GQ5 Hinders Renal Fibrosis in Obstructive Nephropathy by Selectively Inhibiting TGF-β-Induced Smad3 Phosphorylation
GQ5 Hinders Renal Fibrosis in Obstructive Nephropathy by Selectively Inhibiting TGF-β-Induced Smad3 Phosphorylation
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DOI：
10.1681/asn.2014040363
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发表时间：
2015-08-01
影响因子：
13.6
通讯作者：
Hou, Fan Fan
中科院分区：
文献类型：
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作者：
Ai, Jun;Nie, Jing;Hou, Fan Fan
TGF-β 1通过Smad依赖性或非依赖性信号传导，在肾纤维化的发病机制中具有中心作用。该途径已被认为是抗纤维化治疗的潜在靶点。在这里，我们确定了GQ 5，一个小分子酚类化合物，从干燥的树脂漆树，作为一个有效的和选择性的抑制剂TGF-β 1诱导Smad 3磷酸化。在TGF-β 1刺激的肾小管上皮细胞和间质成纤维细胞中，GQ 5抑制Smad 3与TGF-β I型受体的相互作用。通过阻断Smad 3与SARA的结合，抑制Smad 3随后的磷酸化，减少Smad 2，Smad 3和Smad 4的核转位，并下调主要纤维化基因如α-平滑肌肌动蛋白的转录，（α-SMA）、胶原蛋白I和纤连蛋白。值得注意的是，单侧输尿管梗阻（UUO）后立即腹腔注射GQ 5可选择性抑制UUO肾脏中Smad 3磷酸化，抑制α-SMA、胶原蛋白I和纤连蛋白的肾脏表达，并在梗阻性损伤后产生令人印象深刻的肾脏保护作用。晚期给予GQ 5也有效减轻了阻塞性肾病的纤维化病变。总之，我们的结果表明GQ 5通过选择性抑制TGF-β 1诱导的Smad 3磷酸化来阻止大鼠肾纤维化。
TGF-beta 1, via Smad-dependent or Smad-independent signaling, has a central role in the pathogenesis of renal fibrosis. This pathway has been recognized as a potential target for antifibrotic therapy. Here, we identified GQ5, a small molecular phenolic compound isolated from the dried resin of Toxicodendron vernicifluum, as a potent and selective inhibitor of TGF-beta 1-induced Smad3 phosphorylation. In TGF-beta 1-stimulated renal tubular epithelial cells and interstitial fibroblast cells, GQ5 inhibited the interaction of Smad3 with TGF-beta type I receptor (T beta RI) by blocking binding of Smad3 to SARA, suppressed subsequent phosphorylation of Smad3, reduced nuclear translocation of Smad2, Smad3, and Smad4, and downregulated the transcription of major fibrotic genes such as alpha-smooth muscle actin (alpha-SMA), collagen I, and fibronectin. Notably, intraperitoneal administration of GQ5 in rats immediately after unilateral ureteral obstruction (UUO) selectively inhibited Smad3 phosphorylation in UUO kidneys, suppressed renal expression of alpha-SMA, collagen I, and fibronectin, and resulted in impressive renal protection after obstructive injury. Late administration of GQ5 also effectively attenuated fibrotic lesions in obstructive nephropathy. In conclusion, our results suggest that GQ5 hinders' renal fibrosis in rats by selective inhibition of TGF-beta 1-induced Smad3 phosphorylation.