NDT Advance Access originally published online on February 14, 2008
Nephrology Dialysis Transplantation 2008 23(6):1876-1885; doi:10.1093/ndt/gfm901
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Mesangial matrix-activated monocytes express functional scavenger receptors and accumulate intracellular lipid
1 Centre for Nephrology, Department of Medicine, Hampstead Campus, Royal Free and University College Medical School, London, NW3 2PF, UK 2 Faculty of Medicine and Biological Sciences, University of Leicester, LE1 9HN, UK 3 Department of Pathology, Royal Free and University College Medical School, London, NW3 2PF, UK
Correspondence and offprint requests to: Correspondence and offprint requests to: David C. Wheeler, Centre for Nephrology, Royal Free and University College Medical School, Hampstead Campus, Rowland Hill Street, London NW3 2PF, UK. Tel: +44-20-7830-2930; Fax: +44-20-7317-8591; E-mail: d.wheeler{at}medsch.ucl.ac.uk
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Abstract |
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Background. Monocyte recruitment into the mesangium and foam cell formation are recognized features of glomerular injury. External signals encountered by infiltrating mononuclear cells may determine their behaviour and thereby potentially influence disease outcome. Having previously demonstrated that monocytes are activated by exposure to matrix secreted by mesangial cells, we set out to determine whether matrix activation of monocytes led to expression of a macrophage phenotype.
Methods. THP-1 mononuclear cells were incubated for up to 120 h (5 days) with 500 µg/ml solublized matrix extracted from cultured human mesangial cells or with phorbol myristate ester (PMA-positive control) or albumin (negative control). Expression of peroxisome proliferator activated receptor-
(PPAR-) and of scavenger receptors was used as a marker of monocyte to macrophage differentiation. The presence of functional scavenger receptors was examined by assessing cellular uptake of Dil-labelled acetylated (Ac)-LDL by flow cytometry. Matrix-mediated LDL oxidation was assessed using agarose gel electrophoresis to determine mobility shifts.
Results. Matrix activation was associated with an increase in the expression of PPAR-, scavenger receptor-B (CD36) and scavenger receptor-A mRNA with a corresponding increase in PPAR- protein. Matrix-activated cells incubated with Ac-LDL demonstrated foam cell formation, whilst incubation with Dil-labelled Ac-LDL led to an increase in mean fluorescence intensity of 373 ± 34.8% (P < 0.005) as compared to albumin (100%) and PMA (423 ± 55.8%) (P < 0.005). This could be inhibited by the addition of excess unlabelled ligand, suggesting specific involvement of scavenger receptors. Incubation of LDL with mesangial matrix in the absence of mesangial cells or monocytes led to enhanced electrophoretic mobility of the recovered lipoprotein on agarose gel, an effect that could be inhibited by the addition of anti-oxidants.
Conclusion. Exposure to mesangial cell matrix induces expression of monocyte characteristics associated with a macrophage phenotype and promotes oxidation of LDL, thereby converting this lipoprotein to a scavenger receptor ligand. These observations may help to explain foam cell formation in the mesangium in the context of glomerular disease.
Keywords: foam cell; macrophage; mesangial matrix; monocyte; scavenger receptor
Received for publication: 26. 8.05
Accepted in revised form: 27.11.07
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