Abstract: FR-OR111

Erythrocyte Adenosine A2B Receptor (ADORA2B) Promotes Oxygen Release to Counteract Renal Tissue Damage

Session Information

Category: Cell Biology

  • 201 Cell Signaling, Oxidative Stress

Authors

  • Peng, Zhangzhe, Xiangya Hospital, Central South University, Changsha, China
  • Luo, Renna, The First Affiliated Hospital of Dalian Medical University, Dalian, China
  • Tao, Lijian, Xiangya hospital, Central South University, Changsha, China
  • Xia, Yang, Universith of Texas-Medical School, Houston, Texas, United States
Background

Hypoxia, defined as inadequate oxygen supply to the whole body or a region of the body, is commonly seen in patients with chronic kidney disease(CKD), and frequently promotes renal failure. As the only cell type responsible for delivering oxygen, erythrocytes quickly respond to hypoxia by increasing their oxygen delivery ability. However, there is an enormous gap in our understanding of the role of erythrocytes in renal tissue damage.

Methods

Non-biased metabolomics screening was conducted in the whole blood of Angiotensin II(Ang II) treated WT mice. Subsequently, we infused Ang II to mice with specific deletion of ADORA2B in erythrocytes (ADORA2Bf/f/EpoR-Cre+), and examined tissue hypoxia, damage, and erythrocyte function. Human studies were conducted on CKD patient samples.

Results

First, metabolomics profiling revealed that 2,3-BPG, an erythrocyte-specific metabolite regulating oxygen release, was highly elevated in the whole blood of Ang II treated mice. Erythrocyte-specific ADORA2B deficiency suppressed Ang II-induced 2,3-BPG production and 2,3-BPG mutase activity. After Ang II infusion, erythrocyte oxygen release ability (P50) was significantly elevated in EpoR-Cre+ mice but not in ADORA2Bf/f/EpoR-Cre+.Moreover, renal and cardiac hypoxia was more severe in ADORA2Bf/f/EpoR-Cre+ mice. Ang II also significantly increased proteinuria in ADORA2Bf/f/EpoR-Cre+ mice. In addition, both the protein and mRNA levels of HIF-1α in heart and kidney were further increased in kidneys and hearts of ADORA2Bf/f/EpoR-Cre+ mice infused with Ang II, together with the mRNA levels of collagen I, fibronectin, indicating significantly more severe tissue damages. Mechanistically, we revealed that AMPK is an intracellular signaling molecular which functions downstream of ADORA2B underlying elevated 2,3-BPG production by inducing BPG mutase activity. Subsequently, we translate our mouse study to human and confirmed that the levels of 2,3-BPG, P50 and p-AMPK were elevated in erythrocytes of mild CKD patients and further increased in severe CKD patients, indicating a compensation mechanism in response to hypoxia.

Conclusion

Our findings reveal a previously unrecognized beneficial role of erythrocyte ADORA2B signaling in Ang II-induced systemic hypoxia and renal tissue damage and thereby identify novel and important therapeutic possibilities for hypoxia-induced tissue damage.