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The American journal of the medical sciences

The Protective Mechanism of Fluorofenidone in Renal Interstitial Inflammation and Fibrosis.


PMID 26035627

Abstract

Deregulated inflammation has been implicated in the development of renal interstitial fibrosis and progressive renal failure. Previous work has established that fluorofenidone, a pyridone agent, attenuates renal fibrosis. However, the mechanism by which fluorofenidone prevents renal fibrosis remains unclear. The aim of this study was to investigate the in vivo effects of fluorofenidone on unilateral ureteral obstruction-induced fibrosis and the involved molecular mechanism in mouse peritoneal macrophages. Renal fibrosis was induced in rat by unilateral ureteral obstruction for 3, 7 or 14 days. Ipsilateral kidneys were harvested for morphologic analysis. Leukocyte infiltration was assessed by immunohistochemistry staining. The expression of chemokines (MCP-1, RANTAS, IP-10, MIP-1α and MIP-1β) and pro-inflammatory cytokines (TNF-α and IL-1β) was measured by enzyme-linked immunosorbent assay and real-time polymerase chain reaction. Mouse peritoneal macrophages and HK-2 cells were incubated with necrotic MES-13 cells or TNF-α in the presence or absence of fluorofenidone. The production of MCP-1 was measured by enzyme-linked immunosorbent assay, and phosphorylation of ERK1/2, p38 and JNK was quantified by Western blot. Fluorofenidone treatment hampered renal pathologic change and interstitial collagen deposition. Leukocyte infiltration and the expression of chemokines (MCP-1, RANTES, IP-10, MIP-1α and MIP-1β) and pro-inflammatory cytokines (IL-1α) in kidney were significantly reduced by fluorofenidone treatment. Mechanistically, fluorofenidone significantly inhibited TNF-α or necrotic cell-induced activation of MAP kinase pathways in vitro. Fluorofenidone serves as a novel anti-inflammatory agent that attenuates ureteral obstruction-induced renal interstitial inflammation and fibrosis, possibly through the inhibition of the microtubule-associated protein kinase pathways.

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