Targeting renal macrophage accumulation via c-fms kinase reduces tubular apoptosis but fails to modify progressive fibrosis in the obstructed rat kidney

Ma FY, Liu J, Kitching AR, Manthey CL, Nikolic-Paterson DJ. Targeting renal macrophage accumulation via c-fms kinase reduces tubular apoptosis but fails to modify progressive fibrosis in the obstructed rat kidney. Am J Physiol Renal Physiol 296: F177-F185, 2009. First published November 15, 2008; doi: 10.1152/ajprenal.90498.2008.-The role of macrophages in promoting interstitial fibrosis in the obstructed kidney is controversial. Macrophage depletion studies in the unilateral ureter obstruction (UUO) model have produced opposing results, presumably reflecting the subtleties of the individual depletion methods used. To address this question, we targeted the macrophage colony-stimulating factor receptor, c-fms, which is uniquely expressed by cells of the monocyte/macrophage lineage. Administration of 5, 12.5, or 30 mg/kg (bid) of a selective inhibitor of c-fms kinase activity (fms-I) resulted in a dose-dependent inhibition of renal macrophage accumulation in the rat UUO model. This was due to inhibition of local macrophage proliferation in the obstructed kidney and, at higher doses, to depletion of circulating blood monocytes. To determine the contribution of macrophages to renal pathology in the obstructed kidney, groups of animals were treated with 30 mg/kg fms-I and killed 3, 7, or 14 days later. Complete inhibition of renal macrophage accumulation prevented upregulation of the macrophage-associated proinflammatory mediators, tumor necrosis factor (TNF)-alpha and matrix metalloproteinase-12, and significantly reduced tubular apoptosis. Macrophage depletion caused a minor reduction of interstitial myofibroblast accumulation and deposition of interstitial collagen IV at day 3, but no difference was seen in renal fibrosis on day 7 or 14. Similarly, the upregulation of collagen IV, fibronectin, transforming growth factor-beta 1 and connective tissue growth factor mRNA levels on day 7 and 14 in the obstructed kidney was unaffected by macrophage depletion. In conclusion, c-fms blockade was shown to selectively prevent interstitial macrophage accumulation and to reduce tubular apoptosis in the obstructed kidney, but it had no significant impact on the development of interstitial fibrosis.