Targeting c-fms kinase attenuates chronic aristolochic acid nephropathy in mice
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AbstractAristolochic 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.
All Author(s) ListDai X.Y., Huang X.R., Zhou L., Zhang L., Fu P., Manthey C., Nikolic-Paterson D.J., Lan H.Y.
Journal nameOncotarget
Year2016
Month1
Day1
Volume Number7
Issue Number10
PublisherImpact Journals
Place of PublicationUnited States
Pages10841 - 10856
ISSN1949-2553
LanguagesEnglish-United Kingdom
KeywordsAristolochic acid nephropathy, Fibrosis, Fms-i, Inflammation, Macrophages, Pathology section

Last updated on 2021-17-01 at 01:18