Targeting c-fms kinase attenuates chronic aristolochic acid nephropathy in mice

• Published in: Oncotarget Vol. 7; no. 10; pp. 10841 - 10856
• Main Authors: Dai, Xiao Y, Huang, Xiao R, Zhou, Li, Zhang, Lin, Fu, Ping, Manthey, Carl, Nikolic-Paterson, David J, Lan, Hui Y
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 08.03.2016
• Subjects: Animals; Aristolochic Acids - toxicity; Disease Models, Animal; Disease Progression; Fibrosis - chemically induced; Inflammation - chemically induced; Inflammation - pathology; Kidney Diseases - chemically induced; Kidney Diseases - drug therapy; Kidney Diseases - enzymology; Kidney Diseases - pathology; Macrophages - drug effects; Macrophages - metabolism; Macrophages - pathology; Male; Mice; Mice, Inbred C57BL; Protein Kinase Inhibitors - pharmacology; Receptor, Macrophage Colony-Stimulating Factor - antagonists & inhibitors; Research Paper: Pathology; Signal Transduction; aristolochic acid nephropathy; fms-I; macrophages; Pathology Section; fibrosis; inflammation
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.7460

Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by some Chinese herbal medicines, but treatment remains ineffective. Macrophage accumulation is an early feature in human and experimental AAN; however, the role of macrophages in chronic AAN is unknown. We report here that targeting macrophages with fms-I, a selective inhibitor of the tyrosine kinase activity of the macrophage colony-stimulating factor receptor, suppressed disease progression in a mouse model of chronic AAN. Treatment with fms-I (10mg/kg/BID) from day 0 to 28 (prevention study) or from day 14 to 28 (intervention study) substantially inhibited macrophage accumulation and significantly improved renal dysfunction including a reduction in proteinuria and tubular damage. Progressive interstitial fibrosis (myofibroblast accumulation and collagen deposition) and renal inflammation (increased expression of MCP-1, MIF, and TNF-α) were also attenuated by fms-I treatment. These protective effects involved inhibition of TGF-β/Smad3 and NF-kB signaling. In conclusion, the present study establishes that macrophages are key inflammatory cells that exacerbates progressive tubulointerstitial damage in chronic AAN via mechanisms associated with TGF-β/Smad3-mediated renal fibrosis and NF-κB-driven renal inflammation. Targeting macrophages via a c-fms kinase inhibitor may represent a novel therapy for chronic AAN.