Han-Jin Lai1, Ya-Qing Zhan2, Yu-Xin Qiu2, Yi-Hong Ling3, Xu-Yu Zhang2, Ze-Nan Chang1, Yi-Nan Zhang2, Zi-Meng Liu4, Shi-Hong Wen5. 1. Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China. 2. Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China. 3. Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China. 4. Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China. Electronic address: liuzm@mail.sysu.edu.cn. 5. Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China. Electronic address: wshih@mail.sysu.edu.cn.
Abstract
BACKGROUND: Ischemia/reperfusion of the intestine often leads to distant organ injury, but the mechanism of intestinal ischemia/reperfusion-induced renal dysfunction is still not clear. The present study aimed to investigate the mechanisms of acute renal damage after intestinal ischemia/reperfusion challenge and explore the role of released high-mobility group box-1 in this process. METHODS: Intestinal ischemia/reperfusion was induced in male Sprague-Dawley rats by clamping the superior mesenteric artery for 1.5 hours. At different reperfusion time points, anti-high-mobility group box-1 neutralizing antibodies or ethyl pyruvate were administered to neutralize or inhibit circulating high-mobility group box-1, respectively. RESULTS: Significant kidney injury was observed after 6 hours of intestinal reperfusion, as indicated by increased serum levels of urea nitrogen and creatinine, increased expression of neutrophil gelatinase-associated lipocalin, interleukin-6, and MIP-2, and enhanced cell apoptosis, as indicated by cleaved caspase 3 levels in renal tissues. The levels of phosphorylated eIF2ɑ, activating transcription factor 4, and C/EBP-homologous protein (CHOP) were markedly elevated, indicating the activation of endoplasmic reticulum stress in the impaired kidney. High-mobility group box-1 translocated to cytoplasm in the intestine and serum concentrations of high-mobility group box-1 increased notably during the reperfusion phase. Both anti-high-mobility group box-1 antibodies and ethyl pyruvate treatment significantly reduced serum high-mobility group box-1 concentrations, attenuated endoplasmic reticulum stress in renal tissue and inhibited the development of renal damage. Moreover, the elevated expression of receptor for advanced glycation end products in the kidneys after intestinal ischemia/reperfusion was abrogated after high-mobility group box-1 inhibition. CONCLUSION: These results suggested that high-mobility group box-1 signaling regulated endoplasmic reticulum stress and promoted intestinal ischemia/reperfusion-induced acute kidney injury. High-mobility group box-1 neutralization/inhibition might serve as a pharmacological intervention strategy for these pathophysiological processes.
BACKGROUND:Ischemia/reperfusion of the intestine often leads to distant organ injury, but the mechanism of intestinal ischemia/reperfusion-induced renal dysfunction is still not clear. The present study aimed to investigate the mechanisms of acute renal damage after intestinal ischemia/reperfusion challenge and explore the role of released high-mobility group box-1 in this process. METHODS:Intestinal ischemia/reperfusion was induced in male Sprague-Dawley rats by clamping the superior mesenteric artery for 1.5 hours. At different reperfusion time points, anti-high-mobility group box-1 neutralizing antibodies or ethyl pyruvate were administered to neutralize or inhibit circulating high-mobility group box-1, respectively. RESULTS: Significant kidney injury was observed after 6 hours of intestinal reperfusion, as indicated by increased serum levels of ureanitrogen and creatinine, increased expression of neutrophil gelatinase-associated lipocalin, interleukin-6, and MIP-2, and enhanced cell apoptosis, as indicated by cleaved caspase 3 levels in renal tissues. The levels of phosphorylated eIF2ɑ, activating transcription factor 4, and C/EBP-homologous protein (CHOP) were markedly elevated, indicating the activation of endoplasmic reticulum stress in the impaired kidney. High-mobility group box-1 translocated to cytoplasm in the intestine and serum concentrations of high-mobility group box-1 increased notably during the reperfusion phase. Both anti-high-mobility group box-1 antibodies and ethyl pyruvate treatment significantly reduced serum high-mobility group box-1 concentrations, attenuated endoplasmic reticulum stress in renal tissue and inhibited the development of renal damage. Moreover, the elevated expression of receptor for advanced glycation end products in the kidneys after intestinal ischemia/reperfusion was abrogated after high-mobility group box-1 inhibition. CONCLUSION: These results suggested that high-mobility group box-1 signaling regulated endoplasmic reticulum stress and promoted intestinal ischemia/reperfusion-induced acute kidney injury. High-mobility group box-1 neutralization/inhibition might serve as a pharmacological intervention strategy for these pathophysiological processes.