Targeting c-fms Kinase Attenuates Aristolochic Acid Nephropathy in Mice

X.Y. Dai, X.R. Huang, P. Fu, L. Zhou, C. Manthey, D.J. Nikolic-Paterson, H.Y. Lan
2015 Hong Kong Journal of Nephrology  
Aristolochic acid nephropathy (AAN) is a progressive chronic kidney disease related to the use of Chinese herbal medicine and is characterized by extensive tubulointerstitial fibrosis and inflammation with macrophage infiltration. However, treatment of AAN remains ineffective. Thus, the present study aimed to develop a new therapeutic strategy for chronic AAN by targeting macrophages with a selective inhibitor of tyrosine kinase activity of macrophage colony-stimulating factor receptor (fms-I).
more » ... Methods: Chronic AAN was induced in C57BL/6 mice by intraperitoneal injection of aristolochic acid at a dose of 5 mg/kg every other day for 4 weeks. fms-I in an optimal dose of 10 mg/kg twice daily (i.p) was given at the beginning of induction of AAN or at the established AAN on day 14. The therapeutic effect of fms-I on chronic AAN was examined at day 28. Results: Treatment with fms-I largely suppressed F4/80 + macrophage and CD3 + T cell infiltration and upregulation of proinflammatory cytokines (MIF, TNFa, MCP-1), resulting in protection against acute and chronic AAN by inhibiting 24-hour proteinuria, elevated levels of serum creatinine, upregulation of KIM-1, and progressive renal fibrosis including accumulation of a-SMA+ myofibroblasts and collagen I. Moreover, administration of fms-I to the established AAN at day 14 also halted the disease progression of chronic AAN at day 28. Further studies revealed that the therapeutic effect of fms-I on chronic AAN was associated with blockade of both NF-kB and TGF-b/Smad pathways. Conclusion: Macrophages play a pathogenic role in the development of chronic AAN. Targeting macrophages with fms-I has therapeutic potential for chronic AAN. http://dx.
doi:10.1016/j.hkjn.2015.09.007 fatcat:lqtmtehhbfdednw2suop6ctgke