title: Methylglyoxal induces apoptosis through activation of p38 mitogen-activated protein kinase in rat mesangial cells.
abstract: BACKGROUND
  The formation of methylglyoxal (MG), a highly reactive dicarbonyl compound, is accelerated through several pathways, including the glycation reaction under diabetic conditions, presumably contributing to tissue injury in diabetes. On the other hand, apoptotic cell death of glomerular cells has been suggested to play a role in the development of glomerulosclerosis in various types of glomerular injuries. We therefore examined whether MG was capable of inducing apoptosis in rat mesangial cells to address the possible mechanism by which hyperglycemia-related products accelerated pathologic changes in diabetic glomerulosclerosis.
  
  
  METHODS
  Rat mesangial cells were incubated with 0 to 400 micromol/L MG, followed by the detection of apoptosis by both TUNEL method and electrophoretic analysis for DNA fragmentation. In addition, we investigated intracellular mechanisms mediating MG-induced apoptosis, focusing especially on the p38 mitogen-activated protein kinase (MAPK) pathway.
  
  
  RESULTS
  MG induced apoptosis in rat mesangial cells in a dose-dependent manner and was accompanied by the activation of p38alpha isoform. Aminoguanidine and N-acetyl-l-cysteine inhibited the MG-induced p38 MAPK activation, as well as apoptosis in rat mesangial cells, suggesting the involvement of oxidative stress in these phenomena. SB203580, a specific inhibitor of p38 MAPK also suppressed the MG-induced apoptosis in rat mesangial cells.
  
  
  CONCLUSIONS
  These results suggest a potential role for MG in glomerular injury through p38 MAPK activation under diabetic conditions and may serve as a novel insight into the therapeutic strategies for diabetic nephropathy.
authors.affiliation: Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Bing-Fen
authors.initials: BF
authors.lastname: Liu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miyata
authors.forename: Yushi
authors.initials: Y
authors.lastname: Hirota
authors.forename: Satomi
authors.initials: S
authors.lastname: Higo
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyazaki
authors.forename: Michiru
authors.initials: M
authors.lastname: Fukunaga
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hamada
authors.forename: Shigemitsu
authors.initials: S
authors.lastname: Ueyama
authors.forename: Osamu
authors.initials: O
authors.lastname: Muramoto
authors.forename: Atsuko
authors.initials: A
authors.lastname: Uriuhara
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
mesh_terms: D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects*; D003928:Diabetic Nephropathies / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D007678:Kidney Glomerulus / Q000166:cytology* / Q000201:enzymology; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011765:Pyruvaldehyde / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D011765:Pyruvaldehyde; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D020929:Mitogen-Activated Protein Kinase Kinases