Wang Ling, Hu Gao-yun, Shen Hong, Peng Zhang-zhe, Ning Wang-bin, Tao Li-jian
Division of Nephropathy, Department of Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Pharmazie. 2009 Oct;64(10):680-4.
The development of novel antifibrotic agent candidates for the treatment of diabetic nephropathy. The present study was designed to investigate the potential mechanism of fluorofenidone involving the downregulation of CTGF expression induced by TGF-beta1 and the related signaling pathway in mouse mesangial cells (MMCs).
Mouse mesangial cells were applied to explore the involvement of MAPK in TGF-beta1 signal pathway to CTGF, and the regulation of fluorofenidone. The activation of three major members of MAPK, including ERK1/2, P38 and JNK was detected by Western blot; the expression of CTGF was investigated by real time PCR and Western blot.
Fluorofenidone significantly reduced the phosphorylation of ERK1/2, P38 and JNK induced by TGF-beta1. Fluorofenidone, PD98059 and SB203580 could partially inhibit TGF-beta1-induced expression of CTGF in mouse mesangial cells, however, JNK inhibitor II had no effect.
The antifibrotic effects of fluorofenidone are suggested to be mediated byits actions through inhibition of MAPK activation and consequent reduction of CTGF expression.
开发用于治疗糖尿病肾病的新型抗纤维化候选药物。本研究旨在探讨氟非尼酮下调转化生长因子-β1（TGF-β1）诱导的结缔组织生长因子（CTGF）表达的潜在机制以及在小鼠系膜细胞（MMCs）中的相关信号通路。
应用小鼠系膜细胞探讨丝裂原活化蛋白激酶（MAPK）在TGF-β1信号通路至CTGF中的作用以及氟非尼酮的调控作用。通过蛋白质印迹法检测MAPK三个主要成员（包括细胞外信号调节激酶1/2（ERK1/2）、p38和c-Jun氨基末端激酶（JNK））的激活情况；通过实时聚合酶链反应（PCR）和蛋白质印迹法研究CTGF的表达。
氟非尼酮显著降低了TGF-β1诱导的ERK1/2、p38和JNK的磷酸化水平。氟非尼酮、PD98059和SB203580可部分抑制TGF-β1诱导的小鼠系膜细胞中CTGF的表达，然而，JNK抑制剂II无此作用。
氟非尼酮的抗纤维化作用可能是通过抑制MAPK激活并进而降低CTGF表达来介导的。
