Jiajie Hou1, Yongxiang Xia1, Runqiu Jiang1, Dianyu Chen1, Juan Xu2, Lei Deng1, Xingxu Huang2, Xuehao Wang1, Beicheng Sun3. 1. State Key Laboratory of Reproductive Medicine and Liver Transplantation Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing, PR China. 2. MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, PR China. 3. State Key Laboratory of Reproductive Medicine and Liver Transplantation Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing, PR China. Electronic address: sunbc@njmu.edu.cn.
Abstract
BACKGROUND & AIMS: Nuclear factor-κB (NF-κB) activation in hepatocytes and macrophages appeared as a double-edged-sword in hepatic ischemia reperfusion (IR) injury. Protein tyrosine phosphatase receptor type O (PTPRO) was recently identified as a potential activator of c-Src, which can in turn activate the NF-κB pathway. In this study, we aimed to determine the change and function of PTPRO in hepatocytes and macrophages during IR. METHODS: Clinical patients with benign liver condition undergoing liver surgery were recruited in our study. Wild type (WT) and ptpro(-/-) C57BL/6 mice were processed to construct hepatic IR models. Isolated mouse hepatocytes and macrophages were treated with peroxide or TNFα in vitro. RESULTS: In human and mouse IR models, PTPRO level was decreased in the early phase but reversed in the late phase. In vitro studies demonstrated that NF-κB up-regulated PTPRO transcription. Using ptpro(-/-) mice and primary cells, we found that PTPRO deficiency resulted in reduction of NF-κB activation in both hepatocytes and macrophages and was correlated to c-Src phosphorylation; PTPRO in hepatocytes alleviated, but PTPROt in macrophages exacerbated IR injury. CONCLUSIONS: PTPRO activates NF-κB in a positive feedback manner, and plays a dual role in hepatic IR injury.
BACKGROUND & AIMS: Nuclear factor-κB (NF-κB) activation in hepatocytes and macrophages appeared as a double-edged-sword in hepatic ischemia reperfusion (IR) injury. Protein tyrosine phosphatase receptor type O (PTPRO) was recently identified as a potential activator of c-Src, which can in turn activate the NF-κB pathway. In this study, we aimed to determine the change and function of PTPRO in hepatocytes and macrophages during IR. METHODS: Clinical patients with benign liver condition undergoing liver surgery were recruited in our study. Wild type (WT) and ptpro(-/-) C57BL/6 mice were processed to construct hepatic IR models. Isolated mouse hepatocytes and macrophages were treated with peroxide or TNFα in vitro. RESULTS: In human and mouse IR models, PTPRO level was decreased in the early phase but reversed in the late phase. In vitro studies demonstrated that NF-κB up-regulated PTPRO transcription. Using ptpro(-/-) mice and primary cells, we found that PTPRO deficiency resulted in reduction of NF-κB activation in both hepatocytes and macrophages and was correlated to c-Src phosphorylation; PTPRO in hepatocytes alleviated, but PTPROt in macrophages exacerbated IR injury. CONCLUSIONS:PTPRO activates NF-κB in a positive feedback manner, and plays a dual role in hepatic IR injury.
Authors: Elena Urcelay; Ana Isabel Sánchez-Fructuoso; Jose Luis Santiago; Luis Sánchez-Pérez; Isabel Pérez-Flores; Maria Angeles Moreno de la Higuera; Natividad Calvo Romero Journal: J Nephrol Date: 2022-08-10 Impact factor: 4.393
Authors: Ricardo O S Soares; Daniele M Losada; Maria C Jordani; Paulo Évora; Orlando Castro-E-Silva Journal: Int J Mol Sci Date: 2019-10-11 Impact factor: 5.923