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P-2.96 Ischemic preconditioning ameliorates renal ischemia-reperfusion injury through activating the Nrf2/HO-1 pathway enhanced autophagy in mice

Jeongkye Hwang, Korea

Associate professor
Surgery
Department of Surgery, Eunpyeong St. Mary's Hospital, College of Medicine,The catholic university

Abstract

Ischemic preconditioning ameliorates renal ischemia-reperfusion injury through activating the Nrf2/HO-1 pathway enhanced autophagy in mice

Jeongkye Hwang1, HyunSu Choi2, KyungJai Ko1, 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. Recent studies have reported that the activation of autophagy is associated with IPC. However, there is not fully unveiled the underlying mechanisms involving in giving rise in this IPC. 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 Nrf2/HO-1 pathway and induction of autophagy.
In order to gain insights into IPC‑induced alterations at the cellular level, an in vitro model for IPC was designed using the human proximal tubule epithelial cell line HK-2. IPC was performed by a 10 min period of incubation of cells under mineral oil followed by a 30 min recovery period prior to the 120 min ischemic insult and reperfusion, along with the treatment of 3-Methyladenine (3-MA) for inhibit autophagy. In a renal I/R injury model, 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. We found that IPC increased LC3-II and Beclin-1 levels and decreased SQSTM/p62 and cleaved caspase-3 levels during renal I/R injury, as well as increased the number of intracellular double-membrane vesicles in injured renal cells. IPC-induced renal protection was efficiently attenuated by pretreatment with 5mM 3-MA. Also, IPC dynamically affected the expression of Nrf2/HO-1 signaling components. Moreover, Nrf2 antagonist brusatol significantly suppressed LC3-II and Beclin-1 levels, increased SQSTM/p62 and cleaved caspase-3 levels, and abolished the protective effect of IPC against I/R-induced renal damage.
In conclusion, the results of the present study indicate that IPC protects against renal injury induced by IR through activation of autophagy and Nrf2/HO-1 pathway

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