Elimination of Senescent Macrophages by Purinergic Receptor P2RX7 Antagonist to Safeguard Against Kidney Injury and Aging.

Macrophage senescence is a pathological feature in aging or diseased kidneys. However, the role of senescent macrophages in kidney injury and aging has not been fully elucidated yet. We integrated the analysis of single-cell RNA sequencing datasets and the adoptively transfusion of pretreated bone marrow-derived macrophages to investigate the role of renal macrophage senescence in kidney injury. Here, we portrayed the senescence trajectory along multiple time points in infiltrating macrophages, and observed the persistent increase of macrophage-expressed purinergic receptor P2RX7 along the senescence trajectory in injured kidneys of septic mice. Importantly, our discovered small-molecule P2RX7 antagonist strikingly improved kidney function and pathological damage, as well as mitigated macrophage senescence in septic and aging mice. Mechanistically, P2RX7 antagonist could promote the wound healing, migration and proliferation capacity of senescent reparative macrophages, thus exerting anti-inflammatory effects and repairing kidney tissues. Together, our findings illustrate the crucial participation of senescent macrophages in septic kidney injury, and offer novel therapeutic strategy via intervening P2RX7 against immunosenescence-associated kidney injury and aging.