急性肾损伤（AKI）后纤维化的发生发展是肾脏预后不良的根本原因。我们最新的研究发现，肾小管上皮细胞在AKI时发生细胞增殖周期G2/M阻滞从而导致纤维化，而ATM激酶通路的活化是肾小管上皮G2/M 阻滞的主要原因，但是其调控和作用机制尚未阐明。有研究显示，ATM通路可介导氧化应激等诱发的细胞早衰，后者在器官慢性纤维化中具重要意义。本课题拟在体外培养的近端肾小管上皮细胞以及AKI小鼠模型中证实：ATM通路在诱导肾小管上皮细胞G2/M阻滞后进一步诱导细胞早衰；早衰的上皮细胞通过促炎症和促纤维化的旁分泌效应导致AKI后纤维化的持续进展。本研究还将深入探讨ATM通路诱导细胞早衰以及促进炎症和纤维化的相关细胞分子生物学机制，并且阐明ATM激酶活化的原因和调控机制。在研究结果基础上将选择不同环节的作用分子在AKI模型中进行干预研究。本课题将为阐明AKI后纤维化进程的发病机制提供新的理论依据和研究方向。

Our study has shown that epithelial cell cycle arrest in G2/M mediates kidney fibrosis after acute kidney injury (AKI). The activation of ATM kinase pathway has been confirmed to be the trigger of epithelial G2/M arrest in AKI. However, the exact mechanism of how ATM pathway is regulated and how it is involved in the continuous progression of fibrosis has not been fully elucidated. The main purpose of this study is to confirm the hypothesis: ATM pathway, activated after AKI, maintains a premature senescent status of the G2/M arrested epithelial cells, which thus contributes to the progression of fibrosis through a proinflammatory and profibrotic paracrine profile. In this study, we are going to take advantage of various AKI mice models and proximal tubular cells cultured in vitro. We will investigate the possible factors that are responsible for the activation of ATM pathway. Premature senescence will be examined both in vivo and in vitro and the paracrine profile will be tested through Luminex assay. Related signaling pathways will be investigated. We will also develop interventional studies based on the results. This study will establish the important mechanism of tubular cells "fibrotic repair" after AKI and provide possible targets for the further therapeutic studies.