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Receptor for advanced glycation end products (RAGE)-mediated cytotoxicity of 3-hydroxypyridinium derivatives

Yoto Murakami1, Takayuki Fujino1, Toshiki Hasegawa1

  • 1a Department of Agriculture , Meiji University , Tama-ku, Kawasaki , Japan.

Bioscience, Biotechnology, and Biochemistry
|January 11, 2018
PubMed

Insights

Advanced glycation end products (AGEs) from glyceraldehyde and glycolaldehyde contribute to diabetic complications. The study identified 3-hydroxypyridinium (3-HP) as the key structure responsible for RAGE receptor binding and toxicity.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Neuroscience

Background:

  • Advanced glycation end products (AGEs) are implicated in diabetic complications.
  • AGEs interact with the receptor for AGEs (RAGE), influencing disease pathogenesis.
  • Glyceraldehyde (Gcer) and glycolaldehyde (Gcol) are precursors to specific AGEs.

Purpose of the Study:

  • To determine the RAGE-binding structure of Gcer and Gcol-derived AGEs.
  • To identify the minimal molecular structure recognized by RAGE.
  • To understand the mechanism of AGEs-induced toxicity in neuronal cells.

Main Methods:

  • Cytotoxicity assays using PC12 neuronal cells.
  • Inhibition studies with anti-RAGE antibody and soluble RAGE protein.
  • Structure-activity relationship analysis using GLAP analog compounds.
  • Surface plasmon resonance (SPR) to assess direct RAGE interaction.

Main Results:

  • Glyceraldehyde-derived pyridinium (GLAP) and GA-pyridine induced toxicity in PC12 cells.
  • RAGE inhibition significantly reduced the toxic effects of GLAP and GA-pyridine.
  • The 3-hydroxypyridinium (3-HP) structure was identified as sufficient for RAGE-dependent toxicity.
  • SPR confirmed direct binding of 3-HP derivatives to RAGE.

Conclusions:

  • GLAP and GA-pyridine are critical RAGE-binding epitopes.
  • The 3-HP moiety is essential for the interaction between these AGEs and RAGE.
  • This finding clarifies the molecular basis of AGEs-induced neuronal toxicity in diabetes.
Keywords:
3-HP: 3-hydroxypyridinium3-HydroxypyridiniumAGEs: advanced glycation end productsAdvanced glycation end productsDAPI: 6-diamidino-2-phenylindoleGST: glutathione S-transferaseGcer: glyceraldehydeGcol: glycolaldehydeNAC: N-acetylcysteineRAGE: receptor for advanced glycation end productsROS: reactive oxygen speciesSPR: surface plasmon resonanceglyceraldehydeglycolaldehydereceptor for advanced glycation end products

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