PDF(Pubmed)
Abstract：
Induction of the adenosine receptor A2B (A2BAR) expression in diabetic glomeruli correlates with an increased abundance of its endogenous ligand adenosine and the progression of kidney dysfunction. Remarkably, A2BAR antagonism protects from proteinuria in experimental diabetic nephropathy. We found that A2BAR antagonism preserves the arrangement of podocytes on the glomerular filtration barrier, reduces diabetes-induced focal adhesion kinase (FAK) activation, and attenuates podocyte foot processes effacement. In spreading assays using human podocytes in vitro, adenosine enhanced the rate of cell body expansion on laminin-coated glass and promoted peripheral pY397-FAK subcellular distribution, while selective A2BAR antagonism impeded these effects and attenuated the migratory capability of podocytes. Increased phosphorylation of the Myosin2A light chain accompanied the effects of adenosine. Furthermore, when the A2BAR was stimulated, the cells expanded more broadly and more staining of pS19 myosin was detected which co-localized with actin cables, suggesting increased contractility potential in cells planted onto a matrix with a stiffness similar to of the glomerular basement membrane. We conclude that A2BAR is involved in adhesion dynamics and contractile actin bundle formation, leading to podocyte foot processes effacement. The antagonism of this receptor may be an alternative to the intervention of glomerular barrier deterioration and proteinuria in the diabetic kidney disease.
摘要：
糖尿病性肾小球中腺苷受体A2B(A2BAR)表达的诱导与其内源性配体腺苷的丰度增加和肾功能障碍的进展相关。值得注意的是,A2BAR拮抗作用可防止实验性糖尿病肾病中的蛋白尿。我们发现A2BAR拮抗作用保留了肾小球滤过屏障上足细胞的排列，减少糖尿病诱导的粘着斑激酶（FAK）激活，并减轻足细胞足突的消失。在体外使用人足细胞的传播试验中，腺苷提高细胞体在层粘连蛋白包被的玻璃上的扩增速率，并促进外周pY397-FAK亚细胞分布，而选择性A2BAR拮抗作用阻碍了这些作用并减弱了足细胞的迁移能力。Myosin2A轻链的磷酸化增加伴随着腺苷的作用。此外，当A2BAR被刺激时，细胞扩增更广泛，检测到pS19肌球蛋白的染色与肌动蛋白电缆共定位，表明种植在硬度类似于肾小球基底膜的基质上的细胞的收缩潜能增加。我们得出结论，A2BAR参与粘附动力学和收缩肌动蛋白束的形成，导致足细胞足突消失。该受体的拮抗作用可能是干预糖尿病肾病中肾小球屏障恶化和蛋白尿的替代方法。
