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J Am Soc Nephrol. 2004 Apr;15(4):940-8.

Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis.

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  • 1Department of Gastroenterology and Nephrology, Graduate School of Medical Science and Division of Blood Purification, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan. twada@medf.m.kanazawa-u.ac.jp

Abstract

Monocyte chemoattractant protein (MCP)-1, also termed monocyte chemotactic and activating factor (MCAF)/CCL2, plays an important role in progressive organ fibrosis. It was hypothesized that MCP-1, through its cognate receptor, CCR2, regulates the pathogenesis and is therapeutically of importance for renal fibrosis. To achieve this goal, the therapeutic efficacy and efficiency in renal fibrosis induced by a unilateral ureteral obstruction nephropathy model in mice by the blockade of MCP-1/CCR2 signaling was studied. The delivery of N-terminal deletion mutant of the human MCP-1 gene, 7ND, into a skeletal muscle ameliorated renal fibrosis by resulting in decrease in the deposit of type I collagen and in reduced expression of TGF-beta. Concomitantly, gene transfer of 7ND reduced the cell infiltration, most of which were CCR2-positive macrophages, followed by the decrease in MCP-1 expression in the diseased kidneys. These observations suggest that MCP-1 through CCR2 signaling is responsible for Mphi recruitment, which augments downstream events, resulting in renal fibrosis. Moreover, these findings imply that gene therapy against MCP-1/CCR2 signaling via the mutant gene transferred strategy may serve a beneficial therapeutic application for renal fibrosis.

PMID:
15034096
[PubMed - indexed for MEDLINE]
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