肾脏纤维化病理机制及干预靶点研究是当前热点。预实验发现成蛋白2（FMN2）在CKD患者、小鼠肾脏以及细胞模型中均表达上调。敲低FMN2可增加细胞外基质生成，过表达FMN2则明显改善了UUO小鼠肾脏纤维化，同时下调了β-catenin及其靶基因表达。此外还发现FMN2可下调抑制β-catenin泛素化降解的Dvl2的表达，提示FMN2可能通过促进β-catenin泛素化降解来拮抗肾脏纤维化。生物信息学分析发现，FMN2启动子区域存在转录因子TCF21结合位点，过表达TCF21可上调FMN2表达。综上推测：在CKD，TCF21上调FMN2来促进β-catenin泛素化降解，拮抗纤维化；但代偿性的TCF21/FMN2上调不足以有效改善纤维化，通过外源性激活TCF21/FMN2可起到更有效的抗纤维化作用。本课题将从整体、细胞及分子层面阐明FMN2在肾脏纤维化中的作用及机制，为防治CKD提供新视角。

The pathogenesis of renal fibrosis and the target of intervention are the current hotspots. Our preliminary data demonstrated that the expression of Formin 2 (FMN2) was significantly upregulated in CKD patients and animal and cell models of renal fibrosis. Interestingly, knockdown of FMN2 in kidney cells significantly increased the extracellular matrix production, while overexpression of FMN2 improved renal fibrosis in UUO mice in line with the downregulated expression of β-catenin and its target genes. We also found that FMN2 can down-regulate the expression of Dvl2, which was known to inhibit the ubiquitination degradation of β-catenin, suggesting that FMN2 may play a role in antagonizing renal fibrosis by promoting β-catenin ubiquitination degradation. Furthermore, we explored the potential regulator of FMN2 via bioinformatics analysis and found the binding site of transcription factor TCF21 in the promoter region of FMN2. Overexpression of TCF21 in renal cells up-regulated FMN2 expression. Based on the above preliminary studies and reports, we speculate that TCF21 could drive FMN2 to promote β-catenin ubiquitination degradation and antagonize fibrosis in CKD. However, compensatory TCF21/FMN2 up-regulation is not sufficient to effectively improve fibrosis, and exogenous activation of TCF21/FMN2 can play a more effective anti-fibrosis effect. In this proposal, we will employ the human kidney samples and the models of animal, cell, and molecule to elucidate the role and mechanism of FMN2 in protecting against renal fibrosis, which will provide new insights into the prevention and treatment of CKD.