title: Connective tissue growth factor induces tubular epithelial to mesenchymal transition through the activation of canonical Wnt signaling in vitro.
abstract: BACKGROUND
  Overwhelming evidences suggest epithelial to mesenchymal transition (EMT) of tubular epithelial cells contributes to renal fibrosis of chronic kidney disease (CKD). Connective tissue growth factor (CTGF) plays an important role in the pathogenesis of EMT. However, the molecular mechanisms that regulate cell behaviors are not clear.
  
  
  OBJECTIVE
  The purpose of this study was to investigate whether CTGF induces EMT via activation of canonical Wnt signaling in renal tubular epithelial cells.
  
  
  METHODS
  Human renal proximal tubular epithelial cells (HK-2) were divided into control group, CTGF group and dickkopf (Dkk)-1 plus CTGF group. We assessed the biological changes of canonical Wnt signaling, including phosphorylation of low-density lipoprotein receptor-related protein (LRP6) and glycogen synthase kinase-3β (GSK-3β) and accumulation and nuclear localization of β-catenin. Meanwhile, morphological changes of the three groups were observed and tubular EMT was further confirmed by detecting the expression of α-SMA and E-cadherin.
  
  
  RESULTS
  The phosphorylation levels of LRP6 and GSK-3β and the expression of β-catenin in CTGF group were higher than control group (p < 0.05). The accumulation and nuclear localization of β-catenin was induced in CTGF group. Meanwhile, CTGF group cells showed a mesenchymal morphological phenotype and exhibited increased expressions of E-cadherin and decreased expressions of α-SMA compared to control group (p < 0.05), suggesting tubular EMT. Furthermore, we also found that Dkk-1 blocked the above CTGF's effects by binding with LRP6.
  
  
  CONCLUSIONS
  CTGF induces EMT via activation of canonical Wnt signaling in HK-2 cells in vitro, which may play an important role in the renal fibrosis of CKD.
authors.affiliation: Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University , Jinan, Shandong , China.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Yang
authors.forename: Lina
authors.initials: L
authors.lastname: Sun
authors.forename: Huibin
authors.initials: H
authors.lastname: Nie
authors.forename: Haiying
authors.initials: H
authors.lastname: Liu
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Guangju
authors.initials: G
authors.lastname: Guan
mesh_terms: D002460:Cell Line; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism; D010766:Phosphorylation; D051436:Renal Insufficiency, Chronic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051176:beta Catenin; D055513:Connective Tissue Growth Factor; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: Chronic kidney disease; Wnt signaling pathway; connective tissue growth factor; epithelial to mesenchymal transition