Erythrocyte Metabolic Reprogramming by Sphingosine 1-Phosphate in Chronic Kidney Disease and Therapies
Erythrocyte Metabolic Reprogramming by Sphingosine 1-Phosphate in Chronic Kidney Disease and Therapies
复制标题
1-磷酸鞘氨醇在慢性肾脏疾病和治疗中的红细胞代谢重编程。
DOI：
10.1161/circresaha.119.316298
复制
发表时间：
2020-07-17
影响因子：
20.1
通讯作者：
Xia, Yang
中科院分区：
文献类型：
--
作者：
Xie, Tingting;Chen, Changhan;Xia, Yang
理由：缺氧促进肾脏损害和慢性肾脏疾病（CKD）的进展。红细胞是唯一供氧（O-2）输送的细胞类型。鞘氨醇1-磷酸（S1P）是一种在红细胞中高度富集的生物脂，最近被报道在高海拔条件下可诱导正常人增加O(2)的输送。然而，红细胞S1P在CKD中的作用尚不清楚。目的：探讨CKD中红细胞S1P的功能和代谢基础，探讨潜在的治疗方法。方法与结果：在高血压CKD灌注Ang II（血管紧张素II）的实验模型中，我们使用红细胞特异性SphK1（鞘氨酸激酶1，红细胞中唯一产生S1P的酶）敲除小鼠（eSphK1(-/-)），发现与对照组相比，灌注Ang II（-/-）的小鼠存在严重的肾性缺氧、高血压、蛋白尿和纤维化。非靶向代谢组学分析和体内U-(13)C(6)同位素标记的葡萄糖通量分析显示，SphK1是引导糖酵解与戊糖磷酸途径的葡萄糖代谢所必需的，导致Ang ii输注小鼠红细胞特异性Rapoport-Luebering分流增强。从机制上说，红细胞S1P功能的增加通过降低神经酰胺/S1P比率和抑制PP2A（蛋白磷酸酶2A）激活AMPK （amp活化蛋白激酶）1 α和BPGM（双磷酸甘油变化酶），导致2,3-双磷酸甘油（一种红细胞特异性代谢物，负调节Hb[血红蛋白]-O-2结合亲和力）的产生，从而增加O(2)的输送，以抵消肾脏缺氧和CKD的进展。临床前研究表明，AMPK激动剂或PP2A抑制剂挽救了angii输注desphk1（-/-）小鼠的严重CKD表型，并通过诱导2,3-双磷酸甘油生成从而增强肾脏氧合来阻止对照小鼠CKD的发展。转化研究证实了小鼠在高血压CKD患者红细胞和培养的人红细胞中的发现。结论：我们的研究阐明了eSphk1-S1P在高血压CKD中的有益作用，它通过PP2A-AMPK1 α信号通路引导葡萄糖代谢向Rapoport-Luebering分流，并诱导2,3-二磷酸甘油酸的产生和O(2)的传递。这些发现揭示了CKD中红细胞S1P的代谢和分子基础以及新的治疗途径。
Rationale: Hypoxia promotes renal damage and progression of chronic kidney disease (CKD). The erythrocyte is the only cell type for oxygen (O-2) delivery. Sphingosine 1-phosphate (S1P)-a highly enriched biolipid in erythrocytes-is recently reported to be induced under high altitude in normal humans to enhance O(2)delivery. However, nothing is known about erythrocyte S1P in CKD. Objective: To investigate the function and metabolic basis of erythrocyte S1P in CKD with a goal to explore potential therapeutics. Methods and Results: Using erythrocyte-specific SphK1 (sphingosine kinase 1; the only enzyme to produce S1P in erythrocytes) knockout mice (eSphK1(-/-)) in an experimental model of hypertensive CKD with Ang II (angiotensin II) infusion, we found severe renal hypoxia, hypertension, proteinuria, and fibrosis in Ang II-infusedeSphk1(-/-)mice compared with controls. Untargeted metabolomics profiling and in vivo U-(13)C(6)isotopically labeled glucose flux analysis revealed that SphK1 is required for channeling glucose metabolism toward glycolysis versus pentose phosphate pathway, resulting in enhanced erythroid-specific Rapoport-Luebering shunt in Ang II-infused mice. Mechanistically, increased erythrocyte S1P functioning intracellularly activates AMPK (AMP-activated protein kinase) 1 alpha and BPGM (bisphosphoglycerate mutase) by reducing ceramide/S1P ratio and inhibiting PP2A (protein phosphatase 2A), leading to increased 2,3-bisphosphoglycerate (an erythrocyte-specific metabolite negatively regulating Hb [hemoglobin]-O-2-binding affinity) production and thus more O(2)delivery to counteract kidney hypoxia and progression to CKD. Preclinical studies revealed that an AMPK agonist or a PP2A inhibitor rescued the severe CKD phenotype in Ang II-infusedeSphK1(-/-)mice and prevented development of CKD in the control mice by inducing 2,3-bisphosphoglycerate production and thus enhancing renal oxygenation. Translational research validated mouse findings in erythrocytes of hypertensive CKD patients and cultured human erythrocytes. Conclusions: Our study elucidates the beneficial role of eSphk1-S1P in hypertensive CKD by channeling glucose metabolism toward Rapoport-Luebering shunt and inducing 2,3-bisphosphoglycerate production and O(2)delivery via a PP2A-AMPK1 alpha signaling pathway. These findings reveal the metabolic and molecular basis of erythrocyte S1P in CKD and new therapeutic avenues.