemia. Despite this fundamental concept, the mechanisms by which HIF affects different metabolic pathways beyond glycolysis remain unclear. Our long-term goal is to understand how hypoxic metabolic adaptation affects postischemic renal injury and repair. We recently discovered a non-canonical role for HIF signaling on tryptophan metabolism, a pathway that generates several bioactive metabolites with profound protective effects on tissues. Among them, kynurenine and kynurenic acid have emerged as metabolites that exert cytoprotective and anti-inflammatory actions but their role in AKI remains unclear. The objective of this proposal is to understand how alterations in tryptophan metabolism induced by HIF-2 affect postischemic renal injury and repair. The central hypothesis is that HIF-2 activation protects against postischemic renal injury and promotes repair through alterations in tryptophan derived metabolites kynurenine and kynurenic acid. Our rationale is that identification of the mechanism by which HIF-2 induced alterations in tryptophan metabolism provide renoprotection will create urgently needed new targeted therapeutic opportunities in the field of AKI. Our specific aim will test the following hypothesis: Activation of HIF-2 protects against AKI and promotes repair by increasing kynurenine levels systemically and in the kidney tissue in either Slc7a5- or IDO1-dependent manner. Completion of this aim will define a new paradigm in postischemic kidney injury and repair by HIF-2 activation through tryptophan metabolism and will stimulate new areas for experimental therapeutics in AKI. The proposed research is innovative because we investigate the role of hypoxic signaling in tryptophan metabolism in the context of ischemic AKI, an unexplored metabolic axis with exciting translational applications