PUBLICATION

Zhang, Y. et al. Detrimental effects of adenosine signaling in sickle cell disease. Nat Med 17, 79–86 (2011).

Hypoxia can act as an initial trigger to induce erythrocyte sickling and eventual end organ damage in sickle cell disease (SCD). Many factors and metabolites are altered in response to hypoxia and may contribute to the pathogenesis of the disease. Using metabolomic profiling, we found that the steady-state concentration of adenosine in the blood was elevated in a transgenic mouse model of SCD. Adenosine concentrations were similarly elevated in the blood of humans with SCD. Increased adenosine levels promoted sickling, hemolysis and damage to multiple tissues in SCD transgenic mice and promoted sickling of human erythrocytes. Using biochemical, genetic and pharmacological approaches, we showed that adenosine A(2B) receptor (A(2B)R)-mediated induction of 2,3-diphosphoglycerate, an erythrocyte-specific metabolite that decreases the oxygen binding affinity of hemoglobin, underlies the induction of erythrocyte sickling by excess adenosine both in cultured human red blood cells and in SCD transgenic mice. Thus, excessive adenosine signaling through the A(2B)R has a pathological role in SCD. These findings may provide new therapeutic possibilities for this disease.

Keywords: Adenosine, Adenosine Deaminase, Anemia, Sickle Cell, Animals, Hemolysis, Humans, Kidney, Liver, Lung, Mice, Knockout, Transgenic, Receptor, Adenosine A2B, Signal Transduction, Spleen, Xanthines

    Metabolon PUBLICATION

    Contact Us

    Talk with an expert

    Request a quote for our services or more information on sample types and handling procedures, need a letter of support, or simply have questions about how metabolomics can advance your research.

    Corporate Headquarters

    617 Davis Drive, Suite 100
    Morrisville, NC 27560

    Mailing Address:
    P.O. Box 110407
    Research Triangle Park, NC 27709

    +1 (919) 572-1711

    +1 (919) 572-1721

    International Headquarters

    Metabolon GmbH

    Zeppelinstraße 3
    85399 Hallbergmoos
    Germany

    +49 89 99017752