Inhibition of transforming growth factor β1 signaling in resident interstitial cells attenuates profibrotic gene expression and preserves erythropoietin production during experimental kidney fibrosis in mice
Inhibition of transforming growth factor β1 signaling in resident interstitial cells attenuates profibrotic gene expression and preserves erythropoietin production during experimental kidney fibrosis in mice
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在小鼠实验性肾纤维化过程中，抑制常驻间质细胞中的转化生长因子 β1 信号传导可减弱促纤维化基因表达并保留促红细胞生成素的产生
DOI：
10.1016/j.kint.2021.02.035
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发表时间：
2021-06-18
影响因子：
19.6
通讯作者：
Kurtz, Armin
中科院分区：
文献类型：
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作者：
Fuchs, Michaela A. A.;Broeker, Katharina A. E.;Kurtz, Armin
肾纤维化的特征在于起源于驻留肾和移行细胞的肌成纤维细胞的发育。在肾损伤期间，各种细胞因子触发肌成纤维细胞形成和细胞外基质产生。其中，转化生长因子β 1（TGF β 1）被认为是肾纤维化的主要触发因素。我们发现在实验性纤维化中肾间质细胞中TGF β 1和TGF β受体2（TGF β-R2）mRNA的表达高度上调。在此，我们使用腺嘌呤诱导的肾病和单侧输尿管闭塞的小鼠模型，研究了肾间质细胞中TGF β 1信号传导对器官纤维化的贡献。为此目的，通过在表达成纤维细胞标志物血小板衍生生长因子受体-β的间质细胞中诱导性缺失TGF β-R2基因来中断TGF β 1信号传导。在血小板衍生生长因子受体-β阳性的细胞中缺乏TGF β-R2的肾脏中，促纤维化基因的表达减弱高达50%。此外，TGF β-R2的缺失防止了输尿管结扎肾中促红细胞生成素产生的下降。值得注意的是，在靶向缺失TGF β-R2的小鼠中，作为肌成纤维细胞标志物的α-平滑肌肌动蛋白的纤维化相关表达和细胞外胶原沉积没有改变。因此，我们的研究结果表明，TGF β 1信号在常驻间质细胞中的增强作用有助于促纤维化基因表达和促红细胞生成素产生的下调，但不有助于肾纤维化期间肌成纤维细胞的发育。
Kidney fibrosis is characterized by the development of myofibroblasts originating from resident kidney and immigrating cells. Myofibroblast formation and extracellular matrix production during kidney damage are triggered by various cytokines. Among these, transforming growth factor beta 1 (TGF beta 1) is considered a central trigger for kidney fibrosis. We found a highly upregulated expression of TGF beta 1 and TGF beta receptor 2 (TGF beta-R2) mRNAs in kidney interstitial cells in experimental fibrosis. Here, we investigated the contribution of TGF beta 1 signaling in resident kidney interstitial cells to organ fibrosis using the models of adenine induced nephropathy and unilateral ureteral occlusion in mice. For this purpose TGF beta 1 signaling was interrupted by inducible deletion of the TGF beta-R2 gene in interstitial cells expressing the fibroblast marker platelet derived growth factor receptor-beta. Expression of profibrotic genes was attenuated up to 50% in kidneys lacking TGF beta-R2 in cells positive for platelet derived growth factor receptor-beta. Additionally, deletion of TGF beta-R2 prevented the decline of erythropoietin production in ureter ligated kidneys. Notably, fibrosis associated expression of alpha-smooth muscle actin as a myofibroblast marker and deposits of extracellular collagens were not altered in mice with targeted deletion of TGF beta-R2. Thus, our findings suggest an enhancing effect of TGF beta 1 signaling in resident interstitial cells that contributes to profibrotic gene expression and the downregulation of erythropoietin production, but not to the development of myofibroblasts during kidney fibrosis.