Endothelial PHD2/HIF Axis in Ischemic Kidney Injury and Inflammation

项目摘要 缺血性急性肾损伤（acute kidney injury，阿基）是一种常见的临床疾病， 结果，包括死亡率和慢性肾脏疾病发展的高风险。缺血性阿基后， 肾小管周围内皮细胞通过促进炎症和干扰肾功能而促进组织损伤。 通过受损的血运重建恢复。缺氧血管反应的关键调节因子是缺氧- 诱导因子（HIF）-1和-2，其活性被羟化酶原结构域抑制的转录因子 蛋白质1至3（PHD 1至PHD 3），PHD 2是主要的氧传感器。我们最近的研究首次发现 内皮PHD 2在缺血后肾损伤中的关键作用，但其潜在的分子机制 仍然未定义。内皮细胞PHD 2调节缺血后肾损伤的机制的鉴定 损伤和炎症可能在阿基领域创造新的靶向治疗机会。在这 因此，我们假设抑制内皮PHD 2可以抑制缺血后肾脏炎症， 通过HIF依赖性诱导内皮细胞中的代谢重编程促进血管再生。 为了验证这一假设，我们提出了三个具体目标。目的1定义了内皮PHD 2/HIF轴在 通过研究破坏HIF-1或HIF-2如何影响缺血后肾损伤和炎症， 在内皮PHD 2缺乏的背景下缺血性肾脏微环境。目标2审查了 使用遗传模型的缺血后肾修复和血管再生中的内皮PHD 2/HIF信号传导， 其允许PHD 2单独和与HIF-1或HIF-2同时的急性内皮特异性失活 诱导缺血性肾损伤后。目的3定义了糖酵解和线粒体 缺氧信号诱导的呼吸影响内皮炎症和血管生成反应。的 这项研究是创新的，因为我们研究了PHD 2/HIF通路在内皮细胞中的作用， 在阿基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 技术用于确定由PHD 2/HIF介导的代谢产物引起的内皮表型。 重新编程结论是，我们将获得关于内皮PHD 2/HIF 轴影响缺血后肾损伤的结果。

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.