BACKGROUND Prolyl-4-hydroxylase domain-containing proteins 1-3 (PHD1 to PHD3) regulate the activity of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2, transcription factors that are key regulators of hypoxic vascular responses. We previously reported that deficiency of endothelial HIF-2 exacerbated renal ischemia-reperfusion injury, whereas inactivation of endothelial PHD2, the main oxygen sensor, provided renoprotection. Nevertheless, the molecular mechanisms by which endothelial PHD2 dictates AKI outcomes remain undefined. METHODS To investigate the function of the endothelial PHD2/HIF axis in ischemic AKI, we examined the effects of endothelial-specific ablation of PHD2 in a mouse model of renal ischemia-reperfusion injury. We also interrogated the contribution of each HIF isoform by concurrent endothelial deletion of both PHD2 and HIF-1 or both PHD2 and HIF-2. RESULTS Endothelial deletion of Phd2 preserved kidney function and limited transition to CKD. Mechanistically, we found that endothelial Phd2 ablation protected against renal ischemia-reperfusion injury by suppressing the expression of proinflammatory genes and recruitment of inflammatory cells in a manner that was dependent on HIF-1 but not HIF-2. Persistence of renoprotective responses after acute inducible endothelial-specific loss of Phd2 in adult mice ruled out a requirement for PHD2 signaling in hematopoietic cells. Although Phd2 inhibition was not sufficient to induce detectable HIF activity in the kidney endothelium, in vitro experiments implicated a humoral factor in the anti-inflammatory effects generated by endothelial PHD2/HIF-1 signaling. CONCLUSIONS Our findings suggest that activation of endothelial HIF-1 signaling through PHD2 inhibition may offer a novel therapeutic approach against ischemic AKI.

中文翻译：

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抑制内皮PHD2通过缺氧诱导因子1抑制缺血性肾脏炎症。

背景技术含有脯氨酰4-羟化酶结构域的蛋白1-3（PHD1至PHD3）调节缺氧诱导因子（HIF）HIF-1和HIF-2的活性，所述缺氧诱导因子是缺氧血管反应的关键调节因子。我们先前曾报道过，内皮细胞HIF-2的缺乏加剧了肾脏缺血-再灌注损伤，而失活的主要氧气传感器内皮细胞PHD2提供了肾脏保护。然而，内皮PHD2决定AKI结局的分子机制仍然不确定。方法为了研究内皮PHD2 / HIF轴在缺血性AKI中的作用，我们研究了在肾脏缺血再灌注损伤小鼠模型中内皮特异性PHD2消融的作用。我们还询问了同时存在的PHD2和HIF-1或PHD2和HIF-2的内皮细胞缺失对每种HIF同工型的贡献。结果Phd2的内皮细胞缺失保留了肾功能，并且向CKD的过渡受限。从机理上讲，我们发现内皮Phd2消融通过抑制促炎基因的表达和炎症细胞的募集而依赖于HIF-1而不是HIF-2，从而防止肾脏缺血再灌注损伤。在成年小鼠中急性诱导性内皮特异性Phd2丧失后，肾脏保护反应的持续存在排除了造血细胞中PHD2信号转导的需求。尽管Phd2抑制作用不足以在肾内皮中诱导可检测的HIF活性，体外实验涉及体液因子参与由内皮PHD2 / HIF-1信号传导产生的抗炎作用。结论我们的发现表明通过抑制PHD2激活内皮HIF-1信号传导可能提供一种针对缺血性AKI的新型治疗方法。