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  • Title: Activation of the TGF-beta/Smad signaling pathway in focal segmental glomerulosclerosis.
    Author: Kim JH, Kim BK, Moon KC, Hong HK, Lee HS.
    Journal: Kidney Int; 2003 Nov; 64(5):1715-21. PubMed ID: 14531804.
    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.
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