ENT1-AMPD3 As an Imperative Erythrocyte Hypoxia Sensor and Metabolic Regulator Combats Tissue Hypoxia and Fibrosis

As the only cells that carry and deliver oxygen (O₂), erythrocytes play a vital role in maintaining the normal energy metabolism, function, and survival of every cell and organ within our body. Erythrocytes senses and acts rapidly to hypoxia by promoting metabolic reprogramming and O₂ delivery. However, the erythroid specific hypoxic sensor and its metabolic role in tissue hypoxia and fibrosis remain poorly understood. Here we report that erythrocyte enriched equilibrative nucleotide transporter 1 (eENT1)-mediated rapid uptake of extracellular adenosine coordinating with the inhibition of erythrocyte specific AMPD3 (eAMPD3) is an imperative "erythrocyte hypoxia sensory machinery" boosting intracellular AMP and promoting AMP kinase (AMPK)-dependent metabolic reprogramming by inducing bisphosphoglycerate mutase (BPGM), which wires glucose metabolism toward specific erythroid glycolytic-Rapoport-Leubering Shunt (RSL) to trigger 2,3-BPG production, O₂ delivery and anti-ROS capacity to mitigate renal hypoxia and progression in both patients and mice. Mechanistically, we revealed that hypoxia directly inhibits eAMPD3, leading to activation of eAMPK by lowering ROS in both cultured primary human and murine erythrocytes. Altogether, eENT1-eAMPD3 are previously unrecognized master intracellular purinergic components sensing hypoxia and promoting adaptative metabolic reprogramming to mitigate renal hypoxia, insufficient energy, kidney damage and progression by enhancing O₂ delivery and antioxidative stress capacity in a positive feedforward manner.

No relevant conflicts of interest to declare.