PMID- 17968528
OWN - NLM
STAT- MEDLINE
DCOM- 20081017
LR  - 20220317
IS  - 0012-186X (Print)
IS  - 0012-186X (Linking)
VI  - 51
IP  - 1
DP  - 2008 Jan
TI  - Monocyte chemoattractant protein-1 has prosclerotic effects both in a mouse model 
      of experimental diabetes and in vitro in human mesangial cells.
PG  - 198-207
AB  - 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.
FAU - Giunti, S
AU  - Giunti S
AD  - Department of Internal Medicine, University of Turin, C.so AM Dogliotti, 14, 
      10126, Turin, Italy. sara_giunti@katamail.com
FAU - Tesch, G H
AU  - Tesch GH
FAU - Pinach, S
AU  - Pinach S
FAU - Burt, D J
AU  - Burt DJ
FAU - Cooper, M E
AU  - Cooper ME
FAU - Cavallo-Perin, P
AU  - Cavallo-Perin P
FAU - Camussi, G
AU  - Camussi G
FAU - Gruden, G
AU  - Gruden G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20071030
PL  - Germany
TA  - Diabetologia
JT  - Diabetologia
JID - 0006777
RN  - 0 (Chemokine CCL2)
RN  - 0 (Collagen Type IV)
RN  - 0 (Fibronectins)
RN  - 0 (NF-kappa B)
RN  - 0 (Transforming Growth Factor beta1)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Chemokine CCL2/*genetics/*physiology
MH  - Collagen Type IV/metabolism
MH  - Diabetes Mellitus, Experimental/*metabolism
MH  - Diabetic Nephropathies
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Fibronectins/metabolism
MH  - Humans
MH  - Mesangial Cells/*metabolism
MH  - Mice
MH  - Models, Biological
MH  - NF-kappa B/metabolism
MH  - Time Factors
MH  - Transforming Growth Factor beta1/metabolism
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
EDAT- 2007/10/31 09:00
MHDA- 2008/10/18 09:00
CRDT- 2007/10/31 09:00
PHST- 2007/06/22 00:00 [received]
PHST- 2007/08/03 00:00 [accepted]
PHST- 2007/10/31 09:00 [pubmed]
PHST- 2008/10/18 09:00 [medline]
PHST- 2007/10/31 09:00 [entrez]
AID - 10.1007/s00125-007-0837-3 [doi]
PST - ppublish
SO  - Diabetologia. 2008 Jan;51(1):198-207. doi: 10.1007/s00125-007-0837-3. Epub 2007 
      Oct 30.