腺苷A2B受体信号通路促肾纤维化机制：对巨噬细胞募集和极化的影响

申请人近年研究表明持续上调的腺苷通过腺苷A2B受体信号通路促进肾纤维化，但其作用机制并不十分清楚。巨噬细胞的募集和极化在肾纤维化中发挥了重要作用。本课题组新近研究发现腺苷A2B受体基因敲除可以减少肾脏巨噬细胞的浸润，生物信息学方法分析提示巨噬细胞募集和极化相关的细胞因子可能受腺苷A2B受体信号通路调控，据此我们提出“持续上调的腺苷可通过腺苷A2B受体信号通路影响巨噬细胞募集和极化促进肾纤维化”的假说。本项目拟采用单侧输尿管梗阻或血管紧张素II诱导的慢性肾纤维化小鼠模型，观察腺苷A2B受体激动剂/拮抗剂或腺苷A2B受体基因敲除对肾脏巨噬细胞募集和极化的影响，分析与巨噬细胞募集和极化相关因子的表达情况，最后从转录水平研究A2B受体信号通路对巨噬细胞募集和极化相关因子的调控机制，对于揭示腺苷A2B受体信号通路在肾纤维化中的作用具有重要意义。

Our previous studies demonstrated that persistent up-regulated adenosine promoted renal fibrosis through adenosine A2B receptor signaling. However, the mechanism is unclear. Macrophage recruitment and polarization play an important role in the development of renal fibrosis. We found adenosine A2B receptor deficiency can reduce renal macrophage infiltration, and bioinformatic analysis indicated some cytokines related to macrophage recruitment and polarization might be regulated by adenosine A2B receptor. Based on the findings, we hypothesized that adenosine A2B receptor signaling might promote renal fibrosis by affecting macrophage recruitment and polarization. Using Angiotensin II infused or unilateral ureteral obstructed mouse model, we plan to observe the effect of adenosine A2B receptor (agonist/antagonist or adenosine A2B receptor knockout) on macrophage recruitment and polarization, analysis the expression of cytokines related to macrophage recruitment and polarization, and finally elucidate the mechanism of adenosine A2B receptor signaling promoting renal fibrosis by affecting macrophage recruitment and polarization. Our study is of great significance on providing new sights to prevent renal fibrosis.