Advanced glycation end‐products activate extracellular signal‐regulated kinase via the oxidative stress‐EGF receptor pathway in renal fibroblasts

Abstract

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 microg/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 microM) increased RAGE protein level while activating both EGFR and ERK1/2. Low-dose hydrogen peroxide (5 microM) increased whereas high-dose hydrogen peroxide (100 microM) 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 RAGE-ROS-EGFR pathway in NRK-49F cells.

Advanced glycation end‐products increase IL‐6 and ICAM‐1 expression via RAGE, MAPK and NF‐κB pathways in human gingival fibroblasts

“…ROS damaged periodontal tissues by degrading ECM proteins, inducing alveolar bone loss and aggravating periodontal tissue destruction in periodontitis . AGEs increased plasminogen activator inhibitor‐1 levels via ROS and the ERK and NF‐κB pathways in human glomerular mesangial cells, upregulated RAGE protein and intracellular ROS levels through ERK activation, induced mitogenesis in renal fibroblasts and, consequently, influenced the pathogenesis of diabetic nephropathy. We speculate that AGEs exacerbate the progression of DM‐associated periodontitis by stimulating inflammatory cytokines and ROS in gingival fibroblasts.…”

Inhibition of the epidermal growth factor receptor preserves podocytes and attenuates albuminuria in experimental diabetic nephropathy

“…In contrast, the predominant site of EGFR expression is within the proximal tubule 12 . The EGFR has multiple ligands and may also be activated by advanced glycation endproducts, 35 critical mediators of diabetic complications. Our approach of using a small molecule inhibitor of the receptor tyrosine kinase avoided the potential confounder of multiple ligands.…”

RAGE biology, atherosclerosis and diabetes

“…In fact, ligation of RAGE causes a positive feed-forward loop, in which inflammatory stimuli activate NF-κB, which induces RAGE expression, followed again by NF-κB activation [55]. NF-κB up-regulates multiple cellular signalling cascades, such as NADPH oxidase, CDC42, RAC-1, the MAPKs, p21 ras , ERKs p38 MAPK and PKC [56,57,59,60]. This causes increased production of numerous growth factors and cytokines including VCAM-1, ICAM-1 (intercellular adhesion molecule-1), E-selectin, TGF-β1 (transforming growth factor-β1), CTGF (connective tissue growth factor), PDGF (plateletderived growth factor), TNF-α (tumour necrosis factor-α), IL-1 and IL-6 [61][62][63][64][65][66], all of these molecules having been implicated in the development and progression of a variety of diabetic complications.…”