title: Polymorphonuclear leukocyte injury by methylglyoxal and hydrogen peroxide: a possible pathological role for enhanced oxidative stress in chronic kidney disease.
abstract: BACKGROUND
  Accelerated burst of polymorphonuclear leukocytes (PMNs) may be involved in the primary pathology of enhanced oxidative stress in patients with chronic kidney disease (CKD); however, the precise mechanism remains unknown. Methylglyoxal (MGO), an alpha-oxoaldehyde reportedly elevated in CKD, could induce apoptosis in several cell lines, and generates radicals by the reaction with hydrogen peroxide (H(2)O(2)). Thus, we tested if a high MGO of uraemic milieu could play a role in PMN injury by interaction with H(2)O(2).
  
  
  METHODS
  Cellular viability of PMNs, isolated from healthy volunteers, was tested by ATP chemiluminescence levels under MGO and/or H(2)O(2), or 4-beta phorbol 12-beta-myristate 13-alpha-acetate (PMA). Superoxide anion (O(2)(-)) generation and apoptosis were measured by the reduction of ferricytochrome C and fluorocytometric analysis, respectively. Plasma MGO levels were measured by mass spectometry in 29 CKD patients.
  
  
  RESULTS
  At low levels of MGO (1-10 microM) and H(2)O(2) (12.5 microM), no differences were found in cellular viability as compared to controls, whereas their combination significantly decreased PMN viability. PMA stimulation enhanced cellular injury of MGO by a function of MGO levels and preincubation with 5,5-dimethyl-1-pyrroline-N-oxide (free radical trap agent) attenuated it. MGO suppressed O(2)(-) generation by PMA, while it accelerated apoptotic ratios in PMNs. Significant increases of plasma MGO and C-reactive protein levels were found by a function of CKD stage, and clinical level of MGO could induce PMN injury in combination with H(2)O(2).
  
  
  CONCLUSIONS
  These results indicate the combinatory effect of MGO and H(2)O(2) on PMN oxidative injury, and this pathology may be linked to enhanced oxidative stress in CKD.
authors.affiliation: Research Division of Dialysis and Chronic Kidney Disease, Tohoku University Graduate School of Medicine, 1-1 Seiryo machi aoba-ku, Sendai 980-8574, Japan. mnakayama@mail.tains.tohoku.ac.jp
authors.forename: Masaaki
authors.initials: M
authors.lastname: Nakayama
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nakayama
authors.forename: Wan-Jun
authors.initials: WJ
authors.lastname: Zhu
authors.forename: Yuko
authors.initials: Y
authors.lastname: Shirota
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Terawaki
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Sato
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kohno
authors.forename: Sadayoshi
authors.initials: S
authors.lastname: Ito
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000008:administration & dosage / Q000633:toxicity*; D066298:In Vitro Techniques; D007676:Kidney Failure, Chronic / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D008163:Luminescent Measurements; D009336:Necrosis; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D011765:Pyruvaldehyde / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D016897:Respiratory Burst / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D005609:Free Radicals; D011765:Pyruvaldehyde; D006861:Hydrogen Peroxide; D013755:Tetradecanoylphorbol Acetate