The differential expression of TGF-β1, ILK and wnt signaling inducing epithelial to mesenchymal transition in human renal fibrogenesis: an immunohistochemical study

Int J Clin Exp Pathol. 2013 Aug 15;6(9):1747-58. eCollection 2013.

Abstract

Epithelial-to-mesenchymal transition (EMT) is a process for fully differentiated epithelial cells to undergo a phenotypic change to fibroblasts via diverse intracellular signaling pathways. While the pivotal role of fibroblasts in renal fibrosis is widely accepted, their origin remains undefined. In addition, although a large number of studies have provided evidence of EMT in human kidney diseases, specific signaling pathways leading to EMT have not yet been discovered in humans. To evaluate the origin of interstitial fibroblasts and signaling pathways involved in the EMT process, we analyzed the differential expression of EMT-related molecules in paraffin-fixed sections from 19 human fibrotic kidneys and 4 control kidneys. In human fibrotic kidneys, tubular epithelial cells (TECs) with intact tubular basement membrane (TBM) showed loss or down-regulation of an epithelial marker (E-cadherin), de novo expression of mesenchymal markers (vimentin and fibronectin), and significant up-regulation of inducers and mediators controlling the EMT process (transforming growth factor-β1 (TGF-β1), p-Smad2/3, β1-integrin, p38 mitogen-activated protein kinase (MAPK), WNT5B and β-catenin) in the areas of interstitial inflammation and fibrosis, compared with their expression in control kidneys. In conclusion, the type II EMT process in humans is thought to be an adaptive response of TECs to chronic injury and is regulated by interconnections of TGF-β/Smad, integrin/integrin-linked kinase (ILK) and wnt/β-catenin signaling pathways.

Keywords: EMT; TGF-beta/Smad signaling; immunohistochemistry; integrin; renal fibrosis; wnt signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, CD
  • Biomarkers / analysis
  • Cadherins / analysis
  • Case-Control Studies
  • Epithelial-Mesenchymal Transition*
  • Female
  • Fibrosis
  • Humans
  • Immunohistochemistry*
  • Kidney Diseases / enzymology*
  • Kidney Diseases / pathology
  • Kidney Tubules / enzymology*
  • Kidney Tubules / pathology
  • Male
  • Middle Aged
  • Phenotype
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / analysis*
  • Smad2 Protein / analysis
  • Smad3 Protein / analysis
  • Transforming Growth Factor beta1 / analysis*
  • Wnt Proteins / analysis*
  • Wnt Signaling Pathway*
  • Young Adult
  • beta Catenin / analysis

Substances

  • Antigens, CD
  • Biomarkers
  • CDH1 protein, human
  • CTNNB1 protein, human
  • Cadherins
  • SMAD2 protein, human
  • SMAD3 protein, human
  • Smad2 Protein
  • Smad3 Protein
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • WNT5B protein, human
  • Wnt Proteins
  • beta Catenin
  • integrin-linked kinase
  • Protein-Serine-Threonine Kinases