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

Abstract

Activation of the TGF- β/Smad signaling pathway in focal segmental glomerulosclerosis.BackgroundAlthough the pathogenetic relevance of transforming growth factor- β (TGF- β) to glomerulosclerosis is well established, it is not known whether a signal transduction cascade of TGF- β is involved in the development of focal segmental glomerulosclerosis (FSGS), nor is it clear how TGF- β1 is activated during the course of FSGS formation.MethodsWe examined the expression patterns of TGF- β1, thrombospondin-1 (TSP-1), TGF- β type II receptor (TGF- βIIR), 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- β1, TGF- βIIR, and TSP-1 were further evaluated by in situ hybridization in seven biopsies.ResultsIn the controls, immunostaining for TGF- β1, TSP-1, TGF- βIIR, and phosphorylated Smad2/Smad3 was almost negligible, but an apparent signal for TGF- β1, TSP-1, and TGF- βIIR mRNAs was observed in the visceral glomerular epithelial cells (GEC). In the cases of FSGS, the expression levels of TGF- β1, TSP-1, and TGF- βIIR 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.ConclusionThese results suggest that damage to podocyes may stimulate TGF- β1, TSP-1, and TGF- βIIR 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- β/Smad signaling pathway, which is activated in the GEC, appears to be involved in the development of FSGS