Introduction: Insufficient tissue oxygen (O2) availability (hypoxia) is commonly seen in patients with cardiovascular diseases (CVD) ,chronic kidney diseases (CKD), respiratory diseases and certain cancers. Although erythrocyte is the only cell type responsible for delivering and sensoring O2, its function in pathological tissue hypoxia remains largely unknown.
Hypothesis: Erythrocyte A2B adenosine receptor (ADORA2B) plays a key protective role in Ang II-induced tissue damage by increasing 2,3-biphosphoglycerate(2, 3-BPG) and oxygen release to counteract tissue hypoxia.
Methods: We infused angiotensin II (Ang II, 140ng/kg/min) to mice with specific deletion of ADORA2B in erythrocytes (ADORA2Bf/f/EpoR-Cre+) for 14 days and measured the levels of 2,3-BPG,P50,p-AMPK in erythrocytes of mild and severe CKD patients.
Results: We found that 2,3-BPG, an erythrocyte-specific metabolite enhancing O2 delivery, was significantly induced in the erythrocytes of mice infused with Ang II. Mouse genetic studies demonstrated that Ang II induced local tissue accumulation of adenosine and that elevated adenosine-mediated erythrocyte ADORA2B activation was beneficial by inducing 2,3-BPG production, triggering O2 release to counteract tissue hypoxia, heart and kidney damage including proteinuria along with the mRNA levels of collagen I, fibronectin, prepro-ET-1 and endothelin receptor type A, which are known tissue damage associated genes. Mechanistically, we revealed that AMPK is an intracellular signaling molecular functioning downstream of ADORA2B underlying elevated 2,3-BPG production by inducing BPG mutase activity and protects tissue hypoxia, kidney dysfunction and renal fibrosis. Finally, we translated our mouse study to human and confirmed that the levels of 2,3-BPG, P50 and p-AMPK were elevated in erythrocytes of hypertensive CKD patients compared to healthy individuals and correlated to disease severity.
Conclusions: We demonstrate that erythrocyte ADORA2B-mediated AMPK activation plays a key protective role in Ang II-induced tissue damage by increasing 2, 3-BPG and oxygen release to counteract tissue hypoxia and immediately suggest novel therapies for hypertension and CKD.