Role of macrophages in the fibrotic phase of rat crescentic glomerulonephritis.

Abstract

The ability of macrophages to cause acute inflammatory glomerular injury is well-established; however, the role of macrophages in the fibrotic phase of chronic kidney disease remains poorly understood. This study examined the role of macrophages in the fibrotic phase (days 14 to 35) of established crescentic glomerulonephritis. Nephrotoxic serum nephritis (NTN) was induced in groups of eight Wistar-Kyoto rats that were given a selective c-fms kinase inhibitor, fms-I, or vehicle alone from day 14 until being killed on day 35. Rats killed on day 14 NTN had pronounced macrophage infiltration with glomerular damage, fibrocellular crescents in 50% of glomeruli, tubulointerstitial damage, heavy proteinuria, and renal dysfunction. Glomerulosclerosis was more severe by day 35 in vehicle-treated rats, as was periglomerular and interstitial fibrosis, while proteinuria and renal dysfunction continued unabated and some parameters of tubular damage worsened. During the day 14-to-35 period, glomerular and interstitial macrophage infiltration decreased with an apparent change from a proinflammatory M1 phenotype to an alternatively activated M2 phenotype. Treatment with fms-I over days 14 to 35 selectively reduced blood monocyte numbers and abrogated glomerular and interstitial macrophage infiltration. This resulted in improved renal function, significantly reduced glomerular and interstitial fibrosis, and protection against further peritubular capillary loss. However, sustained proteinuria, tubular damage, and interstitial T cell infiltration and activation were unaffected. In conclusion, this study demonstrates that macrophages contribute to renal dysfunction and tissue damage in established crescentic glomerulonephritis as it progresses from the acute inflammatory to a chronic fibrotic phase.