Adenosine A2B Receptor Promotes Erythrocyte Oxygen Release to Counteract Tissue Hypoxia and Injury

Insufficient tissue oxygen (O₂) availability (hypoxia) is commonly seen in patients with cardiovascular diseases (CVD), chronic kidney diseases (CKD), respiratory diseases, hemolytic disorders and certain cancers. Without interference, pathological hypoxia is dangerous because it promotes disease progression, organ damage and failure. Although erythrocyte is the only cell type responsible for delivering O₂, its function in pathological tissue hypoxia remains largely unknown. Here using unbiased high throughput metabolomic profiling, we found that 2,3-biphosphoglycerate (2,3-BPG), an erythrocyte-specific metabolite enhancing O2 delivery, was significantly induced in the erythrocytes of mice infused with angiotensin II (Ang II), a potent vasopeptide commonly increased in the circulation of CVD and CKD patients to induce tissue hypoxia and injury via vasoconstriction. Mouse genetic studies demonstrated that Ang II induced local tissue accumulation of adenosine and that elevated adenosine-mediated erythrocyte A2B adenosine receptor (ADORA2B) activation was beneficial by inducing 2,3-BPG production, triggering O₂ release to prevent multiple tissue hypoxia, inflammation and kidney damage. Mechanistically, we revealed that AMPK is an intracellular signaling molecular functions downstream of ADORA2B underlying elevated 2,3-BPG production by inducing BPG mutase activity. Finally, we translated our mouse study to human and confirmed that the levels of 2,3-BPG and P50 were elevated in erythrocytes of mild CKD patients compared to healthy individuals and further increased in severe CKD patients compared to mild CKD patients. Taken together, we demonstrate that erythrocyte ADORA2B plays a key protective role in Ang II-induced tissue damage by increasing 2, 3-BPG and oxygen release to counteract tissue hypoxia.