Transforming growth factor β-1 stimulates profibrotic epithelial signaling to activate pericyte-myofibroblast transition in obstructive kidney fibrosis.
Transforming growth factor β-1 stimulates profibrotic epithelial signaling to activate pericyte-myofibroblast transition in obstructive kidney fibrosis.
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转化生长因子β-1 刺激促纤维化上皮信号传导，激活阻塞性肾纤维化中的周细胞-肌成纤维细胞转变。
DOI：
10.1016/j.ajpath.2012.09.009
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Lin,Shuei-Liong
中科院分区：
文献类型：
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作者：
Wu,Ching-Fang;Chiang,Wen-Chih;Lai,Chun-Fu;Chang,Fan-Chi;Chen,Yi-Ting;Chou,Yu-Hsiang;Wu,Ting-Hui;Linn,GeoffreyR;Ling,Hong;Wu,Kwan-Dun;Tsai,Tun-Jun;Chen,Yung-Ming;Duffield,JeremyS;Lin,Shuei-Liong
周细胞已被确定为肾纤维化过程中产生疤痕的肌成纤维细胞前体的主要来源。触发周细胞-肌成纤维细胞转变的潜在机制尚不清楚。转化生长因子 β-1 (TGF-β1) 被公认为是一种驱动器官纤维化的多能细胞因子。我们研究了 TGF-β1 在诱导上皮细胞促纤维化信号传导以激活周细胞-肌成纤维细胞转变中的作用。单侧输尿管梗阻后，TGF-β1 表达增加主要在受损上皮中检测到，而来自 TGF-β1 受体的下游信号在受损上皮和周细胞中均增加。在使用泛抗 TGF-β 抗体 (1D11) 或 I 型 TGF-β 受体抑制剂 (SB431542) 治疗的输尿管梗阻小鼠中，肾周细胞-肌成纤维细胞转变减弱。结果是纤维化明显减弱。此外，上皮细胞周期 G2/M 停滞和促纤维化细胞因子的产生均减弱。尽管 TGF-β1 单独并不能在体外引发周细胞增殖，但它可以强烈诱导 α 平滑肌肌动蛋白 (α-SMA)。在培养的肾上皮细胞中，TGF-β1 刺激 G2/M 期停滞和促纤维化细胞因子的产生，这些细胞因子能够刺激周细胞增殖和向肌成纤维细胞的转变。总之，这项研究确定了肾纤维化过程中受损上皮和周细胞-肌成纤维细胞通过 TGF-β1 转变之间的新联系。
Pericytes have been identified as the major source of precursors of scar-producing myofibroblasts during kidney fibrosis. The underlying mechanisms triggering pericyte-myofibroblast transition are poorly understood. Transforming growth factor β-1 (TGF-β1) is well recognized as a pluripotent cytokine that drives organ fibrosis. We investigated the role of TGF-β1 in inducing profibrotic signaling from epithelial cells to activate pericyte-myofibroblast transition. Increased expression of TGF-β1 was detected predominantly in injured epithelium after unilateral ureteral obstruction, whereas downstream signaling from the TGF-β1 receptor increased in both injured epithelium and pericytes. In mice with ureteral obstruction that were treated with the pan anti–TGF-β antibody (1D11) or TGF-β receptor type I inhibitor (SB431542), kidney pericyte-myofibroblast transition was blunted. The consequence was marked attenuation of fibrosis. In addition, epithelial cell cycle G2/M arrest and production of profibrotic cytokines were both attenuated. Although TGF-β1 alone did not trigger pericyte proliferationin vitro, it robustly induced α smooth muscle actin (α-SMA). In cultured kidney epithelial cells, TGF-β1 stimulated G2/M arrest and production of profibrotic cytokines that had the capacity to stimulate proliferation and transition of pericytes to myofibroblasts. In conclusion, this study identified a novel link between injured epithelium and pericyte-myofibroblast transition through TGF-β1 during kidney fibrosis.