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

Takashi Wada, Kengo Furuichi, Norihiko Sakai, Yasunori Iwata, Kiyoki Kitagawa, Yuko Ishida, Toshikazu Kondo, Hiroyuki Hashimoto, Yoshiro Ishiwata, Naofumi Mukaida, Naohisa Tomosugi, Kouji Matsushima, Kensuke Egashira, Hitoshi Yokoyama

Research output: Contribution to journalArticle

143 Citations (Scopus)

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-β. 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 Mφ 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.

Original languageEnglish
Pages (from-to)940-948
Number of pages9
JournalJournal of the American Society of Nephrology
Volume15
Issue number4
DOIs
Publication statusPublished - Apr 1 2004

All Science Journal Classification (ASJC) codes

  • Nephrology

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    Wada, T., Furuichi, K., Sakai, N., Iwata, Y., Kitagawa, K., Ishida, Y., Kondo, T., Hashimoto, H., Ishiwata, Y., Mukaida, N., Tomosugi, N., Matsushima, K., Egashira, K., & Yokoyama, H. (2004). Gene Therapy via Blockade of Monocyte Chemoattractant Protein-1 for Renal Fibrosis. Journal of the American Society of Nephrology, 15(4), 940-948. https://doi.org/10.1097/01.ASN.0000120371.09769.80