Downregulation of Smad transcriptional corepressors SnoN and ski in the fibrotic kidney:: An amplification mechanism for TGF-β1 signaling
Downregulation of Smad transcriptional corepressors SnoN and ski in the fibrotic kidney:: An amplification mechanism for TGF-β1 signaling
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DOI：
10.1097/01.asn.0000099373.33259.b2
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发表时间：
2003-12-01
影响因子：
13.6
通讯作者：
Liu, YH
中科院分区：
文献类型：
--
作者：
Yang, JW;Mang, XH;Liu, YH
TGF-β 1是一种促纤维化细胞因子，在慢性肾脏疾病的发生和进展中起着重要作用。TGF-β 1的活性受到多种机制的严格控制，其中通过辅阻遏物拮抗Smad介导的基因转录是重要的调节组分。本研究检测了Smad转录辅抑制因子在纤维化肾脏中的表达，并研究了它们在控制TGF-β 1反应中的潜在功能。Western blot分析表明，在小鼠单侧输尿管梗阻诱导的纤维化肾脏中，Smad转录辅抑制子SnoN和Ski的蛋白水平以时间依赖性方式进行性降低，而肾脏Smad丰度相对不变。梗阻性损伤后肾小管上皮细胞和肾小管上皮细胞核的Consistent、SnoN和Ski染色减弱。在体外，敲低SnoN表达的RNA干扰在肾小管上皮细胞显着敏化其对TGF-β 1刺激的反应。相反，外源性SnoN或Ski转染后异位表达赋予肾小管上皮细胞对TGF-β 1诱导的上皮细胞向肌成纤维细胞转变的抗性。SnoN和Ski均能阻断Smad介导的TGF-β 1应答启动子的激活，并在消除TGF-β 1的促纤维化作用方面表现出相加效应。这些结果表明，由于Smad转录辅阻遏物的丢失，患病肾脏中的促纤维化TGF-β 1信号传导以比先前认为的大得多的幅度显著放大。因此，旨在增加Smad转录辅抑制因子表达的新策略可能有效地拮抗TGF-β 1信号传导，从而阻断慢性肾纤维化的进展。
TGF-beta1 is a profibrotic cytokine that plays a central role in the onset and progression of chronic renal diseases. The activity of TGF-beta1 is tightly controlled by multiple mechanisms, in which antagonizing Smad-mediated gene transcription by co-repressors is an important regulatory component. This study examined the expression of Smad transcriptional co-repressors in the fibrotic kidney and investigated their potential functions in controlling TGF-beta1 response. Western blot analysis demonstrated that the protein levels of Smad transcriptional co-repressors SnoN and Ski were progressively reduced in a time-dependent manner in the fibrotic kidney induced by unilateral ureteral obstruction in mice, whereas renal Smad abundance was relatively unaltered. Consistently, SnoN and Ski staining was diminished in the nuclei of renal tubular epithelium and interstitium after obstructive injury. In vitro, knockdown of SnoN expression by RNA interference in tubular epithelial cells dramatically sensitized their responsiveness to TGF-beta1 stimulation. Conversely, ectopic expression of exogenous SnoN or Ski after transfection conferred tubular epithelial cell resistance to TGF-beta1-induced epithelial to myofibroblast transition. Both SnoN and Ski could block Smad-mediated activation of TGF-beta1-responsive promoter and exhibited additive effect in abrogating the profibrotic actions of TGF-beta1. These results indicate that as a result of loss of Smad transcriptional co-repressors, the profibrotic TGF-beta1 signaling in diseased kidney is markedly amplified in a magnitude much greater than previously thought. Therefore, new strategy aimed to increase Smad transcriptional co-repressors expression may be effective in antagonizing TGF-beta1 signaling and thereby blocking the progression of chronic renal fibrosis.