Smad3 signaling activates bone marrow-derived fibroblasts in renal fibrosis.
Smad3 signaling activates bone marrow-derived fibroblasts in renal fibrosis.
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DOI：
10.1038/labinvest.2014.43
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发表时间：
2014-05
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最近的研究表明，骨髓来源的成纤维细胞在肾纤维化的发病机制中起着重要作用。然而，肾脏中骨髓源性成纤维细胞激活的信号机制尚不完全清楚。由于TGF-β1/Smad3信号已被证明在肾纤维化的发病机制中发挥重要作用，我们使用Smad3敲除小鼠和Smad3空单核细胞研究了Smad3在梗阻性损伤后肾脏骨髓源性成纤维细胞活化中的作用。与野生型小鼠相比，smad3基因敲除小鼠在梗阻性损伤后肾脏中积累的骨髓源性成纤维细胞明显减少。此外，Smad3基因敲除小鼠在梗阻肾脏中表现出较少的肌成纤维细胞活化和α-SMA表达。与这些发现一致，Smad3基因缺失减少了总胶原沉积，抑制了细胞外基质蛋白的表达。此外，与移植Smad3+/+骨髓细胞的野生型小鼠相比，移植Smad3−/−骨髓细胞的野生型小鼠在梗阻性损伤的肾脏中显示出更少的骨髓源性成纤维细胞，并且显示出更轻的肾纤维化。在培养的单核细胞中，TGF-β1诱导Smad3磷酸化，Smad3缺失可消除TGF-β1诱导的α-SMA和细胞外基质蛋白的表达。综上所述，我们的研究结果表明，在肾纤维化的发病过程中，Smad3信号在肾脏骨髓源性成纤维细胞的激活中起着重要作用。
Recent studies have demonstrated that bone marrow-derived fibroblasts contribute significantly to the pathogenesis of renal fibrosis. However, the signaling mechanisms underlying the activation of bone marrow-derived fibroblasts in the kidney are incompletely understood. Since TGF-β1/Smad3 signaling has been shown to play an important role in the pathogenesis of kidney fibrosis, we investigated the role of Smad3 in the activation of bone marrow-derived fibroblasts in the kidney following obstructive injury using Smad3 knockout mice and Smad3 null monocytes. Compared with wild-type mice, Smad3-knockout mice accumulated significantly fewer bone marrow-derived fibroblasts in the kidney after obstructive injury. Furthermore, Smad3 knockout mice exhibited less myofibroblast activation and expressed less α-SMA in the obstructed kidney. Consistent with these findings, genetic deletion of Smad3 reduced total collagen deposition and suppressed expression of extracellular matrix proteins. Moreover, wild-type mice engrafted with Smad3−/− bone marrow cells displayed fewer bone marrow-derived fibroblasts in the kidney with obstructive injury and showed less severe renal fibrosis compared with wild-type mice engrafted with Smad3+/+ bone marrow cells. In cultured monocytes, TGF-β1 induced phosphorylation of Smad3 and Smad3 deficiency abolished TGF-β1-induced expression of α-SMA and extracellular matrix proteins. Taken together, our results demonstrate that Smad3 signaling plays an essential role in the activation of bone marrow-derived fibroblasts in the kidney during the pathogenesis of renal fibrosis.