Research Papers: Pathology:

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

Xiao Y. Dai, Xiao R. Huang, Xiao R. Huang, Li Zhou, Lin Zhang, Ping Fu, Carl Manthey, David J. Nikolic-Paterson and Hui Y. Lan _

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Oncotarget. 2016; 7:10841-10856. https://doi.org/10.18632/oncotarget.7460

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Xiao Y. Dai1,2,3,*, Xiao R. Huang1,*, Li Zhou3, Lin Zhang2, Ping Fu3, Carl Manthey4, David J. Nikolic-Paterson5 and Hui Y. Lan1

1 Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China

2 Division of Nephrology, Mianyang Central Hospital, Mianyang, China

3 Division of Nephrology, West China Hospital of Sichuan University, Chengdu, China

4 Janssen Research & Development, LLC, Radnor, PA, USA

5 Department of Nephrology, Monash Health and Monash University Department of Medicine, Clayton, VIC, Australia

* These authors have contributed equally to this work

Correspondence to:

Hui Y. Lan, email:

Keywords: aristolochic acid nephropathy, fms-I, macrophages, inflammation, fibrosis, Pathology Section

Received: November 23, 2015 Accepted: February 09, 2016 Published: February 17, 2016


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.

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