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Genetic or pharmacologic inhibition of EGFR ameliorates sepsis-induced AKI

Despite recent studies have demonstrated that the EGF receptor (EGFR) activation provided a renoprotective role during ischemic and folic acid-induced AKI, the role and regulation mechanism of EGFR in septic AKI remains unclear. Here, gefitinib, a highly selective EGFR inhibitor, abrogated LPS-induc...

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Autores principales: Xu, Xuan, Wang, Juan, Yang, Ruhao, Dong, Zheng, Zhang, Dongshan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710948/
https://www.ncbi.nlm.nih.gov/pubmed/29207668
http://dx.doi.org/10.18632/oncotarget.21244
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author Xu, Xuan
Wang, Juan
Yang, Ruhao
Dong, Zheng
Zhang, Dongshan
author_facet Xu, Xuan
Wang, Juan
Yang, Ruhao
Dong, Zheng
Zhang, Dongshan
author_sort Xu, Xuan
collection PubMed
description Despite recent studies have demonstrated that the EGF receptor (EGFR) activation provided a renoprotective role during ischemic and folic acid-induced AKI, the role and regulation mechanism of EGFR in septic AKI remains unclear. Here, gefitinib, a highly selective EGFR inhibitor, abrogated LPS-induced phosphorylation of EGFR, ERK1/2, and STAT3 as well as expression of COX, eNOS, and proinflammatory cytokines in HK-2 cells. In addition, c-Src is an upstream of EGFR signaling pathway and mediates LPS-induced EGFR transactivation. In vivo, either gefitinib or genetic approaches (Wave-2 mutant mice, which have reduced EGFR tyrosine kinase activity) protected against LPS or cecal ligation and puncture (CLP) induced AKI respectively. Interestingly, the beneficial effects of gefitinib or genetic approaches were accompanied by the dephosphorylation of EGFR, ERK1/2, and STAT3, the down regulation of expression of COX, eNOS, macrophage infiltration, proinflammatory cytokines production and the renal cell apoptosis. Furthermore, mRNA array results indicated that gene families involved in cell death, inflammation, proliferation and signal transduction were down regulated in Wave-2 (Wa-2) mice. Take together, these data suggest that EGFR may mediate renal injury by promoting production of inflammatory factors and cell apoptosis. Inhibition of EGFR may have therapeutic potential for AKI during endotoxemia.
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spelling pubmed-57109482017-12-04 Genetic or pharmacologic inhibition of EGFR ameliorates sepsis-induced AKI Xu, Xuan Wang, Juan Yang, Ruhao Dong, Zheng Zhang, Dongshan Oncotarget Research Paper Despite recent studies have demonstrated that the EGF receptor (EGFR) activation provided a renoprotective role during ischemic and folic acid-induced AKI, the role and regulation mechanism of EGFR in septic AKI remains unclear. Here, gefitinib, a highly selective EGFR inhibitor, abrogated LPS-induced phosphorylation of EGFR, ERK1/2, and STAT3 as well as expression of COX, eNOS, and proinflammatory cytokines in HK-2 cells. In addition, c-Src is an upstream of EGFR signaling pathway and mediates LPS-induced EGFR transactivation. In vivo, either gefitinib or genetic approaches (Wave-2 mutant mice, which have reduced EGFR tyrosine kinase activity) protected against LPS or cecal ligation and puncture (CLP) induced AKI respectively. Interestingly, the beneficial effects of gefitinib or genetic approaches were accompanied by the dephosphorylation of EGFR, ERK1/2, and STAT3, the down regulation of expression of COX, eNOS, macrophage infiltration, proinflammatory cytokines production and the renal cell apoptosis. Furthermore, mRNA array results indicated that gene families involved in cell death, inflammation, proliferation and signal transduction were down regulated in Wave-2 (Wa-2) mice. Take together, these data suggest that EGFR may mediate renal injury by promoting production of inflammatory factors and cell apoptosis. Inhibition of EGFR may have therapeutic potential for AKI during endotoxemia. Impact Journals LLC 2017-09-23 /pmc/articles/PMC5710948/ /pubmed/29207668 http://dx.doi.org/10.18632/oncotarget.21244 Text en Copyright: © 2017 Xu et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Xu, Xuan
Wang, Juan
Yang, Ruhao
Dong, Zheng
Zhang, Dongshan
Genetic or pharmacologic inhibition of EGFR ameliorates sepsis-induced AKI
title Genetic or pharmacologic inhibition of EGFR ameliorates sepsis-induced AKI
title_full Genetic or pharmacologic inhibition of EGFR ameliorates sepsis-induced AKI
title_fullStr Genetic or pharmacologic inhibition of EGFR ameliorates sepsis-induced AKI
title_full_unstemmed Genetic or pharmacologic inhibition of EGFR ameliorates sepsis-induced AKI
title_short Genetic or pharmacologic inhibition of EGFR ameliorates sepsis-induced AKI
title_sort genetic or pharmacologic inhibition of egfr ameliorates sepsis-induced aki
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710948/
https://www.ncbi.nlm.nih.gov/pubmed/29207668
http://dx.doi.org/10.18632/oncotarget.21244
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