Macrophage A(2A) Adenosine Receptors Are Essential to Protect from Progressive Kidney Injury

摘要

A(2A) adenosine receptors (A(2A)Rs) are endogenous inhibitor of inflammation. Macrophages that are key effectors of kidney disease progression express A(2A)Rs. We investigated the role of A(2A)Rs in kidney inflammation in a macrophage-mediated anti glomerular basement membrane reactive serum-induced immune nephritis in A(2A)R-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(2A)R(-/-) mice than wild-type (WT) mice. To investigate the role of macrophage A(2A)R 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(2A)R-deficient mice and then treated with an A(2A)R agonist. In mice receiving WT macrophages and treated with an A(2A)R 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(2A)R-deficient macrophages and treated with an A(2A)R 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(2A)R amplifies inflammation to accelerate glomerular damage and endogenous macrophage A(2A)Rs are essential to protect from progressive kidney fibrosis.