CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice
CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice
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DOI：
10.1172/jci39087
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发表时间：
2009-08-01
影响因子：
15.9
通讯作者：
Kelley, Vicki R.
中科院分区：
文献类型：
--
作者：
Menke, Julia;Iwata, Yasunori;Kelley, Vicki R.
缺血性肾损伤后的肾小管损伤通常是可逆的，肾小管上皮细胞（TEC）增殖是肾小管修复的标志。巨噬细胞参与组织修复，而 CSF-1（主要的巨噬细胞生长因子）由 TEC 表达。因此，我们使用急性肾损伤和修复模型、缺血/再灌注（I/R）测试了 CSF-1 对于肾小管修复至关重要的假设。 I/R后注射CSF-1的小鼠表现出加速愈合，肾小管病理减少、纤维化减少和肾功能改善证明了这一点。值得注意的是，CSF-1 治疗增加了 TEC 增殖并减少了 TEC 凋亡。此外，I/R后施用CSF-1受体特异性（CSF-IR特异性）抗体会增加肾小管病理和纤维化，抑制TEC增殖并加剧TEC凋亡。为了确定巨噬细胞对CSF-1依赖性肾修复的贡献，我们评估了CSF-1对CD11b(+)细胞被基因消融的小鼠I/R的影响，并确定巨噬细胞仅部分负责CSF-1依赖性肾小管修复。我们发现，在小鼠和人类肾损伤后，TEC 表达 CSF-1R，并且该受体在 TEC 中上调并与 CSF-1 共表达。此外，通过 CSF-1R 的信号传导可刺激人和小鼠 TEC 的增殖并减少细胞凋亡。综上所述，这些数据表明 CSF-1 通过巨噬细胞依赖性机制和对 TEC 的直接自分泌/旁分泌作用介导肾脏修复。
Tubular damage following ischemic renal injury is often reversible, and tubular epithelial cell (TEC) proliferation is a hallmark of tubular repair. Macrophages have been implicated in tissue repair, and CSF-1, the principal macrophage growth factor, is expressed by TECs. We therefore tested the hypothesis that CSF-1 is central to tubular repair using an acute renal injury and repair model, ischemia/reperfusion (I/R). Mice injected with CSF-1 following I/R exhibited hastened healing, as evidenced by decreased tubular pathology, reduced fibrosis, and improved renal function. Notably, CSF-1 treatment increased TEC proliferation and reduced TEC apoptosis. Moreover, administration of a CSF-1 receptor-specific (CSF-IR-specific) antibody after I/R increased tubular pathology and fibrosis, suppressed TEC proliferation, and heightened TEC apoptosis. To determine the contribution of macrophages to CSF-1-dependent renal repair, we assessed the effect of CSF-1 on I/R in mice in which CD11b(+) cells were genetically ablated and determined that macrophages only partially accounted for CSF-1-dependent tubular repair. We found that TECs expressed the CSF-1R and that this receptor was upregulated and coexpressed with CSF-1 in TECs following renal injury in mice and humans. Furthermore, signaling via the CSF-1R stimulated proliferation and reduced apoptosis in human and mouse TECs. Taken together, these data suggest that CSF-1 mediates renal repair by both a macrophage-dependent mechanism and direct autocrine/paracrine action on TECs.