Activation of the TGF-β/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-beta1 is activated during the course of FSGS formation. Methods. We examined the expression patterns of TGF-beta1, thrombospondin-1 (TSP-1), TGF-beta type II receptor (TGF-betaIIR), 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-beta1, TGF-betaIIR, and TSP-1 were further evaluated by in situ hybridization in seven biopsies. Results. In the controls, immunostaining for TGF-beta1, TSP-1, TGF-betaIIR, and phosphorylated Smad2/Smad3 was almost negligible, but an apparent signal for TGF-beta1, TSP-1, and TGF-betaIIR mRNAs was observed in the visceral glomerular epithelial cells (GEC). In the cases of FSGS, the expression levels of TGF-beta1, 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-beta1, TSP-1, and TGF-betaIIR 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.