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Harnessing hypoxia responses to treat postischemic kidney injury and inflammation

利用缺氧反应治疗缺血后肾损伤和炎症

基本信息

批准号：
10676938
负责人：
Pinelopi P. Kapitsinou
金额：
$ 24万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676938
关键词：
Acute Renal Failure with Renal Papillary Necrosis Address Affect Anti-Inflammatory Agents Area Attenuated Cell Proliferation Cell Respiration Cells Cellular Metabolic Process Cytoprotection Data Dialysis procedure Environment Erythropoiesis Financial cost Genes Genetic Genetic Models Glycolysis Goals Hospitalization Human Hypoxia Hypoxia Inducible Factor Incidence Inflammation Injury Injury to Kidney Intensive Care Units Investigation Investigational Therapies Ischemia Kidney Knowledge Kynurenic Acid Kynurenine Mediating Metabolic Metabolic Pathway Metabolism Morbidity - disease rate N&apos -formylkynurenine Oxidative Phosphorylation Oxygen Pathway interactions Patients Process Procollagen-Proline Dioxygenase Protein Isoforms Public Health Publishing Recovery Reperfusion Injury Research Role Serum Signal Transduction Tertiary Protein Structure Testing Therapeutic Intervention Tissues Tryptophan Tryptophan 2,3 Dioxygenase Tryptophan Metabolism Pathway anaerobic glycolysis angiogenesis bHLH-PAS factor HLF effective therapy hypoxia inducible factor 1 improved injury and repair injury prevention innovation insight kidney repair metabolomics mortality new therapeutic target novel novel therapeutics pharmacologic prevent promote resilience protective effect public health relevance renal ischemia repaired response sensor tissue injury tissue repair transcription factor transcriptomics translational applications uptake

项目摘要

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

修改的项目摘要/摘要部分