Division of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America ; Division of Nephrology, Department of Medicine, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangzhou, China.
PLoS One. 2013 Oct 10;8(10):e77493. doi: 10.1371/journal.pone.0077493. eCollection 2013.
Recent studies have shown that bone marrow-derived fibroblasts contribute significantly to the pathogenesis of renal fibrosis. However, the molecular mechanisms underlying the recruitment of bone marrow-derived fibroblasts into the kidney are incompletely understood. Bone marrow-derived fibroblasts express the chemokine receptor--CCR2. In this study, we tested the hypothesis that CCR2 participates in the recruitment of fibroblasts into the kidney during the development of renal fibrosis. Bone marrow-derived collagen-expressing GFP⁺ fibroblasts were detected in the obstructed kidneys of chimeric mice transplanted with donor bone marrow from collagen α1(I)-GFP reporter mice. These bone marrow-derived fibroblasts expressed PDGFR-β and CCR2. CCR2 knockout mice accumulated significantly fewer bone marrow-derived fibroblast precursors expressing the hematopoietic marker-CD45 and the mesenchymal markers-PDGFR-β or procollagen I in the obstructed kidneys compared with wild-type mice. Furthermore, CCR2 knockout mice displayed fewer bone marrow-derived myofibroblasts and expressed less α-SMA or FSP-1 in the obstructed kidneys compared with wild-type mice. Consistent with these findings, genetic deletion of CCR2 inhibited total collagen deposition and suppressed expression of collagen I and fibronectin. Moreover, genetic deletion of CCR2 inhibits MCP-1 and CXCL16 gene expression associated with a reduction of inflammatory cytokine expression and macrophage infiltration, suggesting a linear interaction between two chemokines/ligand receptors in tubular epithelial cells. Taken together, our results demonstrate that CCR2 signaling plays an important role in the pathogenesis of renal fibrosis through regulation of bone marrow-derived fibroblasts. These data suggest that inhibition of CCR2 signaling could constitute a novel therapeutic approach for fibrotic kidney disease.
最近的研究表明，骨髓源性成纤维细胞对肾纤维化的发病机制有重要贡献。然而，骨髓源性成纤维细胞招募到肾脏的分子机制尚不完全清楚。骨髓源性成纤维细胞表达趋化因子受体 CCR2。在这项研究中，我们检验了这样一个假说，即 CCR2 参与了肾纤维化过程中成纤维细胞向肾脏的募集。在骨髓来源的胶原 α1(I)-GFP 报告小鼠的嵌合小鼠中，在梗阻的肾脏中检测到表达 GFP⁺胶原的骨髓源性成纤维细胞。这些骨髓源性成纤维细胞表达 PDGFR-β 和 CCR2。与野生型小鼠相比，CCR2 敲除小鼠在梗阻的肾脏中积累的表达造血标志物-CD45 和间充质标志物-PDGFR-β 或前胶原 I 的骨髓源性成纤维细胞前体明显减少。此外，与野生型小鼠相比，CCR2 敲除小鼠在梗阻的肾脏中表达的α-SMA 或 FSP-1 较少，骨髓源性肌成纤维细胞也较少。与这些发现一致，CCR2 的基因缺失抑制了总胶原沉积，并抑制了胶原 I 和纤连蛋白的表达。此外，CCR2 的基因缺失抑制了与炎症细胞因子表达和巨噬细胞浸润减少相关的 MCP-1 和 CXCL16 基因表达，这表明在肾小管上皮细胞中两种趋化因子/配体受体之间存在线性相互作用。综上所述，我们的研究结果表明，CCR2 信号通路通过调节骨髓源性成纤维细胞在肾纤维化发病机制中发挥重要作用。这些数据表明，抑制 CCR2 信号通路可能为纤维性肾病提供一种新的治疗方法。
