Menke Julia, Iwata Yasunori, Rabacal Whitney A, Basu Ranu, Yeung Yee G, Humphreys Benjamin D, Wada Takashi, Schwarting Andreas, Stanley E Richard, Kelley Vicki R
Laboratory of Molecular Autoimmune Disease, Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
J Clin Invest. 2009 Aug;119(8):2330-42. doi: 10.1172/JCI39087. Epub 2009 Jul 1.
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-1R-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.
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，主要的巨噬细胞生长因子CSF-1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），来检验CSF-1对肾小管修复至关重要这一假设。I/R后注射CSF-1的小鼠愈合加快，表现为肾小管病理改变减轻、纤维化减少和肾功能改善。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后给予CSF-1受体特异性（CSF-1R特异性）抗体增加了肾小管病理改变和纤维化，抑制了TEC增殖，并加剧了TEC凋亡。为了确定巨噬细胞对CSF-1依赖性肾修复的作用，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参与CSF-1依赖性肾小管修复。我们发现TEC表达CSF-1R，并且在小鼠和人类肾损伤后，该受体在TEC中上调并与CSF-1共表达。此外，通过CSF-1R的信号传导刺激了人和小鼠TEC的增殖并减少了凋亡。综上所述，这些数据表明CSF-1通过巨噬细胞依赖性机制以及对TEC的直接自分泌/旁分泌作用介导肾修复。
