Effects of 1,25-(OH)2D3on endoplasmic reticulum stress and ATG12 expression in pulmonary fibrosis / 医学研究生学报

ABSTRACT

Objective It is not yet clear whether 1,25-(OH)2D3acts on endoplasmic reticulum stress(ERS)and autoph-agy in pulmonary fibrosis(PF).This study aimed to investigate the roles of ERS and autophagy in the development and progression of pulmonary fibrosis in rats and the effects of 1,25-(OH)2D3on the expressions of ERS-related molecules and autophagy-related gene 12 (ATG12). Methods Ninety male SD rats were randomly divided into a control, a PF model and a treatment group of equal number.Bleomycin was injected into the tracheas of the latter two groups of rats to induce PF.On the second day after modeling, the rats of the treatment group were injected intraperitoneally with 1,25-(OH)2D3at 2 μg/kg,those of the PF model group with 1,25-(OH)2D3solvent at 200 μL,and those of the control group with iso-tonic saline at 200 μL,all once 2 days.Then the mRNA expressions of PERK,ATF4 and ATG12 were measured by real-time PCR and the protein expressions of PERK and ATF4 detected by immunohistochemistry. Results At 14, 21 and 28 days after treat-ment,the expression levels of PERK were significantly higher in the PF model group(2.30±0.19, 3.59±0.27, and 4.63±0.19) and treatment group(1.44±0.34,1.92±0.17,and 2.52±0.15)than in the control(1.01±0.23,1.05±0.09,and 1.04±0.08)(P<0.05), and so were the expression levels of ATF4 in the PF models(2.10±0.12, 3.91±0.14, and 6.20±0.28)and treated rats (1.49±0.27,2.52±0.42, and 4.02±0.31)than in the controls(1.04±0.07,1.05±0.08,and 1.03±0.10)(P<0.05).Compared with the control group,the PF model and treatment groups showed markedly increased expression levels of ATG 12 mRNA at 14 days (P<0.05), but decreased at 21 and 28 days(P<0.05).Both the expressions of PERK and ATF4 proteins were remarkably higher in the model and treatment groups than in the control at 14,21 and 28 days(P<0.05), increasing in a time-dependent manner. Conclusion By suppressing the PERK -eIF2α-ATF4 signaling pathway,1,25-(OH)2D3inhibits the development and progression of pulmonary fibrosis.