bay-60-6583 and Ischemia

Acute renal failure from ischemia significantly contributes to morbidity and mortality in clinical settings, and strategies to improve renal resistance to ischemia are urgently needed. Here, we identified a novel pathway of renal protection from ischemia using ischemic preconditioning (IP).. For this purpose, we utilized a recently developed model of renal ischemia and IP via a hanging weight system that allows repeated and atraumatic occlusion of the renal artery in mice, followed by measurements of specific parameters or renal functions. Studies in gene-targeted mice for each individual adenosine receptor (AR) confirmed renal protection by IP in A1(-/-), A2A(-/-), or A3AR(-/-) mice. In contrast, protection from ischemia was abolished in A2BAR(-/-) mice. This protection was associated with corresponding changes in tissue inflammation and nitric oxide production. In accordance, the A2BAR-antagonist PSB1115 blocked renal protection by IP, while treatment with the selective A2BAR-agonist BAY 60-6583 dramatically improved renal function and histology following ischemia alone. Using an A2BAR-reporter model, we found exclusive expression of A2BARs within the reno-vasculature. Studies using A2BAR bone-marrow chimera conferred kidney protection selectively to renal A2BARs.. These results identify the A2BAR as a novel therapeutic target for providing potent protection from renal ischemia.

Topics: Adenosine; Adenosine A2 Receptor Antagonists; Aminopyridines; Animals; Blood Vessels; Cytoprotection; Extracellular Fluid; Female; Inflammation; Ischemia; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide; Receptor, Adenosine A2B; Signal Transduction; Xanthines