Inhibition of Endothelial PHD2 Suppresses Post-Ischemic Kidney Inflammation through Hypoxia-Inducible Factor-1
Inhibition of Endothelial PHD2 Suppresses Post-Ischemic Kidney Inflammation through Hypoxia-Inducible Factor-1
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DOI：
10.1681/asn.2019050523
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发表时间：
2020-03-01
影响因子：
13.6
通讯作者：
Kapitsinou, Pinelopi P.
中科院分区：
文献类型：
--
作者：
Rajendran, Ganeshkumar;Schonfeld, Michael P.;Kapitsinou, Pinelopi P.
背景含脯氨酰-4-羟化酶结构域的蛋白质1-3（PH D1至PH D3）调节缺氧诱导因子（HIF）HIF-1和HIF-2的活性，HIF-1和HIF-2是缺氧血管反应的关键调节因子。我们以前报道过内皮细胞HIF-2的缺乏会加重肾缺血再灌注损伤，而内皮细胞PHD 2（主要的氧传感器）的失活会提供肾保护作用。然而，内皮PHD 2决定阿基outcomes的分子机制仍然undefined.Methods研究内皮PHD 2/HIF轴在缺血性阿基的功能，我们研究了内皮特异性消融PHD 2在肾缺血再灌注损伤小鼠模型中的作用。我们还研究了PHD 2和HIF-1或PHD 2和HIF-2同时缺失时每种HIF亚型的作用。结果PHD 2的内皮缺失保留了肾功能并限制了向CKD的转变。从机制上讲，我们发现内皮Phd 2消融通过抑制促炎基因的表达和炎症细胞的募集来保护肾缺血再灌注损伤，其方式依赖于HIF-1而不是HIF-2。在成年小鼠中，急性诱导的内皮特异性PHD 2丢失后肾保护反应的持续性排除了造血细胞中PHD 2信号传导的需要。虽然Phd 2抑制是不足以诱导可检测的HIF活性在肾内皮细胞，在体外实验中牵连的体液因子产生的抗炎作用的内皮PHD 2/HIF-1 signaling.Conclusions我们的研究结果表明，激活内皮细胞HIF-1信号通过PHD 2抑制可能提供一种新的治疗方法对缺血性阿基。
Background Prolyl-4-hydroxylase domain-containing proteins 1-3 (PH D1 to PHD3) regulate the activity of the hypoxia-inducible factors (HIFs)HIF-1 and HIF-2, transcription factors that are key regulators of hypoxicvascular 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.