Activation of the TGF-beta/Smad signaling pathway in focal segmental glomerulosclerosis.
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.
Kim
Ji Hoon
JH
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
Kim
Byoung Kwon
BK
Moon
Kyung Chul
KC
Hong
Hye Kyoung
HK
Lee
Hyun Soon
HS
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
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