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This Article Full Text Full Text (PDF) All Versions of this Article: 294/1/C145    most recent 00350.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Cai, W. Articles by Vlassara, H. Search for Related Content PubMed PubMed Citation Articles by Cai, W. Articles by Vlassara, H.

RECEPTORS AND SIGNAL TRANSDUCTION

AGE-receptor-1 counteracts cellular oxidant stress induced by AGEs via negative regulation of p66^shc-dependent FKHRL1 phosphorylation

¹Division of Diabetes and Aging Research, The Brookdale Department of Geriatrics and ²Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York; and Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida

Submitted 7 August 2007 ; accepted in final form 15 November 2007

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 N-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.

glycoxidation; aging; diabetes; N-carboxy-methyl-lysine; methylglyoxal; forkhead transcription factors; manganese superoxide dismutase; receptor for advanced glycation end products

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