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Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis
Takashi Wada1, Kengo Furuichi, Norihiko Sakai
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.
Insights
Gene therapy using a modified Monocyte Chemoattractant Protein-1 (MCP-1) gene successfully reduced kidney fibrosis in mice. This approach targets the MCP-1/CCR2 pathway, offering a potential treatment for renal fibrosis.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Monocyte chemoattractant protein (MCP)-1, also known as CCL2, is implicated in progressive organ fibrosis.
- The MCP-1/CCR2 signaling pathway is a key regulator in the pathogenesis of renal fibrosis.
Purpose of the Study:
- To investigate the therapeutic efficacy of blocking MCP-1/CCR2 signaling in a mouse model of renal fibrosis.
- To evaluate the potential of gene therapy using a modified MCP-1 gene for treating renal fibrosis.
Main Methods:
- A unilateral ureteral obstruction nephropathy model was used in mice.
- Gene transfer of an N-terminal deletion mutant of human MCP-1 (7ND) into skeletal muscle was performed.
- Assessment of renal fibrosis markers, including type I collagen deposition, TGF-beta expression, and immune cell infiltration, was conducted.
Main Results:
- Gene transfer of 7ND significantly ameliorated renal fibrosis.
- This resulted in decreased type I collagen deposition and reduced TGF-beta expression.
- Cell infiltration, primarily CCR2-positive macrophages, and MCP-1 expression in kidneys were also reduced.
Conclusions:
- MCP-1/CCR2 signaling drives macrophage recruitment, exacerbating renal fibrosis.
- Gene therapy targeting MCP-1/CCR2 with the 7ND mutant shows promise as a therapeutic strategy for renal fibrosis.
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