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From the Department of Gastroenterology and Nephrology,* Graduate School of Medical Science, the Division of Blood Purification and the Department of Molecular Oncology, Cancer Research Institute, and the Institute for Experimental Animals, Kanazawa University, Kanazawa, Japan; Sanwa Kagaku Kenkyusho Company, Limited, Inabe, Japan; the Second Department of Pathology,¶ Kumamoto University School of Medicine, Kumamoto, Japan; the Department of Molecular Preventive Medicine,** Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and the Section of Molecular Genetics and Microbiology and Institute for Cellular and Molecular Biology,|| University of Texas, Austin, Texas
Fibrosis is a hallmark of progressive organ diseases. Monocyte chemoattractant protein (MCP)-1, also termed as macrophage chemotactic and activating factor (MCAF/CCL2) and its receptor, CCR2 are presumed to contribute to progressive fibrosis. However, the therapeutic efficacy of MCP-1/CCR2 blockade in progressive fibrosis remains to be investigated. We hypothesized that blockade of CCR2 may lead to the improvement of fibrosis. To achieve this goal, we investigated renal interstitial fibrosis induced by a unilateral ureteral obstruction in CCR2 gene-targeted mice and mice treated with propagermanium or RS-504393, CCR2 inhibitors. Cell infiltrations, most of which were F4/80-positive, were reduced in CCR2 knockout mice. In addition, dual staining revealed that CCR2-positive cells were mainly F4/80-positive macrophages. Importantly, CCR2 blockade reduced renal interstitial fibrosis relative to wild-type mice. Concomitantly, renal transcripts and protein of MCP-1, transforming growth factor-ß, and type I collagen were decreased in CCR2-null mice. Further, this CCR2-dependent loop for renal fibrosis was confirmed by treatment with CCR2 antagonists in a unilateral ureteral obstruction model. These findings suggest that the therapeutic strategy of blocking CCR2 may prove beneficial for progressive fibrosis via the decrease in infiltration and activation of macrophages in the diseased kidneys.
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