Summary of study ST001153

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000772. The data can be accessed directly via it's Project DOI: 10.21228/M8WH51 This work is supported by NIH grant, U2C- DK119886.

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Study IDST001153
Study TitleErythrocyte adenosine A2B receptor-mediated AMPK activation: Counteracting CKD by promoting oxygen delivery
Study SummaryBackground: Although the erythrocyte is the most abundant cell type in our body, acting as both a deliverer and sensor of oxygen (O2), its function and regulatory mechanism in chronic kidney disease (CKD) remain unknown. Methods: Unbiased metabolomics screening in the whole blood of mice infused with or without angiotensin II (Ang II) at 140ng/kg/min up to 14 days was conducted. Mice with specific ablation of ADORA2B in erythrocytes and patients with CKD were used to determine its function in CKD, potential mechanisms and human relevance. Results: Unbiased metabolomics revealed that 2,3-biphosphoglycerate (2,3-BPG), an erythrocyte-specific metabolite promoting O2 delivery, was significantly induced in an experimental model of CKD induced by Ang II. Mouse genetic studies revealed that erythrocyte ADORA2B signaling via AMPK-stimulated activation of BPG mutase was a key compensatory cellular response to counteract kidney hypoxia, tissue damage and disease progression in Ang II-induced CKD by promoting 2,3-BPG production and O2 delivery. Preclinical studies showed that enhancing AMPK activation offset kidney hypoxia by triggering 2,3-BPG production and O2 delivery. Human translational studies validated mouse findings that erythrocyte 2,3-BPG levels, AMPK activity and O2 delivery capacity were significantly induced in the erythrocytes of CKD patients compared to normal controls and their elevations were correlated to disease severity. Conclusion: Overall, we have provided both mouse and human evidence that ADORA2B-AMPK signaling cascade-induced 2,3-BPG production is a beneficial erythrocyte response to promote O2 delivery to counteract kidney hypoxia and progression of CKD. These findings pave a way to novel therapeutic avenues in CKD.
Institute
University of Texas Health Science Center at Houston
DepartmentMcGovern Medical School
Last NameXia
First NameYang
Address6431 Fannin, MSB 6.202,Houston, TX 77030
Emailyang.xia@uth.tmc.edu
Phone713-500-5039
Submit Date2019-02-18
Raw Data AvailableYes
Raw Data File Type(s).mzML
Analysis Type DetailMS
Release Date2019-07-17
Release Version1
Yang Xia Yang Xia
https://dx.doi.org/10.21228/M8WH51
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR000772
Project DOI:doi: 10.21228/M8WH51
Project Title:Role of erythrocyte ADORA2B in Chronic Kidney Disease (CKD)
Project Summary:we have provided both mouse and human evidence that ADORA2B-AMPK signaling cascade-induced 2,3-BPG production is a beneficial erythrocyte response to promote O2 delivery to counteract kidney hypoxia and progression of CKD. These findings pave a way to novel therapeutic avenues in CKD.
Institute:University of Texas Health Science Center at Houston
Department:McGovern Medical School
Last Name:Xia
First Name:Yang
Address:6431 Fannin, MSB 6.202,Houston, TX 77030
Email:yang.xia@uth.tmc.edu
Phone:713-500-5039

Subject:

Subject ID:SU001218
Subject Type:Mammal
Subject Species:Mus musculus
Taxonomy ID:10090

Factors:

Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Infused
SA080039A2Ang II
SA080040A3Ang II
SA080041A5Ang II
SA080042A1Ang II
SA080043A4Ang II
SA080044C6Saline
SA080045C2Saline
SA080046C3Saline
SA080047C4Saline
SA080048C5Saline
SA080049C1Saline
Showing results 1 to 11 of 11

Collection:

Collection ID:CO001212
Collection Summary:Approximately 1 mL mouse blood was collected with EDTA-contained tube and and stored at −80°C before further analysis.
Sample Type:Blood (whole)

Treatment:

Treatment ID:TR001233
Treatment Summary:WT mice were subcutaneously infused with Angiotensin II or saline by mini-pump.

Sample Preparation:

Sampleprep ID:SP001226
Sampleprep Summary:The sample preparation process was carried out using the automated MicroLab STAR® system from Hamilton Company. Recovery standards were added prior to the first step in the extraction process for QC purposes. Sample preparation was conducted using a proprietary series of organic and aqueous extractions to remove the protein fraction while allowing maximum recovery of small molecules. The resulting extract was divided into two fractions; one for analysis by LC and one for analysis by GC. Samples were placed briefly on a TurboVap® (Zymark) to remove the organic solvent. Each sample was then frozen and dried under vacuum. Samples were then prepared for the appropriate instrument, either LC/MS or GC/MS.

Combined analysis:

Analysis ID AN001903
Analysis type MS
Chromatography type GC
Chromatography system Thermo-finnegan DSQ
Column Restek 5% phenyl
MS Type EI
MS instrument type GC/MS
MS instrument name Thermo DSQ
Ion Mode UNSPECIFIED
Units AU

Chromatography:

Chromatography ID:CH001378
Chromatography Summary:The samples destined for GC/MS analysis were re-dried under vacuum desiccation for a minimum of 24 hours prior to being derivatized under dried nitrogen using bistrimethyl-silyl-triflouroacetamide (BSTFA). The GC column was 5% phenyl and the temperature ramp is from 40° to 300° C in a 16 minute period. Samples were analyzed on a Thermo-Finnigan Trace DSQ fast-scanning single-quadrupole mass spectrometer using electron impact ionization. The instrument was tuned and calibrated for mass resolution and mass accuracy on a daily basis. The information output from the raw data files was automatically extracted as discussed below.
Instrument Name:Thermo-finnegan DSQ
Column Name:Restek 5% phenyl
Chromatography Type:GC

MS:

MS ID:MS001759
Analysis ID:AN001903
Instrument Name:Thermo DSQ
Instrument Type:GC/MS
MS Type:EI
MS Comments:MS type: Single Quadrupole Ion Mode: Electron Impact Comments: Metabolon Proprietary software used for data analysis and compound annotation
Ion Mode:UNSPECIFIED
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