Truong Luan D, Trostel Jessica, McMahan Rachel, Chen Jiang-Fan, Garcia Gabriela E
Department of Pathology, Baylor College of Medicine, Houston, Texas; Department of Pathology, Methodist Hospital, Houston, Texas.
Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, Colorado.
Am J Pathol. 2016 Oct;186(10):2601-13. doi: 10.1016/j.ajpath.2016.06.017. Epub 2016 Aug 9.
A2A adenosine 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.
A2A 腺苷受体（A2ARs）是炎症的内源性抑制剂。巨噬细胞是肾脏疾病进展的关键效应细胞，表达 A2ARs。我们在 A2AR 缺陷小鼠中，研究了 A2ARs 在巨噬细胞介导的抗肾小球基底膜反应性血清诱导的免疫性肾炎中的肾脏炎症作用。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 A2AR（-/-）小鼠中诱导了更严重、更持久的肾脏损伤，伴有更高水平的促炎细胞因子和更多的炎症细胞积聚。为了研究巨噬细胞 A2AR 在进行性肾损伤中的作用，在 CD11b-DTR 转基因小鼠中诱导肾小球肾炎。在疾病的既定阶段选择性清除巨噬细胞，并用来自 WT 或 A2AR 缺陷小鼠的巨噬细胞进行重建，然后用 A2AR 激动剂治疗。在接受 WT 巨噬细胞并接受 A2AR 激动剂治疗的小鼠中，与对照组相比，肾小球细胞数量、新月体形成、硬化性肾小球和肾小管间质损伤显著减少。相反，在用 A2AR 缺陷巨噬细胞重建并接受 A2AR 激动剂治疗的小鼠中，肾脏损伤更严重，I、III 和 IV 型胶原蛋白沉积增加。这些发现表明，保护性 A2AR 的破坏会放大炎症以加速肾小球损伤，内源性巨噬细胞 A2AR 对于预防进行性肾纤维化至关重要。
