title: Targeting c-fms kinase attenuates chronic aristolochic acid nephropathy in mice.
abstract: 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.
authors.affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.|Division of Nephrology, Mianyang Central Hospital, Mianyang, China.|Division of Nephrology, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Xiao Y
authors.initials: XY
authors.lastname: Dai
authors.affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Xiao R
authors.initials: XR
authors.lastname: Huang
authors.affiliation: Division of Nephrology, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Division of Nephrology, Mianyang Central Hospital, Mianyang, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Nephrology, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Fu
authors.affiliation: Janssen Research and Development, LLC, Radnor, PA, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Manthey
authors.affiliation: Department of Nephrology, Monash Health and Monash University Department of Medicine, Clayton, VIC, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Nikolic-Paterson
authors.affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Hui Y
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000633:toxicity*; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis / Q000139:chemically induced; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction
chemical_list: D034341:Aristolochic Acids; D047428:Protein Kinase Inhibitors; D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: Pathology Section; aristolochic acid nephropathy; fibrosis; fms-I; inflammation; macrophages