随着人口老龄化，衰老引发的肾脏损伤严重威胁人类健康。肾小管作为重要组成，其损伤机制尚不完全清楚。我们近期研究发现，m6A去甲基化酶ALKBH5在肾近端小管上皮细胞（HK2）衰老模型和衰老小鼠肾脏中的mRNA及蛋白表达均下调，且HK2细胞过表达ALKBH5后，显著缓解细胞老化并增加抗衰老蛋白Sirt1表达，暗示其可能去甲基化Sirt1的新生转录本增加其表达，激活抗氧化信号通路抑制HK2衰老。在此基础上，本课题：（1）利用体内外衰老模型，检测增减ALKBH5基因表达后衰老相关指标变化；（2）结合MeRIP-seq测序，通过双荧光素酶表达系统验证NRF2是否为ALKBH5的靶点及其他靶基因；（3）在衰老细胞模型中，敲除靶基因后观察ALKBH5生物学功能变化。本项目旨在阐明ALKBH5保护肾脏衰老导致的肾小管损伤的生物学机制，为防治衰老相关肾损伤提供新的靶点。

With the aging of population and the improvement of living standards, renal injury caused by aging has been a serious threat to human health. As one of the important components, the damages mechanism of renal tubules has not been fully clarified. Our recently study show that the expression of ALKBH5, a N6-Methyladenosine mRNA erasers is decreased in renal epithelial cells of renal proximal tubules (HK2) in both the aging model and the aging mice. Moreover, ALKBH5 overexpression in HK2 cells significantly alleviated cell senscence and increased the expression of anti-aging protein Sirt1. We explore the possibility that it can demethylations the nascent transcript of Sirt1 and inhibits the senescence of HK2 cells by activating the antioxidant response element signaling pathway. In this application, the applicant proposes: (1) To study the age-related changes by regulating the expression of ALKBH5 gene using a model of cell cultures and in vivo;(2)To detect whether ALKBH5 could drive Sirt1 expression using double luciferase reporter system combined with RNA sequencing (MeRIP-seq); (3) To investigate the biological function of ALKBH5 after knockout of target genes in the aging cell model. The aim of this project was to elucidation the biological function of ALKBH5 to protect the tubule damage caused by renal aging which providing a new target for the prevention and treatment of aging-related renal tubular injury.