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J Am Soc Nephrol 15:940-948, 2004
© 2004 American Society of Nephrology

BASIC SCIENCE

Gene Therapy via Blockade of Monocyte Chemoattractant Protein-1 for Renal Fibrosis

Takashi Wada*, Kengo Furuichi*, Norihiko Sakai*, Yasunori Iwata*, Kiyoki Kitagawa*, Yuko Ishida{ddagger}, Toshikazu Kondo{ddagger}, Hiroyuki Hashimoto§, Yoshiro Ishiwata§, Naofumi Mukaida{dagger}, Naohisa Tomosugi||, Kouji Matsushima, Kensuke Egashira# and Hitoshi Yokoyama*

*Department of Gastroenterology and Nephrology, Graduate School of Medical Science and Division of Blood Purification, and {dagger}Department of Molecular Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, {ddagger}Department of Forensic Medicine, Wakayama Medical University, Wakayama, §Sanwa Kagaku Co., Inabe, ||Division of Nephrology, Department of Internal Medicine, Kanazawa Medical University, Uchinada, Department of Molecular Preventive Medicine, University of Tokyo, and #Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.

Correspondence to: Dr. Takashi Wada, Division of Blood Purification, Department of Gastroenterology and Nephrology, Graduate School of Medical, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan. Phone: +81-76-265-2000, ext. 3462; Fax: +81-76-234-4250; E-mail: twada{at}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 M{phi} 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.




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