Endothelial PHD2/HIF Axis in Ischemic Kidney Injury and Inflammation

缺血性肾损伤和炎症中的内皮 PHD2/HIF 轴

• 批准号: 10600614
• 负责人: Pinelopi P. Kapitsinou
• 金额: $ 8万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-07 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10600614
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Affect; Blood Vessels; Cell Culture Techniques; Chronic Kidney Failure; Clinical; Cost Measures; Development; Endothelial Cells; Endothelium; Financial Hardship; Genetic Models; Glycolysis; Hypoxia; Hypoxia Inducible Factor; Hypoxia-Inducible Factor Pathway; Impairment; Inflammation; Inflammatory; Injury to Kidney; Ischemia; Kidney; Mediating; Metabolic; Mitochondria; Mixed Function Oxygenases; Molecular; Outcome; Oxygen; Patient-Focused Outcomes; Phenotype; Public Health; Recovery; Research; Respiration; Role; Signal Transduction; Tertiary Protein Structure; Testing; bHLH-PAS factor HLF; cell type; clinical care; high risk; hypoxia inducible factor 1; injury and repair; innovation; insight; kidney repair; mortality risk; neglect; novel therapeutics; prevent; response; sensor; targeted treatment; therapeutically effective; tissue injury; transcription factor

PROJECT SUMMARY Acute kidney injury (AKI) due to ischemia is a common clinical condition, which is associated with poor patient outcomes, including high risk for mortality and development of chronic kidney disease. Following ischemic AKI, peritubular endothelial cells contribute to tissue injury by promoting inflammation and interfere with renal recovery through impaired revascularization. Key regulators of hypoxic vascular responses are Hypoxia- Inducible-Factors (HIF)-1 and –2, transcriptional factors whose activity is inhibited by proly-hydroxylase domain proteins 1 to 3 (PHD1 to PHD3), PHD2 being the main oxygen sensor. Our recent study was the first to identify a crucial role for endothelial PHD2 in post-ischemic renal injury but the underlying molecular mechanisms remain undefined. Identification of the mechanisms whereby endothelial PHD2 regulates post-ischemic renal injury and inflammation may create novel and targeted therapeutic opportunities in the field of AKI. In this proposal, we hypothesize that inhibition of endothelial PHD2 suppresses post-ischemic renal inflammation and promotes revascularization through HIF-dependent induction of metabolic reprogramming in endothelial cells. To test this hypothesis, we propose three specific aims. Aim 1 defines the role of endothelial PHD2/HIF axis in post-ischemic kidney injury and inflammation by investigating how disrupting HIF-1 or HIF-2 affects the post- ischemic kidney microenvironment in the context of endothelial PHD2 deficiency. Aim 2 examines the role of endothelial PHD2/HIF signaling in post-ischemic kidney repair and revascularization using genetic models, which allow acute endothelial specific inactivation of PHD2 alone and concurrently with either HIF-1 or HIF-2 after the induction of ischemic kidney injury. Aim 3 defines how alterations in glycolysis and mitochondrial respiration induced by hypoxic signaling affect endothelial inflammatory and angiogenic responses. The proposed research is innovative because we investigate the role of PHD2/HIF pathway in endothelial cells, a neglected cell type in the field of AKI, using powerful genetic models. Furthermore, state-of–the art cell culture techniques are employed to determine endothelial phenotypes resulting from PHD2/HIF-mediated metabolic reprogramming. Upon conclusion, we will obtain fundamentally new insights into how endothelial PHD2/HIF axis affects post-ischemic kidney injury outcomes.

项目总结 急性肾损伤(AKI)是一种常见的临床症状，患者病情较差。 结果，包括高风险的死亡和慢性肾脏疾病的发展。缺血性急性心肌梗死后， 肾小管周内皮细胞通过促进炎症和干扰肾脏而导致组织损伤 通过受损的血管重建恢复。低氧血管反应的关键调节因素是低氧- 诱导因子(HIF)-1和-2，其活性受Pro-羟基酶结构域抑制的转录因子 蛋白质1至3(Phd1至PHD3)，PHD2是主要的氧感受器。我们最近的研究首次发现 内皮细胞PHD2在缺血后肾损伤中的重要作用及其分子机制 仍然没有定义。内皮细胞PHD2调节缺血后肾脏的机制研究 损伤和炎症可能在AKI领域创造新的和有针对性的治疗机会。在这 建议，我们假设抑制内皮细胞PHD2抑制缺血后的肾脏炎症和 通过HIF依赖的对内皮细胞代谢重编程的诱导，促进血管重建。 为了检验这一假设，我们提出了三个具体目标。目的1确定内皮细胞PHD2/HIF轴在 通过研究干扰HIF-1或HIF-2对缺血后肾损伤和炎症的影响 血管内皮细胞PHD2缺乏背景下的肾脏微环境缺血。《目标2》考察了 利用遗传模型研究血管内皮细胞PHD2/HIF信号在肾缺血后修复和血管重建中的作用 其允许单独以及与HIF-1或HIF-2同时发生的PHD2的急性内皮特异性失活 诱导后肾组织发生缺血性损伤。目标3定义糖酵解和线粒体的变化 低氧信号诱导的呼吸影响内皮细胞炎症和血管生成反应。这个 拟议的研究具有创新性，因为我们研究了PHD2/HIF通路在内皮细胞中的作用， 在AKI领域被忽视的细胞类型，使用强大的遗传模型。此外，最先进的细胞培养 使用技术来确定由PHD2/HIF介导的代谢产生的内皮表型 重新编程。在结论中，我们将从根本上获得关于内皮PHD2/HIF如何 AXIS影响缺血后肾损伤的预后。

项目成果

Role of Endothelial Prolyl-4-Hydroxylase Domain Protein/Hypoxia-Inducible Factor Axis in Acute Kidney Injury.

• DOI: 10.1159/000518632
• 发表时间: 2022
• 期刊: Nephron
• 影响因子: 2.5
• 作者: Tiwari R;Kapitsinou PP
• 通讯作者: Kapitsinou PP

Hypoxic preconditioning protects against ischemic kidney injury through the IDO1/kynurenine pathway.

• DOI: 10.1016/j.celrep.2021.109547
• 发表时间: 2021-08-17
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Torosyan R;Huang S;Bommi PV;Tiwari R;An SY;Schonfeld M;Rajendran G;Kavanaugh MA;Gibbs B;Truax AD;Bohney S;Calcutt MW;Kerr EW;Leonardi R;Gao P;Chandel NS;Kapitsinou PP
• 通讯作者: Kapitsinou PP