title: Role of CX3C-chemokine CX3C-L/fractalkine expression in a model of slowly progressive renal failure.
abstract: BACKGROUND
  The chemokine/chemokine receptor pair CX(3)C-L/CX(3)C-R is suspected to play a role in renal fibrogenesis. The aim of this study was to investigate their function in an animal model of slowly progressive chronic renal failure.
  
  
  METHODS
  Functional data were analysed in folic acid nephropathy (FAN) at different time points (up to day 142 after induction). Immunostaining for CX(3)C-L, CD3, S100A4, collagen type I, fibronectin, alpha-smooth muscle actin, Tamm-horsfall protein, aquaporin 1 and 2 as well as quantitative real-time PCR (qRT-PCR) for CX(3)C-L, CX(3)C-R and fibroblast-specific protein 1 (FSP-1) were performed. Additionally, regulatory mechanisms and functional activity of CX(3)C-L in murine proximal and distal tubular epithelial cells as well as in fibroblasts were investigated.
  
  
  RESULTS
  CX(3)C-L/GAPDH ratio was upregulated in FAN 3.4-fold at day 7 further increasing up to 7.1-fold at day 106. The expression of mRNA CX(3)C-L correlated well with CX(3)C-R (R(2) = 0.96), the number of infiltrating CD3+ cells (R(2) = 0.60) and the degree of tubulointerstitial fibrosis (R(2) = 0.56) and moderately with FSP-1 (R(2) = 0.33). Interleukin-1beta, tumour necrosis factor-alpha, transforming growth factor-beta as well as the reactive oxygen species (ROS) H(2)O(2) were identified by qRT-PCR as inductors of CX(3)C-L/fractalkine (FKN) in tubular epithelial cells. Functionally, CX(3)C-L/FKN chemoattracts peripheral blood mononuclear cells, activates several aspects of fibrogenesis and induces the mitogen-activated protein kinases in renal fibroblasts.
  
  
  CONCLUSIONS
  In FAN, there is a good correlation between the expression of CX(3)C-L with markers of interstitial inflammation and fibrosis which may result from upregulation by pro-inflammatory and pro-fibrotic cytokines as well as by ROS in tubular epithelial cells. The FKN system may promote renal inflammation and renal fibrogenesis.
authors.affiliation: Department of Nephrology and Rheumatology, Georg-August University Göttingen, 37075 Göttingen, Germany. mkoziolek@med.uni-goettingen.de
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Koziolek
authors.forename: Gerhard-Anton
authors.initials: GA
authors.lastname: Müller
authors.forename: Antonia
authors.initials: A
authors.lastname: Zapf
authors.forename: Daniel
authors.initials: D
authors.lastname: Patschan
authors.forename: Holger
authors.initials: H
authors.lastname: Schmid
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.forename: Stefan
authors.initials: S
authors.lastname: Koschnick
authors.forename: Radovan
authors.initials: R
authors.lastname: Vasko
authors.forename: Carsten
authors.initials: C
authors.lastname: Bramlage
authors.forename: Frank
authors.initials: F
authors.lastname: Strutz
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D020523:Chemokines, CX3C / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005355:Fibrosis; D005492:Folic Acid / Q000009:adverse effects; D006801:Humans; D007686:Kidney Tubules, Distal / Q000378:metabolism* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D017382:Reactive Oxygen Species / Q000378:metabolism; D051437:Renal Insufficiency / Q000139:chemically induced / Q000378:metabolism*; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins
chemical_list: D002135:Calcium-Binding Proteins; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D016207:Cytokines; D017382:Reactive Oxygen Species; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D005492:Folic Acid