Macrophage A_2A Adenosine Receptors Are Essential to Protect from Progressive Kidney Injury

A_2A adenosine receptors (A_2ARs) are endogenous inhibitor of inflammation. Macrophages that are key effectors of kidney disease progression express A_2ARs. We investigated the role of A_2ARs in kidney inflammation in a macrophage-mediated anti–glomerular basement membrane reactive serum-induced immune nephritis in A_2AR-deficient mice. Sub-threshold doses of glomerular basement membrane–reactive serum induced more severe and prolonged kidney damage with higher levels of proinflammatory cytokines and greater accumulation of inflammatory cells in A_2AR^−/− mice than wild-type (WT) mice. To investigate the role of macrophage A_2AR in progressive kidney injury, glomerulonephritis was induced in CD11b-DTR transgenic mice. Macrophages were selectively depleted in the established phase of the disease and reconstituted with macrophages from WT or A_2AR-deficient mice and then treated with an A_2AR agonist. In mice receiving WT macrophages and treated with an A_2AR agonist, the glomerular cellularity, crescent formation, sclerotic glomeruli, and tubulointerstitial injury were significantly reduced compared with the control group. In contrast, in mice reconstituted with A_2AR-deficient macrophages and treated with an A_2AR agonist, the kidney injury was more severe with increased deposition of collagen I, III, and IV. These findings suggest that disruption of the protective A_2AR amplifies inflammation to accelerate glomerular damage and endogenous macrophage A_2ARs are essential to protect from progressive kidney fibrosis.