RGD Reference Report - Monocyte chemoattractant protein-1 has prosclerotic effects both in a mouse model of experimental diabetes and in vitro in human mesangial cells. - Rat Genome Database

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Monocyte chemoattractant protein-1 has prosclerotic effects both in a mouse model of experimental diabetes and in vitro in human mesangial cells.

Authors: Giunti, S  Tesch, GH  Pinach, S  Burt, DJ  Cooper, ME  Cavallo-Perin, P  Camussi, G  Gruden, G 
Citation: Giunti S, etal., Diabetologia. 2008 Jan;51(1):198-207. Epub 2007 Oct 30.
RGD ID: 2306991
Pubmed: PMID:17968528   (View Abstract at PubMed)
DOI: DOI:10.1007/s00125-007-0837-3   (Journal Full-text)

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-beta1) 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-kappaB), p38 mitogen-activated protein kinase and protein kinase C, and an anti-TGF-beta1 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-beta1 (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-beta1- and NF-kappaB-dependent. In diabetic mice, loss of MCP-1 diminished glomerular fibronectin protein production and both renal cortical Tgf-beta1 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Diabetic Nephropathies susceptibilityISOCcl2 (Mus musculus)2306991; 2306991associated with Diabetes Mellitus and ExperimentalRGD 
Diabetic Nephropathies susceptibilityIAGP 2306991associated with Diabetes Mellitus and ExperimentalRGD 

Objects Annotated

Genes (Rattus norvegicus)
Ccl2  (C-C motif chemokine ligand 2)

Genes (Mus musculus)
Ccl2  (C-C motif chemokine ligand 2)

Genes (Homo sapiens)
CCL2  (C-C motif chemokine ligand 2)

Objects referenced in this article
Gene CCL13 C-C motif chemokine ligand 13 Homo sapiens

Additional Information