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

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

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4 Citations (Scopus)

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-a) were also attenuated by fms-I treatment. These protective effects involved inhibition of TGF-ß/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-ß/Smad3-mediated renal fibrosis and NF- kB-driven renal inflammation. Targeting macrophages via a c-fms kinase inhibitor may represent a novel therapy for chronic AAN.

Original languageEnglish
Pages (from-to)10841-10856
Number of pages16
JournalOncotarget
Volume7
Issue number10
DOIs
Publication statusPublished - 2016

Keywords

  • Aristolochic acid nephropathy
  • Fibrosis
  • Fms-i
  • Inflammation
  • Macrophages
  • Pathology section

Cite this

Dai, X. Y., Huang, X. R., Zhou, L., Zhang, L., Fu, P., Manthey, C., Nikolic-Paterson, D. J., & Lan, H. Y. (2016). Targeting c-fms kinase attenuates chronic aristolochic acid nephropathy in mice. Oncotarget, 7(10), 10841-10856. https://doi.org/10.18632/oncotarget.7460