title: High glucose induced-macrophage activation through TGF-β-activated kinase 1 signaling pathway.
abstract: OBJECTIVE
  Transforming growth factor-β-activated kinase 1 (TAK1) plays a pivotal role in innate immune responses and kidney disease, and is critically involved in macrophage activation. However, there is a paucity of data to explore the role of high glucose (HG) in the regulation of TAK1 signaling and its functional role in macrophage activation. We assume that TAK1 signaling in hyperglycemic condition could be a key factor leading to macrophage activation and inflammation response.
  
  
  METHODS
  Mice macrophages were seeded on a 96-well cell culture plate; cell viability was tested after treatment with different concentration of TAK1 inhibitors. Cells were divided into groups (OZ300; MC; NC; HG; HG + OZ30, 100, 300 nM) and treated for given time course. Monocyte chemotactic protein1(MCP-1) and tumor necrosis factor-α (TNF-α) mRNA levels were evaluated by qRT-PCR. Flow cytometry and confocal microscopy are used to analyse the activated macrophage induced by HG. Expression levels of p-TAK1, TAB 1, p-JNK, p-p38MAPK, NF-κBpp65 were detected by western blot. Nuclear translocation of NF-κBp65 was assessed by confocal microscopy.
  
  
  RESULTS
  Our data revealed that high glucose not only significantly increased macrophage activation and subsequently abnormal high-expression of MCP-1 and TNF-α, but likewise remarkably enhanced TAK1 activation, MAPK phosphorylation, NF-κB expression in macrophages. Furthermore, pharmacological inhibition of TAK1 attenuated high glucose-triggered signal pathways, macrophage activation and inflammatory cytokines in a simulated diabetic environment.
  
  
  CONCLUSIONS
  Our findings suggested that high glucose activated macrophages mainly in TAK1/MAPKs and TAK1/NF-κB-dependent manners, which lead to the polarization of macrophages towards a pro-inflammatory phenotype, and finally lead to diabetic nephropathy. In sum, the study raises novel data about the molecular mechanisms involved in the high glucose-mediated inflammatory response in macrophages.
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China.
authors.forename: Xingxin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China.
authors.forename: Xiangming
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Fu
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China.
authors.forename: Shiyao
authors.initials: S
authors.lastname: Feng
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China. wuyonggui@medmail.com.cn.
authors.forename: Yonggui
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015025:Zearalenone / Q000031:analogs & derivatives / Q000494:pharmacology / Q000008:administration & dosage; D000099151:MAP Kinase Kinase Kinase 7; D007783:Lactones; D012118:Resorcinols
chemical_list: D018932:Chemokine CCL2; D005947:Glucose; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D015025:Zearalenone; D000099151:MAP Kinase Kinase Kinase 7; C505734:7-oxozeanol; D007783:Lactones; D012118:Resorcinols; C491768:Ccl2 protein, mouse
keywords: Diabetic nephropathy; High glucose; Inflammation; MAPKs; NF-κB; TAK1