Effects of fluvastatin on epithelial-myofibroblast transdifferentiation and activation of ERK1/2 in HKC cells stimulated by AGEs / 中国药理学通报

ABSTRACT

Aim To investigate the effects of fluvastatin on epithelial-myofibroblast transdifferentiation and activation of ERK1/2 in HKC cells stimulated by AGEs. Methods HKC are divided into four groups control group, AGEs group, AGEs plus fluvastatin group and AGEs plus ERK1/2 MAP kinase inhibitor PD98059 group. Immunocytochemistry staining was used to detect expression of ?-SMA. The protein expressions of ?-SMA, E-cadherin, Col I, ERK1/2 and p-ERK1/2 were observed by Western blot. The protein synthesis of TGF-?1 in the supernatants of the HKC was detected by enzyme-linked immunoadsorbent assay (ELISA).?-SMA and E-cadherin mRNA were measured by reverse transcription and polymerase chain reaction (RT-PCR). Results Compared with those of control group,the expressions of ?-SMA protein and mRNA,and Col I were significantly increased in HKC cells with AGEs stimulation and there was high concentration of TGF-?1 in the supernatants. However, the expressions of E-cadherin protein and mRNA were decreased with AGEs stimulation. AGEs induced ERK1/2 phosphorylation in HKC in a time-dependent manner, being significant at 15 minutes and peak occured at 1 h. PD98059 and fluvastatin inhibited AGEs-induced activation of ERK1/2 and high expression of Col I and ?-SMA protein and mRNA, and reversed the expression of E-cadherin protein and mRNA induced by AGEs. Meanwhile, fluvastatin and PD98059 reduced the concentration of TGF-?1 in the supernatants of HKC with AGEs stimulation. Conclusions Fluvastatin inhibited AGEs-induced HKC epithelial-myofibroblast transdifferentiation and collagen I synthesis might be partly through blocking activation of ERK1/2.