Deletion of FHL2 in fibroblasts attenuates fibroblasts activation and kidney fibrosis via restraining TGF-β1-induced Wnt/β-catenin signaling
Deletion of FHL2 in fibroblasts attenuates fibroblasts activation and kidney fibrosis via restraining TGF-β1-induced Wnt/β-catenin signaling
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敲除成纤维细胞中的 FHL2 通过抑制 TGF-β1 诱导的 Wnt/β-连环蛋白信号传导减弱成纤维细胞活化和肾纤维化
DOI：
10.1007/s00109-019-01870-1
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发表时间：
2020-02-01
影响因子：
4.7
通讯作者：
He, Weichun
中科院分区：
文献类型：
--
作者：
Duan, Ying;Qiu, Yumei;He, Weichun
四个半 LIM 结构域蛋白 2 (FHL2) 已被认为参与 β-连环蛋白活性。我们之前报道过 FHL2 通过激活 Wnt/β-catenin 信号传导介导 TGF-β1 诱导的肾小管上皮间质转化。然而，FHL2 在 TGF-β1 诱导的成纤维细胞活化和肾纤维化中的潜在作用和机制仍不清楚。在这里，我们最初在患者和小鼠的纤维化肾脏中观察到较高水平的 FHL2 表达，特别是在间质中的 α-平滑肌肌动蛋白 (α-SMA) 阳性细胞中。在培养的间质成纤维细胞中，FHL2 表达由 TGF-β 1 诱导。FHL2 的敲低显着抑制 TGF-β 1 诱导的 α-SMA、I 型胶原和纤连蛋白表达，而 FHL2 的过表达足以激活成纤维细胞。在小鼠中，输尿管梗阻后 2 周，成纤维细胞特异性缺失 FHL2 减少了 α-SMA、I 型胶原和纤连蛋白的肾脏诱导以及间质细胞外基质沉积。接下来我们研究了 Wnt/β-catenin 活性，发现梗阻性肾病小鼠肾间质中大多数 FHL2 阳性细胞中 β-catenin 被激活。在体外，TGF-β1 诱导 FHL2 和 β-连环蛋白之间的物理相互作用，尤其是在细胞核中。 FHL2的下调抑制TGF-β1诱导的活性β-连环蛋白上调、β-连环蛋白核转位和β-连环蛋白介导的转录，而FHL2的过度表达能够激活Wnt/β-连环蛋白信号传导。 ICG-001 可以阻碍 FHL2 过表达诱导的 β-catenin 介导的基因转录，但 FHL2 过表达诱导的活性 β-catenin 上调却不能。总的来说，这项研究揭示了FHL2对β-连环蛋白的信号调节作用在TGF-β1诱导的成纤维细胞活化和肾纤维化中发挥重要作用。
Four-and-a-half LIM domains protein 2 (FHL2) has been proposed involving in beta-catenin activity. We previously reported that FHL2 mediates TGF-beta 1-induced tubular epithelial-to-mesenchymal transition through activating Wnt/beta-catenin signaling. However, the potential role and mechanism for FHL2 in TGF-beta 1-induced fibroblast activation and kidney fibrosis remains unknown. Here, we initially observed higher levels of FHL2 expression in fibrotic kidneys from both patients and mice, especially in alpha-smooth muscle actin (alpha-SMA)-positive cells in the interstitium. In cultured interstitial fibroblasts, FHL2 expression was induced by TGF-beta 1. Knockdown of FHL2 remarkably suppressed TGF-beta 1-induced alpha-SMA, type I collagen, and fibronectin expression, while overexpression of FHL2 was sufficient to activate fibroblasts. In mice, fibroblast-specific deletion of FHL2 diminished renal induction of alpha-SMA, type I collagen, and fibronectin and interstitial extracellular matrix deposition at 2 weeks after ureteral obstruction. We next investigated Wnt/beta-catenin activity and found that beta-catenin was activated in most FHL2-positive cells in renal interstitium from mice with obstructive nephropathy. In vitro, TGF-beta 1 induced a physical interaction between FHL2 and beta-catenin, especially in the nucleus. Downregulation of FHL2 inhibited TGF-beta 1-induced active beta-catenin upregulation, beta-catenin nuclear translocation, and beta-catenin-mediated transcription, whereas overexpression of FHL2 was able to activate Wnt/beta-catenin signaling. FHL2 overexpression-induced beta-catenin-mediated gene transcription could be hindered by ICG-001, but FHL2 overexpression-induced upregulation of active beta-catenin could not be. Collectively, this study reveals that the signal regulatory effect of FHL2 on beta-catenin plays an important role in TGF-beta 1-induced fibroblast activation and kidney fibrosis.