EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress

// Zheng Xu 1, * , Yunjie Zhao 1, * , Peng Zhong 1 , Jingying Wang 1 , Qiaoyou Weng 1, 3 , Yuanyuan Qian 1 , Jibo Han 1 , Chunpeng Zou 2 , Guang Liang 1 1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China 2 Department of Ultrasonography, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China 3 Department of Interventional Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China * These authors contribute equally to this work Correspondence to: Guang Liang, email: wzmcliangguang@163.com Chunpeng Zou, email: chpzou@126.com Keywords: diabetic nephropathy, epidermal growth factor receptor, inhibitor, ER stress, oxidative stress Received: December 06, 2016      Accepted: February 23, 2017      Published: March 06, 2017 ABSTRACT Diabetic nephropathy (DN) is a progressive kidney disease due to glomerular capillary damage in diabetic patients. Endoplasmic reticulum (ER) stress caused by reactive oxygen species (ROS) is associated with DN progression. Epidermal growth factor receptor (EGFR) mediates oxidative stress and damage of cardiomyocytes in diabetic mice. Here we demonstrated that AG1478, a specific inhibitor of EGFR, blocked EGFR and AKT phosphorylation in diabetic mice. Oxidative stress and ER stress markers were eliminated after AG1478 administration. AG1478 decreased pro-fibrotic genes TGF-β and collagen IV. Furthermore, we found that high glucose (HG) induced oxidative stress and ER stress, and subsequently increased ATF4 and CHOP. These changes were eliminated by either AG1478 or ROS scavenger N-acetyl-L-cysteine (NAC) administration. These results were confirmed by knock-down approaches in renal mesangial SV40 cells. However, AG1478, not NAC, reversed HG induced EGFR and AKT phosphorylation. These results suggest that EGFR/AKT/ROS/ER stress signaling plays an essential role in DN development and inhibiting EGFR may serve as a potential therapeutic strategy in diabetic kidney diseases.