Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
Department of Geriatric Nephrology, First Affiliated Hospital to Nanjing Medical University, Nanjing, China.
Exp Mol Med. 2023 May;55(5):987-998. doi: 10.1038/s12276-023-00990-6. Epub 2023 May 1.
Myofibroblasts, characterized by the expression of the matricellular protein periostin (Postn), mediate the profibrogenic response during tissue repair and remodeling. Previous studies have demonstrated that systemic deficiency in myocardin-related transcription factor A (MRTF-A) attenuates renal fibrosis in mice. In the present study, we investigated the myofibroblast-specific role of MRTF-A in renal fibrosis and the underlying mechanism. We report that myofibroblast-specific deletion of MRTF-A, achieved through crossbreeding Mrtfa-flox mice with Postn-Cre mice, led to amelioration of renal fibrosis. RNA-seq identified zinc finger E-Box binding homeobox 1 (Zeb1) as a downstream target of MRTF-A in renal fibroblasts. MRTF-A interacts with TEA domain transcription factor 1 (TEAD1) to bind to the Zeb1 promoter and activate Zeb1 transcription. Zeb1 knockdown retarded the fibroblast-myofibroblast transition (FMyT) in vitro and dampened renal fibrosis in mice. Transcriptomic assays showed that Zeb1 might contribute to FMyT by repressing the transcription of interferon regulatory factor 9 (IRF9). IRF9 knockdown overcame the effect of Zeb1 depletion and promoted FMyT, whereas IRF9 overexpression antagonized TGF-β-induced FMyT. In conclusion, our data unveil a novel MRTF-A-Zeb1-IRF9 axis that can potentially contribute to fibroblast-myofibroblast transition and renal fibrosis. Screening for small-molecule compounds that target this axis may yield therapeutic options for the mollification of renal fibrosis.
肌成纤维细胞表达细胞外基质蛋白骨桥蛋白（Postn），在组织修复和重塑过程中介导致纤维化反应。先前的研究表明，心肌相关转录因子 A（MRTF-A）的系统性缺乏可减轻小鼠的肾脏纤维化。在本研究中，我们研究了 MRTF-A 在肾脏纤维化中的肌成纤维细胞特异性作用及其潜在机制。我们报告称，通过将 Mrtfa-flox 小鼠与 Postn-Cre 小鼠杂交实现肌成纤维细胞特异性 MRTF-A 缺失，可改善肾脏纤维化。RNA-seq 鉴定出锌指 E-Box 结合同源盒 1（Zeb1）是肾脏成纤维细胞中 MRTF-A 的下游靶标。MRTF-A 与 TEA 结构域转录因子 1（TEAD1）相互作用，结合 Zeb1 启动子并激活 Zeb1 转录。Zeb1 敲低可在体外延缓成纤维细胞-肌成纤维细胞转化（FMyT）并减轻小鼠肾脏纤维化。转录组学分析表明，Zeb1 可能通过抑制干扰素调节因子 9（IRF9）的转录来促进 FMyT。IRF9 敲低克服了 Zeb1 耗竭的影响并促进了 FMyT，而 IRF9 过表达拮抗 TGF-β诱导的 FMyT。总之，我们的数据揭示了一个新的 MRTF-A-Zeb1-IRF9 轴，它可能有助于成纤维细胞-肌成纤维细胞转化和肾脏纤维化。筛选针对该轴的小分子化合物可能为缓和肾脏纤维化提供治疗选择。
