EGFR mediates hyperlipidemia-induced renal injury via regulating inflammation and oxidative stress: the detrimental role and mechanism of EGFR activation
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Qilu Fang1, Chunpeng Zou2, Peng Zhong1, Feng Lin3, Weixin Li1, Lintao Wang1, Yali Zhang1, Chao Zheng4, Yi Wang1, Xiaokun Li1, Guang Liang1
1Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
2Department of Ultrasonography, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
3Department of Gynecology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
4Department of Endocrinology, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
Guang Liang, e-mail: firstname.lastname@example.org
Keywords: obesity, obesity-induced kidney injury, epidermal growth factor receptor, palmitate, c-Src
Received: January 13, 2016 Accepted: March 02, 2016 Published: March 21, 2016
Previous studies have implicated inflammation, oxidative stress, and fibrosis as key factors in the development of obesity-induced kidney diseases. Epidermal growth factor receptor (EGFR) plays an important role in cancer development. Recently, the EGFR pathway has been increasingly implicated in chronic cardiovascular diseases via regulating inflammation and oxidative stress. However, it is unclear if EGFR is involved in obesity-related kidney injury. Using ApoE-/- and C57BL/6 mice models and two specific EGFR inhibitors, we investigated the potential effects of EGFR inhibition in the treatment of obesity-related nephropathy and found that EGFR inhibition alleviates renal inflammation, oxidative stress and fibrosis. In NRK-52E cells, we also elucidated the mechanism behind hyperlipidemia-induced EGFR activation. We observed that c-Src and EGFR forms a complex, and following PA stimulation, it is the successive phosphorylation, not formation, of the c-Src/EGFR complex that results in the subsequent cascade activation. Second, we found that TLR4 regulates the activation EGFR pathway mainly through the phosphorylation of the c-Src/EGFR complex. These results demonstrate the detrimental role of EGFR in the pathogenesis of obesity-related nephropathy, provide a new understanding of the mechanism behind hyperlipidemia/FFA-induced EGFR activation, and support the use of EGFR inhibitors in the treatment of obesity-induced kidney diseases.
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