Blockade of IP-10/CXCR3 promotes progressive renal fibrosis

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 via its receptor, CXCR3, remains unclear. To contribute to the clarification of this issue was the aim of this study.

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.

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.

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.