Blockade of IP-10/CXCR3 promotes progressive renal fibrosis.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Izaya
I
Nakaya
Takashi
T
Wada
Kengo
K
Furuichi
Norihiko
N
Sakai
Kiyoki
K
Kitagawa
Hitoshi
H
Yokoyama
Yuko
Y
Ishida
Toshikazu
T
Kondo
Takeshi
T
Sugaya
Hiroshi
H
Kawachi
Fujio
F
Shimizu
Shosaku
S
Narumi
Makoto
M
Haino
Craig
C
Gerard
Kouji
K
Matsushima
Shuichi
S
Kaneko
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation; D005355:Fibrosis; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000172:deficiency* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation; D014517:Ureteral Obstruction / Q000150:complications
D000911:Antibodies, Monoclonal; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D053773:Transforming Growth Factor beta1; D017228:Hepatocyte Growth Factor; D006909:Hydroxyproline