c-fms blockade reverses glomerular macrophage infiltration and halts development of crescentic anti-GBM glomerulonephritis in the rat

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