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

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Abstract

Background. The chemokine/chemokine receptor pair CX3C-L/CX3C-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 CX3C-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 CX3C-L, CX3C-R and fibroblast-specific protein 1 (FSP-1) were performed. Additionally, regulatory mechanisms and functional activity of CX3C-L in murine proximal and distal tubular epithelial cells as well as in fibroblasts were investigated.Results. CX3C-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 CX3C-L correlated well with CX3C-R (R2 = 0.96), the number of infiltrating CD3+ cells (R2 = 0.60) and the degree of tubulointerstitial fibrosis (R2 = 0.56) and moderately with FSP-1 (R2 = 0.33). Interleukin-1β, tumour necrosis factor-α, transforming growth factor-β as well as the reactive oxygen species (ROS) H2O2 were identified by qRT-PCR as inductors of CX3C-L/fractalkine (FKN) in tubular epithelial cells. Functionally, CX3C-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 CX3C-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.

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Koziolek, M. J., Müller, G. A., Zapf, A., Patschan, D., Schmid, H., Cohen, C. D., … Strutz, F. (2010). Role of CX3C-chemokine CX3C-L/fractalkine expression in a model of slowly progressive renal failure. Nephrology Dialysis Transplantation, 25(3), 684–698. https://doi.org/10.1093/ndt/gfp602

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