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Blockade of IP-10/CXCR3 Promotes Progressive Renal Fibrosis

Nakaya I.a · Wada T.a, b · Furuichi K.a, b · Sakai N.a · Kitagawa K.a · Yokoyama H.c · Ishida Y.d · Kondo T.d · Sugaya T.e · Kawachi H.f · Shimizu F.f · Narumi S.g · Haino M.g · Gerard C.h · Matsushima K.g · Kaneko S.a
aDepartment of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, and bDivision of Blood Purification, Kanazawa University, Kanazawa, cDivision of Nephrology, Kanazawa Medical University, Kahoku, dDepartment of Forensic Medicine, Wakayama Medical University, Wakayama, eCMIC Company Ltd., Tokyo, fDepartment of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, and gDepartment of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; hPerlmutter Laboratory, Children’s Hospital and Harvard Medical School, Boston, Mass., USA Nephron Exp Nephrol 2007;107:e12–e21 (DOI:10.1159/000106505)


Background/Aim: Fibrosis is a hallmark of progressive organ disease. The 10-kDa interferon-inducible protein IP-10/CXCL10 is a potent chemoattractant for activated T lymphocytes, natural killer cells, and monocytes. However, the involvement of IP-10 in the pathogenesis of renal diseases viaits receptor, CXCR3, remains unclear. To contribute to the clarification of this issue was the aim of this study. Methods: The impacts of IP-10 on renal fibrosis were investigated in a unilateral ureteral obstruction model in CXCR3-deficient mice and mice treated with anti-IP-10-neutralizing monoclonal antibody. Anti-IP-10 monoclonal antibody (5 mg/kg/day) was injected intravenously once a day until sacrifice on days 1, 4, or 7 after treatment. The effects of IP-10 were confirmed in cultured tubular epithelial cells. Results: IP-10 and CXCR3 were upregulated in progressive renal fibrosis. Blockade of IP-10/CXCR3 promotes renal fibrosis, as evidenced by increases in interstitial fibrosis and hydroxyproline contents, concomitant decrease in hepatocyte growth factor expression, and converse increase in transforming growth factor-β1 in diseased kidneys. IP-10 blockade affected neither macrophage nor T cell infiltration in diseased kidneys. Conclusion: These results suggest that blockade of IP-10 via CXCR3 contributes to renal fibrosis, possibly by upregulation of transforming growth factor-β1, concomitant with downregulation of hepatocyte growth factor.


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