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RETRACTED: Melatonin inhibits autophagy and endoplasmic reticulum stress in mice with carbon tetrachloride‐induced fibrosis
Author(s) -
SanMiguel Beatriz,
Crespo Irene,
Sánchez Diana I.,
GonzálezFernández Bárbara,
Ortiz de Urbina Juan J.,
Tuñón María J.,
GonzálezGallego Javier
Publication year - 2015
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12247
Subject(s) - unfolded protein response , endoplasmic reticulum , atf6 , glucose regulated protein , sequestosome 1 , xbp1 , atg5 , endocrinology , autophagy , medicine , biology , chemistry , protein kinase a , microbiology and biotechnology , biochemistry , phosphorylation , apoptosis , rna , rna splicing , gene
This study aimed to investigate whether inhibition of autophagy and endoplasmic reticulum ( ER stress) associates with the antifibrogenic effect of melatonin in mice treated with carbon tetrachloride ( CC l 4 ). Mice received CC l 4 5 μ L/g body wt i.p. twice a week for 4 wk or 6 wk. Melatonin was given at 5 or 10 mg/kg/day i.p, beginning 2 wk after the start of CC l 4 administration. Treatment with CC l 4 resulted in fibrosis evidenced by the staining of α ‐smooth muscle actin ( α ‐ SMA )‐positive cells. CC l 4 induced an autophagic response measured as the presence of autophagic vesicles, protein 1 light chain 3 ( LC 3) staining, conversion of LC 3‐I to autophagosome‐associated LC 3‐ II , changes in expression of beclin‐1, UV radiation resistance‐associated gene ( UVRAG ), ubiquitin‐like autophagy‐related (Atg5), Atg12, Atg16L1, sequestosome 1 (p62/ SQSTM 1), and lysosome‐associated membrane protein ( LAMP )‐2, and increased phosphorylation of the mammalian target of rapamycin ( mTOR ). There was an increase in the expression of the ER stress chaperones CCAAT /enhancer‐binding protein homologous protein ( CHOP ), immunoglobulin‐heavy‐chain‐binding protein (BiP/ GRP 78), and 94‐ kD a glucose‐regulated protein ( GRP 94), and in the mRNA levels of pancreatic ER kinase ( PERK ), activating transcription factor 6 ( ATF 6), ATF 4, inositol‐requiring enzyme 1 ( IRE 1), and spliced X‐box‐binding protein‐1 ( XBP 1). Phospho‐ IRE 1, ATF 6, and phospho‐ PERK protein concentration also increased significantly. Immunohistochemical staining of α ‐ SMA indicated an abrogation of hepatic stellate cells activation by melatonin. Furthermore, treatment with the indole resulted in significant inhibition of the autophagic flux and the unfolded protein response. Findings from this study give new insight into molecular pathways accounting for the protective effect of melatonin in fibrogenesis.