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: Xiao Y Dai, Xiao R Huang, Li Zhou, Lin Zhang, Ping Fu, Carl Manthey, David J Nikolic-Paterson, Hui Y Lan
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 10 Pg. 10841-56 (Mar 08 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26909597 (Publication Type: Journal Article)

Chemical References

• Aristolochic Acids
• Protein Kinase Inhibitors
• Receptor, Macrophage Colony-Stimulating Factor

Topics

• Animals
• Aristolochic Acids (toxicity)
• Disease Models, Animal
• Disease Progression
• Fibrosis (chemically induced)
• Inflammation (chemically induced, pathology)
• Kidney Diseases (chemically induced, drug therapy, enzymology, pathology)
• Macrophages (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Protein Kinase Inhibitors (pharmacology)
• Receptor, Macrophage Colony-Stimulating Factor (antagonists & inhibitors)
• Signal Transduction