Suppression of renal fibrosis by galectin-1 in high glucose-treated renal epithelial cells.
Diabetic nephropathy is the most common cause of chronic kidney disease. We investigated the ability of intracellular galectin-1 (Gal-1), a prototype of endogenous lectin, to prevent renal fibrosis by regulating cell signaling under a high glucose (HG) condition. We demonstrated that overexpression of Gal-1 reduces type I collagen (COL1) expression and transcription in human renal epithelial cells under HG conditions and transforming growth factor-β1 (TGF-β1) stimulation. Matrix metalloproteinase 1 (MMP1) is stimulated by Gal-1. HG conditions and TGF-β1 treatment augment expression and nuclear translocation of Gal-1. In contrast, targeted inhibition of Gal-1 expression reduces COL1 expression and increases MMP1 expression. The Smad3 signaling pathway is inhibited, whereas two mitogen-activated protein kinase (MAPK) pathways, p38 and extracellular signal-regulated kinase (ERK), are activated by Gal-1, indicating that Gal-1 regulates these signaling pathways in COL1 production. Using specific inhibitors of Smad3, ERK, and p38 MAPK, we showed that ERK MAPK activated by Gal-1 plays an inhibitory role in COL1 transcription and that activation of the p38 MAPK pathway by Gal-1 plays a negative role in MMP1 production. Taken together, two MAPK pathways are stimulated by increasing levels of Gal-1 in the HG condition, leading to suppression of COL1 expression and increase of MMP1 expression.
Okano
Kazuhiro
K
Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo 162-8666, Japan. kaokano@kc.twmu.ac.jp
Tsuruta
Yuki
Y
Yamashita
Tetsuri
T
Takano
Mari
M
Echida
Yoshihisa
Y
Nitta
Kosaku
K
D002460:Cell Line; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D037483:Galectin 1 / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D021381:Protein Transport / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D024042:Collagen Type I; D037483:Galectin 1; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D003094:Collagen; D048049:Extracellular Signal-Regulated MAP Kinases; D020781:Matrix Metalloproteinase 1; D005947:Glucose