scholarly journals Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins

1994 ◽  
Vol 269 (13) ◽  
pp. 9889-9897 ◽  
Author(s):  
S.D. Yan ◽  
A.M. Schmidt ◽  
G.M. Anderson ◽  
J. Zhang ◽  
J. Brett ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Binding Proteins ◽  
Oxidant Stress ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products

AGE-receptor-1 counteracts cellular oxidant stress induced by AGEs via negative regulation of p66shc-dependent FKHRL1 phosphorylation

2008 ◽  
Vol 294 (1) ◽  
pp. C145-C152 ◽  
Author(s):  
Weijing Cai ◽  
John Cijiang He ◽  
Li Zhu ◽  
Xue Chen ◽  
Gary E. Striker ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Oxidant Stress ◽  
Serine Phosphorylation ◽  
Hek293 Cells ◽  
Antioxidant Defenses ◽  
Kidney Cells ◽  
Dependent Manner ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products

Advanced glycation end products (AGEs) promote reactive oxygen species (ROS) formation and oxidant stress (OS) in diabetes and aging-related diseases. AGE-induced OS is suppressed by AGER1, an AGE-receptor that counteracts receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR)-mediated Shc/Ras signal activation, resulting in decreased OS. Akt, FKHRL1, and antioxidants; e.g., MnSOD, regulate OS. Serine phosphorylation of p66 shc also promotes OS. We examined the effects of two defined AGEs Nε-carboxy-methyl-lysine (CML) and methyl-glyoxal derivatives (MG) on these cellular pathways and their functional relationship to AGER1 in human embryonic kidney cells (HEK293). Stimulation of HEK293 cells with either AGE compound increased phosphorylation of Akt and FKHRL1 by approximately threefold in a redox-dependent manner. The use of p66 shc mutants showed that the AGE-induced effects required Ser-36 phosphorylation of p66 shc. AGE-induced phosphorylation of FKHRL1 led to a 70% downregulation of MnSOD, an effect partially blocked by a phosphatidylinositol 3-kinase inhibitor (LY-294002) and strongly inhibited by an antioxidant ( N-acetylcysteine). These pro-oxidant responses were suppressed in AGER1 overexpressing cells and reappeared when AGER1 expression was reduced by small interfering RNA (siRNA). These studies point to a new pathway for the induction of OS by AGEs involving FKHRL1 inactivation and MnSOD suppression via Ser-36 phosphorylation of p66 shc in human kidney cells. This represents a key mechanism by which AGER1 maintains cellular resistance against OS. Thus the decrease of AGER1 noted in aging and diabetes may further enhance OS and reduce innate antioxidant defenses.

scholarly journals Protection against Loss of Innate Defenses in Adulthood by Low Advanced Glycation End Products (AGE) Intake: Role of the Antiinflammatory AGE Receptor-1

2009 ◽  
Vol 94 (11) ◽  
pp. 4483-4491 ◽  
Author(s):  
Helen Vlassara ◽  
Weijing Cai ◽  
Susan Goodman ◽  
Renata Pyzik ◽  
Angie Yong ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Mononuclear Cell ◽  
Advanced Glycation End Products ◽  
Oxidant Stress ◽  
Healthy Adults ◽  
Advanced Glycation ◽  
Peripheral Mononuclear Cell ◽  
Glycation End Products ◽  
End Products

Context: Increased oxidant stress and inflammation (OS/infl) are linked to both aging-related diseases and advanced glycation end products (AGEs). Whereas AGE receptor-1 (AGER1) reduces OS/infl in animals, this has not been assessed in normal humans. Objective: The objectives of the study were to determine whether AGER1 correlates with AGEs and OS/infl and a reduction of dietary AGEs (dAGEs) lowers OS/infl in healthy adults and chronic kidney disease (CKD-3) patients. Design: This study was cross-sectional with 2-yr follow-up studies of healthy adults and CKD-3 patients, a subset of which received a reduced AGE or regular diet. Setting: The study was conducted at general community and renal clinics. Participants: Participants included 325 healthy adults (18–45 and >60 yr old) and 66 CKD-3 patients. Intervention: An isocaloric low-AGE (30–50% reduction) or regular diet was given to 40 healthy subjects for 4 months and to nine CKD-3 patients for 4 wk. Main Outcome: Relationships between age, dAGEs, serum AGEs, peripheral mononuclear cell AGE-receptors, and OS/Infl before and after reduction of dAGE intake were measured. Results: AGEs, oxidant stress, receptor for AGE, and TNFα were reduced in normal and CKD-3 patients after the low-AGE diet, independently of age. AGER1 levels in CKD-3 patients on the low-AGE diet resembled 18- to 45-yr-old normal subjects. Dietary, serum, and urine AGEs correlated positively with peripheral mononuclear cell AGER1 levels in healthy participants. AGER1 was suppressed in CKD-3 subjects, whereas receptor for AGE and TNFα were increased. Conclusions: Reduction of AGEs in normal diets may lower oxidant stress/inflammation and restore levels of AGER1, an antioxidant, in healthy and aging subjects and CKD-3 patients. AGE intake has implications for health outcomes and costs and warrants further testing. Reduction of advanced glycation endproducts (AGE) in normal diets lowers oxidant stress/inflammation, and restores levels of AGE receptor-1 in healthy, aging, and chronic kidney disease-3 patients.

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