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EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress.
Oncotarget 2017; 8(20):32655-32667O

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.

Authors+Show Affiliations

Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Department of Interventional Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China.Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.Department of Ultrasonography, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28427241

Citation

Xu, Zheng, et al. "EGFR Inhibition Attenuates Diabetic Nephropathy Through Decreasing ROS and Endoplasmic Reticulum Stress." Oncotarget, vol. 8, no. 20, 2017, pp. 32655-32667.
Xu Z, Zhao Y, Zhong P, et al. EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress. Oncotarget. 2017;8(20):32655-32667.
Xu, Z., Zhao, Y., Zhong, P., Wang, J., Weng, Q., Qian, Y., ... Liang, G. (2017). EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress. Oncotarget, 8(20), pp. 32655-32667. doi:10.18632/oncotarget.15948.
Xu Z, et al. EGFR Inhibition Attenuates Diabetic Nephropathy Through Decreasing ROS and Endoplasmic Reticulum Stress. Oncotarget. 2017 May 16;8(20):32655-32667. PubMed PMID: 28427241.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress. AU - Xu,Zheng, AU - Zhao,Yunjie, AU - Zhong,Peng, AU - Wang,Jingying, AU - Weng,Qiaoyou, AU - Qian,Yuanyuan, AU - Han,Jibo, AU - Zou,Chunpeng, AU - Liang,Guang, PY - 2016/12/06/received PY - 2017/02/23/accepted PY - 2017/4/22/pubmed PY - 2018/3/24/medline PY - 2017/4/22/entrez KW - ER stress KW - diabetic nephropathy KW - epidermal growth factor receptor KW - inhibitor KW - oxidative stress SP - 32655 EP - 32667 JF - Oncotarget JO - Oncotarget VL - 8 IS - 20 N2 - 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/28427241/EGFR_inhibition_attenuates_diabetic_nephropathy_through_decreasing_ROS_and_endoplasmic_reticulum_stress_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=15948 DB - PRIME DP - Unbound Medicine ER -