Macrophage A2A Adenosine Receptors Are Essential to Protect from Progressive Kidney Injury.
Macrophage A2A Adenosine Receptors Are Essential to Protect from Progressive Kidney Injury.
复制标题
DOI：
10.1016/j.ajpath.2016.06.017
复制
发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
L. Truong;Jessica Trostel;Rachel H. McMahan;Jiang-fan Chen;G. Garcia
中科院分区：
文献类型：
--
作者：
L. Truong;Jessica Trostel;Rachel H. McMahan;Jiang-fan Chen;G. Garcia
A2 A腺苷受体（A2 A adenosine receptor，A2 AR）是内源性炎症抑制剂。作为肾脏疾病进展的关键效应物的巨噬细胞表达A2 AR。我们研究了A2 AR在巨噬细胞介导的抗肾小球基底膜反应性血清诱导的A2 AR缺陷小鼠免疫性肾炎中的肾脏炎症中的作用。与野生型（WT）小鼠相比，亚阈值剂量的肾小球基底膜反应性血清在A2 AR −/−小鼠中诱导了更严重和更长时间的肾损伤，促炎细胞因子水平更高，炎性细胞积累更多。为了研究巨噬细胞A2 AR在进行性肾损伤中的作用，在CD 11b-DTR转基因小鼠中诱导肾小球肾炎。巨噬细胞在疾病的建立阶段被选择性耗尽，并用来自WT或A2 AR缺陷小鼠的巨噬细胞重建，然后用A2 AR激动剂处理。在接受WT巨噬细胞并用A2 AR激动剂处理的小鼠中，与对照组相比，肾小球细胞构成、新月体形成、肾小球硬化和肾小管间质损伤显著减少。相反，在用A2 AR缺陷型巨噬细胞重建并用A2 AR激动剂治疗的小鼠中，肾损伤更严重，胶原蛋白I、III和IV沉积增加。这些研究结果表明，破坏保护性A2 AR放大炎症，加速肾小球损伤，内源性巨噬细胞A2 AR对防止进行性肾纤维化至关重要。
A2Aadenosine receptors (A2ARs) are endogenous inhibitor of inflammation. Macrophages that are key effectors of kidney disease progression express A2ARs. We investigated the role of A2ARs in kidney inflammation in a macrophage-mediated anti–glomerular basement membrane reactive serum-induced immune nephritis in A2AR-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 A2AR−/−mice than wild-type (WT) mice. To investigate the role of macrophage A2AR 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 A2AR-deficient mice and then treated with an A2AR agonist. In mice receiving WT macrophages and treated with an A2AR 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 A2AR-deficient macrophages and treated with an A2AR agonist, the kidney injury was more severe with increased deposition of collagen I, III, and IV. These findings suggest that disruption of the protective A2AR amplifies inflammation to accelerate glomerular damage and endogenous macrophage A2ARs are essential to protect from progressive kidney fibrosis.