Advanced Glycation End-Products Activate Extracellular Signal-Regulated Kinase Via the Oxidative Stress-EGF Receptor Pathway in Renal Fibroblasts

作者：Chen San Cher; Guh Jinn Yuh; Hwang Chi Ching; Chiou Shean Jaw; Lin Tai Du; Ko Yu Ming; Huang Jau Shyang; Yang Yu Lin; Chuang Lea Yea^*

来源：Journal of Cellular Biochemistry, 2010, 109(1): 38-48.

DOI：10.1002/jcb.22376

• RENAL INTERSTITIAL FIBROBLASTS
• MITOGENESIS
• ADVANCED GLYCATION END-PRODUCTS
• OXIDATIVE STRESS
• EGFR
• ERK

Advanced glycation end-products (AGEs), epidermal growth factor receptor (EGFR), reactive oxygen species (ROS), and extracellular signal-regulated kinases (ERK) are implicated in diabetic nephropathy (DN). Therefore, we asked if AGEs-induced ERK protein phosphorylation and mitogenesis are dependent on the receptor for AGEs (RAGE)-ROS-EGFR pathway in normal rat kidney interstitial fibroblast (NRK-49F) cells. We found that AGEs (100 mu g/ml) activated EGFR and ERK1/2, which was attenuated by RAGE short-hairpin RNA (shRNA). AGEs also increased RAGE protein and intracellular ROS levels while RAGE shRNA and N-acetylcysteine (NAC) attenuated AGEs-induced intracellular ROS. Hydrogen peroxide (5-25 mu M) increased RAGE protein level while activating both EGFR and ERK1/2. Low-dose hydrogen peroxide (5 mu M) increased whereas high-dose hydrogen peroxide (100 mu M) decreased mitogenesis at 3 days. AGEs-activated EGFR and ERK1/2 were attenuated by an anti-oxidant (NAC) and an EGFR inhibitor (Iressa). Moreover, AGEs-induced mitogenesis was attenuated by RAGE shRNA, NAC, Iressa, and an ERK1/2 inhibitor (PD98059). In conclusion, it was found that AGEs-induced mitogenesis is dependent on the RAGE-ROS-EGFR-ERK1/2 pathway whereas AGEs-activated ERK1/2 is dependent on the PAGE-ROS-EGFR pathway in NRK-49F cells. J. Cell. Biochem. 109: 38-48, 2010.

• 出版日期2010-1-1
• 单位河北医科大学