title: Activation of the TGF-beta/Smad signaling pathway in focal segmental glomerulosclerosis.
abstract: BACKGROUND
  Although the pathogenetic relevance of transforming growth factor-beta (TGF-beta) to glomerulosclerosis is well established, it is not known whether a signal transduction cascade of TGF-beta is involved in the development of focal segmental glomerulosclerosis (FSGS), nor is it clear how TGF-beta 1 is activated during the course of FSGS formation.
  
  
  METHODS
  We examined the expression patterns of TGF-beta 1, thrombospondin-1 (TSP-1), TGF-beta type II receptor (TGF-beta IIR), phosphorylated Smad2/Smad3, and podocyte-specific epitopes [Wilms' tumor protein-1 (WT-1) and glomerular epithelial protein-1 (GLEPP-1)] in 15 renal biopsy specimens with idiopathic FSGS and six renal biopsies with no detectable abnormalities by means of immunohistochemistry. The mRNA expression patterns of TGF-beta 1, TGF-beta IIR, and TSP-1 were further evaluated by in situ hybridization in seven biopsies.
  
  
  RESULTS
  In the controls, immunostaining for TGF-beta 1, TSP-1, TGF-beta IIR, and phosphorylated Smad2/Smad3 was almost negligible, but an apparent signal for TGF-beta 1, TSP-1, and TGF-beta IIR mRNAs was observed in the visceral glomerular epithelial cells (GEC). In the cases of FSGS, the expression levels of TGF-beta 1, TSP-1, and TGF-betaIIR proteins and mRNAs and phosphorylated Smad2/Smad3 were significantly increased, particularly in the GEC of the sclerotic segments, wherein WT-1 and GLEPP-1 were not detected.
  
  
  CONCLUSIONS
  These results suggest that damage to podocyes may stimulate TGF-beta 1, TSP-1, and TGF-beta IIR expression in GEC, thereby activating the Smad signaling pathway and, in so doing, leading to overproduction of the extracellular matrix (ECM). Thus, a signal transduction cascade of the TGF-beta/Smad signaling pathway, which is activated in the GEC, appears to be involved in the development of FSGS.
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Kim
authors.forename: Byoung Kwon
authors.initials: BK
authors.lastname: Kim
authors.forename: Kyung Chul
authors.initials: KC
authors.lastname: Moon
authors.forename: Hye Kyoung
authors.initials: HK
authors.lastname: Hong
authors.forename: Hyun Soon
authors.initials: HS
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000032:analysis; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein; D051900:Smad3 Protein; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
chemical_list: D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; C508960:TGFB1 protein, human; D019700:Thrombospondin 1; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II