Molecular insight of erythrocyte hypoxic metabolic reprogramming in chronic kidney disease

慢性肾病红细胞缺氧代谢重编程的分子洞察

基本信息

批准号：
9368074
负责人：
Yang Xia
金额：
$ 39.02万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9368074
关键词：
AMP-activated protein kinase kinase Ablation Address Adenosine Adenosine A2B Receptor Affinity Altitude Angiotensin II Angiotensins Binding Body Regions Chronic Chronic Kidney Failure Coupled Dangerousness Disease Disease Progression Disease model End stage renal failure Erythrocytes Experimental Models FDA approved Fibrosis Genetic Genetic study Glucose Goals Hemoglobin Human Hypoxia Individual Inflammation Infusion procedures Injury Innovative Therapy Isotope Labeling Kidney Kidney Diseases Knock-out Knowledge Mediating Medical Metabolic Modeling Molecular Morbidity - disease rate Mus Organ Transplantation Oxygen Pathogenesis Pathogenicity Pathologic Patients Pharmaceutical Preparations Physiological Plasma Play Production Proteomics Publishing RNA Renal Tissue Renal dialysis Research Role SPHK1 enzyme Severity of illness Signal Pathway Signal Transduction Techniques Testing Therapeutic Therapeutic Effect Tissues Translating United States Urethral Obstruction Vasoconstrictor Agents Work base cell type deep sequencing effective therapy epithelial to mesenchymal transition follow-up hypoxia inducible factor 1 innovation insight metabolomics mortality multidisciplinary novel novel strategies novel therapeutics preclinical study prevent protein activation renal hypoxia respiratory screening sensor sphingosine 1-phosphate sphingosine kinase therapeutic development therapeutic evaluation therapy design tool

项目摘要

Although hypoxia drives chronic kidney disease (CKD) and promotes end stage renal disease, the mechanisms underlying the pathogenesis of renal hypoxia and disease progression are poorly understood. Thus, the goal of proposed research is to identify distinct signals and networks underlying renal hypoxia and establish novel approaches to increase kidney oxygenation and prevent disease progression. The erythrocyte is the most abundant cell type in our body, acting as both a deliverer and sensor of oxygen (O2). However, their role in increasing renal oxygenation to slow disease progression in CKD remain unknown. The proposed research builds on our unbiased high throughput metabolomics screening and mouse genetic studies showing that plasma adenosine and erythrocyte sphingosine 1-phosphate (S1P) are elevated in humans ascending to high altitude and that these two metabolites work together to induce 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte specific allosteric modulator that decreases hemoglobin-O2 binding affinity, and thus increases O2 delivery to counteract hypoxic tissue damage in mice. Significantly, increased erythrocyte 2,3-BPG and the O2 delivery are also observed in CKD patients and associated with disease severity. Follow-up mouse genetic studies demonstrated that activation of the erythrocyte A2B adenosine receptor (ADORA2B) induces 2,3-BPG production and enhances O2 delivery that has a general protective role to counteract renal hypoxia, damage and disease progression in two independent experimental models of CKD. Mechanistically, we discovered that AMPK, a cellular master energy sensor, functions downstream of ADORA2B underlying adenosine induced-2,3-BPG production and O2 delivery. Moreover, we revealed that elevated sphingosine kinase I (SphK1) also functions downstream of ADORA2B contributing to hypoxia-induced S1P production and that increased intracellular S1P directly binds Hb and promotes erythrocyte hypoxic metabolic reprogramming to induce 2,3-BPG production and O2 delivery and thus counteract renal hypoxia. Overall, our recent findings support the intriguing hypotheses that erythrocyte hypoxic metabolic reprogramming mediated by adenosine-ADORA2B-AMPK and SphK1-S1P signaling networks has a beneficial role to lower renal hypoxia and slow disease progression by inducing 2,3- BPG production and O2 delivery. To test these hypotheses, AIM I and II include multiple novel genetic tools coupled with multidisciplinary unbiased, robust and state of art techniques including proteomic, metabolomics, RNA deep sequencing and isotopically labelled glucose flux to determine how ADORA2B-AMPK and S1P- mediated erythrocyte hypoxic metabolic reprogramming protects renal hypoxia and disease progression in CKD. In AIM III, we will conduct preclinical studies to test the therapeutic effects of multiple FDA approved drugs to enhance our newly identified erythrocyte signaling pathways in CKD. Overall, the proposed research has interrelated goals to translate our findings into innovative therapeutics for CKD by providing new molecular insight into “erythrocyte metabolic hypoxia reprogramming” in CKD and disease progression.

尽管缺氧会导致慢性肾病 (CKD) 并促进终末期肾病，但其机制肾脏缺氧和疾病进展的发病机制尚不清楚。拟议的研究旨在识别肾缺氧背后的不同信号和网络，并建立新的增加肾脏氧合和防止疾病进展的方法中红细胞最多。我们体内有丰富的细胞类型，它们既充当氧气 (O2) 的传递者又充当传感器。增加肾氧合以减缓 CKD 疾病进展仍不清楚。建立在我们公正的高通量代谢组学筛选和小鼠遗传学研究的基础上，表明血浆登上高海拔地区的人体内腺苷和红细胞鞘氨醇 1-磷酸 (S1P) 会升高这两种代谢物共同作用诱导 2,3-二磷酸甘油酸 (2,3-BPG)，一种红细胞特异性变构调节剂，可降低血红蛋白-O2 结合亲和力，从而增加 O2 输送至显着地抵消小鼠缺氧组织损伤，增加红细胞 2,3-BPG 和 O2 输送。在 CKD 患者中也观察到并与疾病严重程度相关。证明红细胞 A2B 腺苷受体 (ADORA2B) 的激活可诱导 2,3-BPG 产生并增强 O2 输送，具有对抗肾脏缺氧、损伤和疾病的一般保护作用在两个独立的 CKD 实验模型中，我们发现 AMPK 的进展。细胞主能量传感器，在腺苷诱导的 ADORA2B 下游发挥作用 - 2,3-BPG 此外，我们发现升高的鞘氨醇激酶 I (SphK1) 也发挥作用。 ADORA2B 下游有助于缺氧诱导 S1P 的产生并增加细胞内 S1P 直接结合 Hb 并促进红细胞缺氧代谢重编程，诱导 2,3-BPG 产生总体而言，我们最近的研究结果支持了有趣的假设。腺苷-ADORA2B-AMPK和SphK1-S1P介导的红细胞缺氧代谢重编程信号网络通过诱导 2,3- 减少肾脏缺氧并减缓疾病进展。为了检验这些假设，AIM I 和 II 包括多种新颖的遗传工具。加上多学科公正、稳健和最先进的技术，包括蛋白质组学、代谢组学、 RNA 深度测序和同位素标记的葡萄糖通量以确定 ADORA2B-AMPK 和 S1P- 介导的红细胞缺氧代谢重编程可保护 CKD 中的肾缺氧和疾病进展。在AIM III中，我们将进行临床前研究，测试多种FDA批准药物的治疗效果，以增强我们新发现的 CKD 中的红细胞信号通路。通过提供新的分子，将我们的发现转化为 CKD 的创新疗法深入了解 CKD 和疾病进展中的“红细胞代谢缺氧重编程”。