Effect of the Monocyte Chemoattractant Protein-1/CC Chemokine Receptor 2 System on Nephrin Expression in Streptozotocin-Treated Mice and Human Cultured Podocytes
- Elena Tarabra1,
- Sara Giunti1,2,
- Federica Barutta1,
- Gennaro Salvidio3,
- Davina Burt1,
- Giacomo Deferrari3,
- Roberto Gambino1,
- Daniela Vergola3,
- Silvia Pinach1,
- Paolo Cavallo Perin1,
- Giovanni Camussi1 and
- Gabriella Gruden1
- 1Diabetic Nephropathy Laboratory, Department of Internal Medicine, University of Turin, Italy;
- 2Emergency Medicine Division, Umberto Parini Hospital, Aosta, Italy;
- 3Department 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.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received July 4, 2008.
- Accepted May 26, 2009.
- © 2009 by the American Diabetes Association.
