title: The Protective Mechanism of Fluorofenidone in Renal Interstitial Inflammation and Fibrosis.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Nephrology (YT, FZ, LH, QY, JQ, BL, NW, YX, LW, WW, ZP, LT), Xiangya Hospital, Central South University, Changsha, Hunan, China; School of Pharmaceutical Sciences (GH), Central South University, Changsha, Hunan, China; State Key Laboratory of Medical Genetics of China (LT), Changsha, Hunan, China; Sunshine Lake Pharma Co, Ltd (JL), Guangdong, China; Surgical Department, North Shore University Hospital (KK), Manhasset, New York; and Central South University, Changsha, China.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Tang
authors.forename: Fangfang
authors.initials: F
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.forename: Qiongjing
authors.initials: Q
authors.lastname: Yuan
authors.forename: Jiao
authors.initials: J
authors.lastname: Qin
authors.forename: Bingxin
authors.initials: B
authors.lastname: Li
authors.forename: Nasui
authors.initials: N
authors.lastname: Wang
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Xie
authors.forename: Linghao
authors.initials: L
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Kevin
authors.initials: K
authors.lastname: Kwan
authors.forename: Zhangzhe
authors.initials: Z
authors.lastname: Peng
authors.forename: Gaoyun
authors.initials: G
authors.lastname: Hu
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Lijian
authors.initials: L
authors.lastname: Tao
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D015153:Blotting, Western; D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000378:metabolism; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005355:Fibrosis; D053582:Interleukin-1alpha / Q000096:biosynthesis; D007668:Kidney / Q000187:drug effects* / Q000276:immunology / Q000473:pathology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D009395:Nephritis, Interstitial / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011728:Pyridones / Q000008:administration & dosage / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley
chemical_list: C511655:5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone; D000893:Anti-Inflammatory Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D053582:Interleukin-1alpha; D011728:Pyridones