Effect of the Monocyte Chemoattractant Protein-1/CC Chemokine Receptor 2 System on Nephrin Expression in Streptozotocin-Treated Mice and Human Cultured Podocytes
Effect of the Monocyte Chemoattractant Protein-1/CC Chemokine Receptor 2 System on Nephrin Expression in Streptozotocin-Treated Mice and Human Cultured Podocytes Elena Tarabra 1 , Sara Giunti 1 , 2 , Federica Barutta 1 , Gennaro Salvidio 3 , Davina Burt 1 , Giacomo Deferrari 3 , Roberto Gambino 1 ,...
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Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2009-09, Vol.58 (9), p.2109-2118 |
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Zusammenfassung: | Effect of the Monocyte Chemoattractant Protein-1/CC Chemokine Receptor 2 System on Nephrin Expression in Streptozotocin-Treated
Mice and Human Cultured Podocytes
Elena Tarabra 1 ,
Sara Giunti 1 , 2 ,
Federica Barutta 1 ,
Gennaro Salvidio 3 ,
Davina Burt 1 ,
Giacomo Deferrari 3 ,
Roberto Gambino 1 ,
Daniela Vergola 3 ,
Silvia Pinach 1 ,
Paolo Cavallo Perin 1 ,
Giovanni Camussi 1 and
Gabriella Gruden 1
1 Diabetic Nephropathy Laboratory, Department of Internal Medicine, University of Turin, Italy;
2 Emergency Medicine Division, Umberto Parini Hospital, Aosta, Italy;
3 Department of Cardionephrology, University of Genoa, Italy.
Corresponding author: Gabriella Gruden, ggruden{at}hotmail.com .
Abstract
OBJECTIVE Monocyte chemoattractant protein-1 (MCP-1), a chemokine binding to the CC chemokine receptor 2 (CCR2) and promoting monocyte
infiltration, has been implicated in the pathogenesis of diabetic nephropathy. To assess the potential relevance of the MCP-1/CCR2
system in the pathogenesis of diabetic proteinuria, we studied in vitro if MCP-1 binding to the CCR2 receptor modulates nephrin
expression in cultured podocytes. Moreover, we investigated in vivo if glomerular CCR2 expression is altered in kidney biopsies
from patients with diabetic nephropathy and whether lack of MCP-1 affects proteinuria and expression of nephrin in experimental
diabetes.
RESEARCH DESIGN AND METHODS Expression of nephrin was assessed in human podocytes exposed to rh-MCP-1 by immunofluorescence and real-time PCR. Glomerular
CCR2 expression was studied in 10 kidney sections from patients with overt nephropathy and eight control subjects by immunohistochemistry.
Both wild-type and MCP-1 knockout mice were made diabetic with streptozotocin. Ten weeks after the onset of diabetes, albuminuria
and expression of nephrin, synaptopodin, and zonula occludens-1 were examined by immunofluorescence and immunoblotting.
RESULTS In human podocytes, MCP-1 binding to the CCR2 receptor induced a significant reduction in nephrin both mRNA and protein expression
via a Rho-dependent mechanism. The MCP-1 receptor, CCR2, was overexpressed in the glomerular podocytes of patients with overt
nephropathy. In experimental diabetes, MCP-1 was overexpressed within the glomeruli and the absence of MCP-1 reduced both
albuminuria and downregulation of nephrin and synaptopodin.
CONCLUSIONS These findings suggest that the MCP-1/CCR2 system may be relevant in the pathogenesis of proteinuria in diabetes.
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ISSN: | 0012-1797 1939-327X |
DOI: | 10.2337/db08-0895 |