Monocyte chemoattractant protein-1 has prosclerotic effects both in a mouse model of experimental diabetes and in vitro in human mesangial cells |
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Authors: | S Giunti G H Tesch S Pinach D J Burt M E Cooper P Cavallo-Perin G Camussi G Gruden |
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Institution: | (1) Department of Internal Medicine, University of Turin, C.so AM Dogliotti, 14, 10126 Turin, Italy;(2) Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia;(3) Danielle Alberti Memorial Centre for Diabetic Complications, Diabetes and Metabolism Division, Baker Heart Research Institute, Melbourne, Victoria, Australia |
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Abstract: | Aims/hypothesis Diabetic nephropathy is characterised by mesangial extracellular matrix accumulation. Monocyte chemoattractant protein-1 (MCP-1),
a chemokine promoting monocyte infiltration, is upregulated in the diabetic glomerulus. We performed in vitro and in vivo
studies to examine whether MCP-1 may have prosclerotic actions in the setting of diabetes, presumably via its receptor, chemokine
(C-C motif) receptor 2 (CCR2), which has been described in mesangial cells.
Methods Human mesangial cells were exposed to recombinant human (rh)-MCP-1 (100 ng/ml) for 12, 24 and 48 h and to rh-MCP-1 (10, 100
and 200 ng/ml) for 24 h. Fibronectin, collagen IV and transforming growth factor, beta 1 (TGF-β1) protein levels were measured
by ELISA and pericellular polymeric fibronectin levels by western blotting. The intracellular mechanisms were investigated
using specific inhibitors for CCR2, nuclear factor kappa B (NF-κB), p38 mitogen-activated protein kinase and protein kinase
C, and an anti-TGF-β1 blocking antibody. In both non-diabetic and streptozotocin-induced diabetic mice that were deficient
or not in MCP-1, glomerular fibronectin accumulation was examined by immunohistochemistry, while cortical Tgf-β1 (also known as Tgfb1) and fibronectin mRNA and protein levels were examined by real-time PCR and western blotting.
Results In mesangial cells, MCP-1 binding to CCR2 induced a 2.5-fold increase in fibronectin protein levels at 24 h followed by a
rise in pericellular fibronectin, whereas no changes were seen in collagen IV production. MCP-1-induced fibronectin production
was TGF-β1- and NF-κB-dependent. In diabetic mice, loss of MCP-1 diminished glomerular fibronectin protein production and
both renal cortical Tgf-β1 and fibronectin mRNA and protein levels.
Conclusions/interpretation Our in vitro and in vivo findings indicate a role for the MCP-1/CCR2 system in fibronectin deposition in the diabetic glomerulus,
providing a new therapeutic target for diabetic nephropathy. |
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Keywords: | CCR2 Chemokine (C-C motif) receptor 2 Diabetic nephropathy Experimental diabetes Fibronectin Glomerulosclerosis Glomerulus MCP-1 Mesangial cells Monocyte chemoattractant protein-1 |
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