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

Am J Physiol Cell Physiol. 2008 Jan;294(1):C145-52. doi: 10.1152/ajpcell.00350.2007. Epub 2007 Nov 21.


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(epsilon)-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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylcysteine / pharmacology
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Antioxidants / metabolism
  • Antioxidants / pharmacology
  • Cell Line
  • Chromones / pharmacology
  • Down-Regulation
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / metabolism*
  • Glycation End Products, Advanced / metabolism*
  • Humans
  • Lysine / analogs & derivatives*
  • Lysine / metabolism
  • Morpholines / pharmacology
  • Mutation
  • Oxidative Stress* / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyruvaldehyde / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Serine / metabolism
  • Shc Signaling Adaptor Proteins
  • Signal Transduction* / drug effects
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Superoxide Dismutase / metabolism
  • Transfection


  • Adaptor Proteins, Signal Transducing
  • Antioxidants
  • Chromones
  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Glycation End Products, Advanced
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • SHC1 protein, human
  • Shc Signaling Adaptor Proteins
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Serine
  • N(6)-carboxymethyllysine
  • Pyruvaldehyde
  • Superoxide Dismutase
  • Proto-Oncogene Proteins c-akt
  • Lysine
  • Acetylcysteine