The blocking of CXCR3 and CCR5 suppresses the infiltration of T lymphocytes in rat renal ischemia reperfusion.
BACKGROUND
Recent studies have identified T cells and natural killer T (NKT) cells as important mediators in renal ischemia-reperfusion (I/R) injury. The recruitment of these cells is induced by chemotaxis factors. We investigated the effects of blocking CXCR3 and CCR5 by an antagonist (TAK) using a rat renal I/R injury model.


METHODS
The Sprague-Dawley rats were either subjected to sham operation or left renal occlusion for 45 min followed by reperfusion and contralateral nephrectomy. The control or TAK groups were, respectively, injected phosphate-buffered saline or TAK at 30 min prior to clamp. Serum creatinine, tubular injury, chemokines expression and infiltrating cells were assessed.


RESULTS
TAK treatment significantly suppressed the elevation in serum creatinine (sham 0.40 ± 0.05 mg/dL, control 2.86 ± 0.67 mg/dL, TAK 1.60 ± 0.73 mg/dL) and resulted in a lower tubular injury score compared with the control group (sham 0, control 4.8 ± 0.3, TAK 3.3 ± 1). The mRNA expression of chemokines that bind to CXCR3 and CCR5 in the post-ischemic kidneys was elevated at 1 h after reperfusion in each group. Moreover, the infiltration of CD4+ T cells and CD8+ NKT cells in the control group increased compared with the sham group and TAK injection significantly suppressed the number of CD4+ T cells (sham 13.5 ± 3.5 × 10(4) cells, control 28.9 ± 15.4 × 10(4) cells, TAK 11.8 ± 3.5 × 10(4) cells) and the number of CD8+ NKT cells (sham 11.7 ± 5.4 × 10(4) cells, control 30.1 ± 8.6 × 10(4) cells, TAK 11.8 ± 2.9 × 10(4) cells).


CONCLUSIONS
These findings suggest that the blocking of CXCR3 and CCR5 suppress the infiltration of T cells and NKT cells and have a protective effect on kidneys that are injured by I/R.
Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Koichi
K
Tsutahara
Masayoshi
M
Okumi
Yoichi
Y
Kakuta
Toyofumi
T
Abe
Koji
K
Yazawa
Shuji
S
Miyagawa
Katsuyoshi
K
Matsunami
Hideaki
H
Otsuka
Junya
J
Kaimori
Shiro
S
Takahara
Norio
N
Nonomura
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D065100:CCR5 Receptor Antagonists; D007511:Ischemia / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D007668:Kidney / Q000098:blood supply / Q000276:immunology / Q000293:injuries* / Q000473:pathology; D008297:Male; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019713:Receptors, CCR5 / Q000235:genetics; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015427:Reperfusion Injury / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*
D000577:Amides; D065100:CCR5 Receptor Antagonists; C515189:Cxcr3 protein, rat; D000644:Quaternary Ammonium Compounds; D012333:RNA, Messenger; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; C119369:TAK 779