Department of Nephrology, Monash Medical Centre, Clayton, VIC, Australia.
Lab Invest. 2011 Jul;91(7):978-91. doi: 10.1038/labinvest.2011.61. Epub 2011 Apr 25.
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-α, 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.
耗竭和过继转移研究表明，巨噬细胞在实验性抗肾小球基底膜（anti-GBM）肾小球肾炎中诱导肾小球病变。然而，目前没有一种治疗策略可以快速且选择性地从肾小球中清除这些细胞，以阻止疾病的发展。本研究探讨了抑制巨噬细胞集落刺激因子受体（称为 c-fms）是否可以消除新月体性抗 GBM 肾小球肾炎大鼠模型中的巨噬细胞浸润。Wistar-Kyoto 大鼠从抗 GBM 血清注射时起，每天接受 10 或 30mg/kg 双剂量 fms-I（一种选择性 c-fms 激酶抑制剂）治疗，直到 1、5 或 14 天后处死。fms-I 治疗对第 1 天的肾小球巨噬细胞浸润仅有轻微影响，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了 60%，并在第 14 天完全逆转了巨噬细胞浸润。此外，fms-I 治疗在第 1 天和第 5 天下调了肾小球内促炎分子（TNF-α、NOS2、MMP-12、CCL2 和 IL-12）的表达，表明抑制了巨噬细胞 M1 型反应。尽管肾小球足细胞早期大量丢失，持续性蛋白尿和肾小球毛糙附着于鲍曼氏囊，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 激酶抑制是一种针对急性肾小球损伤浸润巨噬细胞的选择性方法，在快速进展性新月体性肾小球肾炎中可能具有治疗潜力。
