C/EBPδ Contributes to Myofibroblast Transdifferentiation and Renal Disease Progression

肌成纤维细胞通过产生多种炎性细胞因子和细胞外基质，在肺、肝、肾等多种器官的病理过程中发挥重要作用。然而，从原始细胞向肌成纤维细胞转分化的机制仍不清楚。平滑肌α-肌动蛋白的表达是肌成纤维细胞最具特征的特征，我们推测任何促进平滑肌α-肌动蛋白表达的因素都可能是肌成纤维细胞向肌成纤维细胞转化和疾病恶化的关键。经鉴定，转录因子C/EBPd可与含有α-肌动蛋白内含子1的Carg基序的序列结合并增强该启动子的转录活性。在系膜增生性肾小球肾炎模型大鼠抗Thy1肾炎和小鼠兔毒肾小球肾炎模型中，α-肌动蛋白和C/EBPd的表达明显上调。在后一种模型中，与野生型小鼠相比，C/EBPd基因敲除小鼠在第8天肾小球区的平滑肌α-肌动蛋白表达显著减少，第14天也有类似的下降，肾功能恶化程度也较轻。这些数据提示C/EBPd在肌成纤维细胞转分化和肾小球肾炎加重中起重要作用。

Myofibroblast is regarded to play pivotal roles in pathological process of a wide variety of organs such as lung, liver and kidney, by producing several inflammatory cytokines and extracellular matrices. However, the mechanisms by which transdifferentiation from original cell to myofibroblast occurs are still unclear. The expression of smooth muscle a-actin is the most characteristic feature of myofibroblast, and we speculated any factors that promote smooth muscle a-actin expression might be the key of transdifferenfiation to myofibroblast and disease exacerbation. A transcription factor C/EBPd was identified to bind to the sequence including CArG motif of smooth muscle a-actin intron 1 and to increase transcriptional activity of this promoter. The expression of smooth muscle a-actin and C/EBPd was evidently up-regulated in rat anti-Thy1 glomerulonephritis and mouse Habu-venom glomerulonephritis, which are models of mesangioproliferative glomerulonephritis. In the latter model, C/EBPd knockout mice demonstrated, in comparison to wild-type mice, significantly less smooth muscle a-actin expression in the glomerular area on day 8, which was decreased similarly on day 14, and less renal functional deteriolation. These data suggest the important role of C/EBPd in myofibroblast transdifferentiation and glonerulonephritis exacerbation.