Genetic or pharmacologic inhibition of EGFR ameliorates sepsis-induced AKI
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Xuan Xu1,2,5,*, Juan Wang1,2,*, Ruhao Yang1,2,*, Zheng Dong3,4 and Dongshan Zhang1,2,3
1Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
2Emergency Medicine and Difficult Diseases Institute, Central South University, Changsha, Hunan, People's Republic of China
3Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
4Department of Cellular Biology and Anatomy, Medical College of Georgia and Charlie Norwood VA Medical Center, Augusta, Georgia, USA
5Department of Emergency Medicine, Second Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China
*These authors have contributed equally to this work
Dongshan Zhang, email: firstname.lastname@example.org
Keywords: CLP, EGFR, inflammation
Received: June 30, 2017 Accepted: August 06, 2017 Published: September 23, 2017
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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