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.
Highlights
Diabetes mellitus is a major health risk worldwide
AG1478, not NAC, reversed high glucose (HG) induced Epidermal growth factor receptor (EGFR) and AKT phosphorylation. These results suggest that EGFR/AKT/reactive oxygen species (ROS)/Endoplasmic reticulum (ER) stress signaling plays an essential role in Diabetic nephropathy (DN) development and inhibiting EGFR may serve as a potential therapeutic strategy in diabetic kidney diseases
We investigated the role of EGFR/ AKT/ROS/ER stress pathway in the progression of DN using AG1478, a specific and commercial inhibitor of EGFR
Summary
The metabolic abnormality and microvascular complications caused by the sustained hyperglycemia lead to diabetic nephropathy (DN) [1]. Diabetic kidney disease is the leading cause of morbidity and end-stage renal disease (ESRD) [2,3,4]. Many receptor tyrosine kinases (RTKs) are implicated in DN pathogenesis. EGFR phosphorylation is increased in diabetic animals [8], suggesting its activation is involved in diabetic damages. Recent studies have demonstrated that pharmacological antagonists of EGFR efficiently block downstream cascades activation in diabetic animals [8]. Hyperglycemia increases reactive oxygen species (ROS) in diabetic patients. Accumulating evidence indicates that the ROS overproduction contributes to DN pathogenesis. We previously demonstrated that activation of EGFR leads to cardiac damage and remodeling via ROS generation in STZ-induced diabetic mice [9].
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call