Erythrocyte Adenosine A2B Receptor-Mediated AMPK Activation: A Missing Component Counteracting CKD by Promoting Oxygen Delivery
Erythrocyte Adenosine A2B Receptor-Mediated AMPK Activation: A Missing Component Counteracting CKD by Promoting Oxygen Delivery
复制标题
红细胞腺苷 A2B 受体介导的 AMPK 激活：通过促进氧输送对抗 CKD 的缺失成分
DOI：
10.1681/asn.2018080862
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发表时间：
2019-08-01
影响因子：
13.6
通讯作者：
Xia, Yang
中科院分区：
文献类型：
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作者：
Peng, Zhangzhe;Luo, Renna;Xia, Yang
背景 肾脏缺氧或缺氧会导致 CKD 并导致终末器官损伤。红细胞输送氧气 (O-2) 的作用受到缺氧的调节，但 CKD 的影响尚不清楚。方法我们筛选了以每分钟 140 ng/kg 输注血管紧张素 II (Ang II) 长达 14 天模拟 CKD 的小鼠全血中的所有代谢物，并将其代谢物与未治疗小鼠的代谢物进行比较。研究人员对红细胞上缺乏 ADORA2B 受体（可增加 O-2 输送）的小鼠和 CKD 患者进行了研究，以评估 ADORA2B 介导的 O-2 输送在 CKD 中的作用。结果非靶向代谢组学显示，在给予 Ang II 诱导 CKD 的小鼠中，2,3-二磷酸甘油酸 (2,3-BPG) 的产生增加，2,3-二磷酸甘油酸 (2,3-BPG) 是一种促进 O-2 输送的红细胞特异性代谢物。小鼠遗传学研究表明，红细胞 ADORA2B 信号传导导致 AMPK 刺激的 BPG 变位酶激活，促进 2,3-BPG 产生和 O-2 输送，以抵消 Ang II 诱导的 CKD 中的肾脏缺氧、组织损伤和疾病进展。增强小鼠 AMPK 激活可通过触发 2,3-BPG 产生和 O-2 输送来抵消肾脏缺氧。与对照组相比，CKD 患者的红细胞中 2,3-BPG 水平、AMPK 活性和 O-2 输送量较高。变化与疾病严重程度成正比，表明具有保护作用。 结论 小鼠和人类证据表明，ADORA2B-AMPK 信号级联诱导的 2,3-BPG 产生可促进红细胞输送 O-2，从而抵消肾脏缺氧和 CKD 的进展。这些发现为针对该途径的 CKD 治疗新途径铺平了道路。
Background Oxygen deprivation or hypoxia in the kidney drives CKD and contributes to end organ damage. The erythrocyte's role in delivery of oxygen (O-2) is regulated by hypoxia, but the effects of CKD are unknown.Methods We screened all of the metabolites in the whole blood of mice infused with angiotensin II (Ang II) at 140 ng/kg per minute up to 14 days to simulate CKD and compared their metabolites with those from untreated mice. Mice lacking a receptor on their erythrocytes called ADORA2B, which increases O-2 delivery, and patients with CKD were studied to assess the role of ADORA2B-mediated O-2 delivery in CKD.Results Untargeted metabolomics showed increased production of 2,3-biphosphoglycerate (2,3-BPG), an erythrocyte-specific metabolite promoting O-2 delivery, in mice given Ang II to induce CKD. Genetic studies in mice revealed that erythrocyte ADORA2B signaling leads to AMPK-stimulated activation of BPG mutase, promoting 2,3-BPG production and O-2 delivery to counteract kidney hypoxia, tissue damage, and disease progression in Ang II-induced CKD. Enhancing AMPK activation in mice offset kidney hypoxia by triggering 2,3-BPG production and O-2 delivery. Patients with CKD had higher 2,3-BPG levels, AMPK activity, and O-2 delivery in their erythrocytes compared with controls. Changes were proportional to disease severity, suggesting a protective effect.Conclusions Mouse and human evidence reveals that ADORA2B-AMPK signaling cascade-induced 2,3-BPG production promotes O-2 delivery by erythrocytes to counteract kidney hypoxia and progression of CKD. These findings pave a way to novel therapeutic avenues in CKD targeting this pathway.