c-fms blockade reverses glomerular macrophage infiltration and halts development of crescentic anti-GBM glomerulonephritis in the rat
c-fms blockade reverses glomerular macrophage infiltration and halts development of crescentic anti-GBM glomerulonephritis in the rat
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DOI：
10.1038/labinvest.2011.61
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发表时间：
2011-07-01
影响因子：
5
通讯作者：
Nikolic-Paterson, David J.
中科院分区：
文献类型：
--
作者：
Han, Yingjie;Ma, Frank Y.;Nikolic-Paterson, David J.
消耗和过继转移研究表明，巨噬细胞诱导实验性抗肾小球基底膜（抗GBM）肾小球肾炎的肾小球病变。然而，目前还没有治疗策略可以快速和选择性地从肾小球中去除这些细胞，以阻止疾病的发展。本研究检查了是否抑制巨噬细胞集落刺激因子（称为c-fms）的受体，这是选择性表达的单核细胞/巨噬细胞，可以消除巨噬细胞浸润在大鼠模型的新月体抗GBM肾小球肾炎。从注射抗GBM血清开始，直至1、5或14天后处死，Wistar-Kyoto大鼠每天2次，每次10或30 mg/kg fms-I（一种选择性c-fms激酶抑制剂）。fms-I处理在第1天对肾小球巨噬细胞浸润仅有微小的影响，并且不能阻止随后的蛋白尿诱导。然而，fms-I治疗在第5天使肾小球巨噬细胞浸润减少60%，并且在第14天完全逆转巨噬细胞浸润。此外，fms-I治疗在第1天和第5天下调了促炎分子（TNF-α、NOS 2、MMP-12、CCL 2和IL-12）的肾小球表达，表明抑制了巨噬细胞M1型反应。尽管肾小球足细胞的显著早期损失、持续的蛋白尿和肾小球簇与鲍曼氏囊的粘连，但巨噬细胞浸润的逆转阻止了肾小球硬化、新月体形成、肾小管间质损伤和肾功能障碍的发展。总之，本研究确定了c-fms激酶抑制作为急性肾小球损伤中靶向浸润巨噬细胞的选择性方法，这可能对快速进展性新月体肾小球肾炎具有治疗潜力。实验室调查（2011）91，978-991; doi：10.1038/labinvest.2011.61; 2011年4月25日在线发表
Depletion and adoptive transfer studies have demonstrated that macrophages induce glomerular lesions in experimental anti-glomerular basement membrane (anti-GBM) glomerulonephritis. However, there is no current therapeutic strategy that can rapidly and selectively remove these cells from the glomerulus in order to halt disease development. This study examined whether inhibition of the receptor for macrophage colony-stimulating factor (known as c-fms), which is selectively expressed by monocyte/macrophages, can eliminate the macrophage infiltrate in a rat model of crescentic anti-GBM glomerulonephritis. Wistar-Kyoto rats were treated with 10 or 30 mg/kg bid of fms-I (a selective c-fms kinase inhibitor) from the time of anti-GBM serum injection until being killed 1, 5 or 14 days later. fms-I treatment had only a minor effect upon the glomerular macrophage infiltrate on day 1 and did not prevent the subsequent induction of proteinuria. However, fms-I treatment reduced the glomerular macrophage infiltrate by 60% at day 5 and completely reversed the macrophage infiltrate by day 14. In addition, fms-I treatment downregulated the glomerular expression of pro-inflammatory molecules (TNF-alpha, NOS2, MMP-12, CCL2 and IL-12) on days 1 and 5, suggesting a suppression of the macrophage M1-type response. Despite a significant early loss of glomerular podocytes, ongoing proteinuria and glomerular tuft adhesions to Bowman's capsule, the reversal of the macrophage infiltrate prevented the development of glomerulosclerosis, crescent formation, tubulointerstitial damage and renal dysfunction. In conclusion, this study has identified c-fms kinase inhibition as a selective approach to target infiltrating macrophages in acute glomerular injury, which may have therapeutic potential in rapidly progressive crescentic glomerulonephritis. Laboratory Investigation (2011) 91, 978-991; doi:10.1038/labinvest.2011.61; published online 25 April 2011