Activation of the TGF-beta/Smad signaling pathway in focal segmental glomerulosclerosis

Kidney Int. 2003 Nov;64(5):1715-21. doi: 10.1046/j.1523-1755.2003.00288.x.

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.

Conclusion: 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.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Child
  • DNA-Binding Proteins / metabolism*
  • Female
  • Glomerulosclerosis, Focal Segmental / metabolism*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Male
  • Middle Aged
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • RNA, Messenger / analysis
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / physiology*
  • Smad2 Protein
  • Smad3 Protein
  • Thrombospondin 1 / genetics
  • Thrombospondin 1 / metabolism
  • Trans-Activators / metabolism*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta1

Substances

  • DNA-Binding Proteins
  • RNA, Messenger
  • Receptors, Transforming Growth Factor beta
  • SMAD2 protein, human
  • SMAD3 protein, human
  • Smad2 Protein
  • Smad3 Protein
  • TGFB1 protein, human
  • Thrombospondin 1
  • Trans-Activators
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II