Ischemic preconditioning attenuates renal ischemia-reperfusion injury by TLR4 suppression and eNOS activation
Jeongkye Hwang1, SungKeun Kang1, HyunSu Choi2, MiHyeong Kim1, KangWoong Jun1, SangDong Kim1, SunCheol Park1, JiIl Kim1, InSung Moon1.
1Surgery, The Catholic University of Korea, Seoul, Korea; 2Clinical Research Center, Daejoen St. Mary's Hospital, The Catholic University , Daejeon, Korea
Ischemic preconditioning (IPC), which is a brief and nonlethal episode of ischemia, confers protection against subsequent ischemia-reperfusion (I/R) through the up-regulation of endogenous protective mechanisms. In this study, we investigated the role of IPC in renal I/R injury and demonstrated that IPC could ameliorate renal I/R injury by activating the AKT/eNOS pathway and suppression of HMGB1/TLR4 signaling.
A total of 25 male C57BL/6 mice were randomly divided into 3 groups (sham group (n=5), I/R group, IPC group). In a renal I/R injury model, after right nephrectomy mice were subjected to 30 min of renal ischemia followed by 24 h of reperfusion. IPC was produced by 5 min of ischemia followed by 10 min of reperfusion prior to sustained ischemia.
IPC markedly improve renal I/R injury by attenuating renal apoptosis, reducing reactive oxygen species (ROS) levels and inflammatory responses. In addition, IPC significantly inhibited the expressions of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and chemokines (MCP-1). Western blot analysis indicated that the expression levels of HMGB1 and TLR4 were upregulated in the I/R group, while IPC groups were shown to inhibit the expressions. In addition, we found that IPC increased eNOS level during renal I/R injury, IPC dynamically affected the expression of AKT/eNOS signaling components. These findings suggest that the protective effect of ischemic preconditioning on renal I/R injury by nitric oxide production following the increase in eNOS expression.
In conclusion, the results of the present study indicate that IPC protects against renal injury induced by IR through activation of AKT/eNOS pathway and suppression of HMGB1/TLR4 signaling
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