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

SUBMITTER: Dai XY

PROVIDER: S-EPMC4905443 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Dai Xiao Y XY Huang Xiao R XR Zhou Li L Zhang Lin L Fu Ping P Manthey Carl C Nikolic-Paterson David J DJ Lan Hui Y HY

Oncotarget 20160301 10

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 ...[more]

PMID: 26909597

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Project description:Lycopene (LYC) is a carotenoid, has antioxidant properties. This study investigated whether lycopene attenuates aristolochic acids (AAs) -induced chronic kidney disease. In this experiment, lycopene was used to intervene C57BL/6 mice with renal injury induced by aristolochic acid exposure. The histomorphological changes and serological parameters of the kidney were measured in order to assess the alleviating effect of lycopene on renal injury in aristolochic acid nephropathy. In vitro and in vivo experiments were carried out to verify the main mechanism of action and drug targets of lycopene in improving aristolochic acid nephropathy (AAN) and by various experimental methods such as ELISA, immunohistochemistry, immunofluorescence, Western-blot and qRT-PCR. The results showed that oxidative stress injury was induced in the kidney of mice after AAI exposure, resulting in inflammatory response and tubular epithelial cell apoptosis. The results showed that the Nrf2/HO-1 antioxidant signaling pathway was inhibited after AAI exposure. AAI induces oxidative stress injury in the kidney, which ultimately leads to inflammation and tubular epithelial cell apoptosis. After LYC intervened in the body, it activated Nrf2 nuclear translocation and its downstream HO-1 and NQO1 antioxidant signaling pathways. LYC inhibited ROS production by renal tubular epithelial cells, and alleviated mitochondrial damage. LYC further modulated the TNF-α/NF-κB signaling cascade, thereby reduced the accumulation of inflammatory factors in the renal interstitium. Moreover, LYC was able to up-regulate the expression of Bcl-2, down-regulate Bax expression and inhibit the activation of cleaved forms of Caspase-9 and Caspase-3, which finally attenuated the apoptosis of the mitochondrial pathway induced by AAI exposure. It was concluded that lycopene was able to activate the Nrf2 antioxidant signaling pathway to maintain the homeostasis of renal oxidative stress and ultimately attenuated renal inflammatory response and apoptosis. These results suggested that lycopene can be used as a drug to relieve AAN.

Project description:Limitations in the current therapeutic strategies for the prevention of progression of chronic kidney disease (CKD) to end stage renal disease has been a drawback to improving patient recovery. It is therefore imperative that a solution is found to alleviate this problem and improve the health and well-being of patients overall. Aristolochic acid (AA) induced nephropathy, a type of nephrotoxic CKD is characterised by cortical tubular injury, inflammation, leading to interstitial fibrosis. Extracellular vesicles derived from human bone marrow mesenchymal stem cells (MSC-EVs) display therapeutic properties in various disease models including kidney injury. In the current study, we intended to investigate the ability of MSC-EVs on ameliorating tubular injury and interstitial fibrosis in a mouse model of aristolochic acid nephropathy (AAN). The chronic model of AAN is comprised of an intraperitoneal injection of AA in NSG mice, followed by a three-day incubation period and then inoculation of MSC-EVs intravenously. This routine was performed on a weekly basis for four consecutive weeks, accompanied by the monitoring of body weight of all mice. Blood and tissue samples were collected post sacrifice. All animals administered with AA developed kidney injury and renal fibrosis. A gradual loss of body weight was observed, together with a deterioration in kidney function. Although no significant recovery was observed in weight loss following treatment with MSC-EVs, a significant reduction in: blood creatinine and blood urea nitrogen (BUN), tubular necrosis, and interstitial fibrosis was observed. In addition, infiltration of CD45 positive immune cells, fibroblasts, and pericytes which were elevated in the interstitium post AA induced injury, were also significantly reduced by MSC-EVs. Kidneys were also subjected to molecular analyses to evaluate the regulation of pro-fibrotic genes. MSC-EVs significantly reduced AA induction of the pro-fibrotic genes α-Sma, Tgfb1 and Col1a1. A downregulation in pro-fibrotic genes was also observed in fibroblasts activated by AA injured mTECs in vitro. Furthermore, meta-analyses of miRNAs downregulated by MSC-EVs, such as miR21, revealed the regulation of multiple pathways involved in kidney injury including fibrosis, inflammation, and apoptosis. These results therefore suggest that MSC-EVs could play a regenerative and anti-fibrotic role in AAN through the transfer of biologically active cargo that regulates the disease both at a protein and genetic level.

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

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

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