Blockade of IP-10/CXCR3 Promotes Progressive Renal Fibrosis.
Nephron Exp Nephrol. 2007 Jul 5;107(1):e12-e21
Nakaya I, Wada T, Furuichi K, Sakai N, Kitagawa K, Yokoyama H, Ishida Y, Kondo T, Sugaya T, Kawachi H, Shimizu F, Narumi S, Haino M, Gerard C, Matsushima K, Kaneko S.
Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
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-beta1 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-beta1, concomitant with downregulation of hepatocyte growth factor. |
