Activation of the TGF-β/Smad signaling pathway in focal segmental glomerulosclerosis
Activation of the TGF-β/Smad signaling pathway in focal segmental glomerulosclerosis
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DOI：
10.1046/j.1523-1755.2003.00288.x
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发表时间：
2003-11-01
影响因子：
19.6
通讯作者：
Lee, HS
中科院分区：
文献类型：
--
作者：
Kim, JH;Kim, BK;Lee, HS
背景。虽然转化生长因子- β (tgf - β)与肾小球硬化症的病理相关性已经得到证实，但目前尚不清楚tgf - β的信号转导级联是否参与局灶节段性肾小球硬化症（FSGS）的发展，也不清楚tgf - β在FSGS形成过程中是如何被激活的。我们在15例特发性FSGS肾活检标本和6例未检测到异常的肾活检标本中检测了tgf - β 1、血小板反应蛋白-1 （TSP-1）、tgf - β II型受体（TGF-betaIIR）、磷酸化Smad2/Smad3和足细胞特异性表位[Wilms肿瘤蛋白-1 （WT-1）和肾小球上皮蛋白-1 (GLEPP-1)]的表达模式。通过原位杂交进一步评价7个活检组织中tgf - β 1、tgf - β air和TSP-1 mRNA的表达模式。在对照组中，TGF-beta1、TSP-1、TGF-betaIIR和磷酸化Smad2/Smad3的免疫染色几乎可以忽略不计，但在内脏肾小球上皮细胞（GEC）中观察到TGF-beta1、TSP-1和TGF-betaIIR mrna的明显信号。在FSGS病例中，TGF-beta1、TSP-1、TGF-betaIIR蛋白和mrna以及磷酸化Smad2/Smad3的表达水平显著升高，特别是在硬化段的GEC中，未检测到WT-1和GLEPP-1。这些结果表明，足部损伤可能刺激GEC中TGF-beta1、TSP-1和TGF-betaIIR的表达，从而激活Smad信号通路，从而导致细胞外基质（ECM）的过量产生。因此，在GEC中激活的tgf - β /Smad信号通路的信号转导级联似乎参与了FSGS的发展。
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.