Role of CX3C-chemokine CX3C-L/fractalkine expression in a model of slowly progressive renal failure.

Michael J Koziolek, Gerhard-Anton Müller, Antonia Zapf, Daniel Patschan, Holger Schmid, Clemens D Cohen, Stefan Koschnick, Radovan Vasko, Carsten Bramlage, Frank Strutz

Department of Nephrology and Rheumatology, Georg-August University Göttingen, 37075 Göttingen, Germany. mkoziolek@med.uni-goettingen.de

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 2010 Mar

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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. 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. 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. 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.

Citation

Michael J Koziolek, Gerhard-Anton Müller, Antonia Zapf, Daniel Patschan, Holger Schmid, Clemens D Cohen, Stefan Koschnick, Radovan Vasko, Carsten Bramlage, Frank Strutz. Role of CX3C-chemokine CX3C-L/fractalkine expression in a model of slowly progressive renal failure. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2010 Mar;25(3):684-98