Protective effects of Toll-like receptor 4 inhibitor eritoran on renal ischemia-reperfusion injury.
BACKGROUND
Ischemia-reperfusion injury (I/R) has a negative effect on renal allograft survival. Using a rat model of kidney IR injury, we demonstrated inhibition of Toll-like receptor (TLR) 4 with erotoran may shed new light on I/R therapy.


METHODS
All 44 Fisher rats were anesthetized with ethrane. Animals were randomly divided into the S group (sham, n = 11) that received only right kidney nephrectomy or the I/R group of right kidney nephrectomy and ichemia for 40 minutes by clamping of left renal artery (n = 11). In addition, the E group (Eritoran, n = 11) and the V group (vehicle, n = 11) received eritoran (5 mg x kg(-1)) and vehicle pretreatment, respectively. Analysis of renal histology, function, cytokine/chemokine production, as well as animal mortality was performed in parallel groups by ribonuclease protection assay (RPA).


RESULTS
At 24 hours, the creatinine value 1.49 +/- 0.2 mg/dL in the eritoran group was significantly lower than untreated controls (2.17 +/- 0.4 mg/dL). Histological findings showed tubular loss and morphological stutus as well as animal survival post-I/R injury compared to vehicle-treated rats; the difference between the S versus E groups was significant. Eritoran administration significantly attenuated monocyte infiltration into the kidney. RPA assays showed the following fold increase over sham normalized to that of GAPDH mRNA expression of tumor necrosis factor-alpha (4.67 +/- 1.52 vs 1.37 +/- 0.05), interleukin (IL)-1beta (5.11 +/- 1.17 vs 1.92 +/- 0.27), IL-6 (4.20 +/- 0.29 vs 1.21 +/- 0.37) and monocyte chemoattractant protein-1 (8.77 +/- 1.24 vs 2.57 +/- 1.59). GAPDH was markedly reduced by eritoran treatment (eritoran vs vehicle group).


CONCLUSIONS
These data demonstrated that inhibition of TLR4 with eritoran reduced I/R-related inflammatory responses and improved the course of kidney I/R injury.
Liu
M
M
Nan Jing Medical University First Affiliated Hospital, Department of Urology and Kidney transplantation, Nanjing, Jiangsu Province, China.
Gu
M
M
Xu
D
D
Lv
Q
Q
Zhang
W
W
Wu
Y
Y
D000818:Animals; D018925:Chemokines / Q000235:genetics; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000235:genetics; D004187:Disaccharides / Q000627:therapeutic use*; D004195:Disease Models, Animal; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D012077:Renal Artery / Q000473:pathology / Q000502:physiology; D012079:Renal Circulation / Q000187:drug effects; D015427:Reperfusion Injury / Q000188:drug therapy*; D013403:Sugar Phosphates / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*
D018925:Chemokines; D016207:Cytokines; D004187:Disaccharides; D012333:RNA, Messenger; D013403:Sugar Phosphates; D051197:Toll-Like Receptor 4; C512420:eritoran; D003404:Creatinine