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 . 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)-1 beta (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). Conclusion. These data demonstrated that inhibition of TLR4 with eritoran reduced I/R-related inflammatory responses and improved the course of kidney I/R injury.