title: Renoprotective antioxidant effect of alagebrium in experimental diabetes.
abstract: BACKGROUND
  Despite the beneficial effects of alagebrium (ALA), a putative advanced glycation end-product (AGE) breaker, on diabetic nephropathy, its renoprotective mechanisms are incompletely understood. Since oxidative stress exacerbates diabetic renal injury through interaction with AGE, the present study examined the antioxidative property of ALA in db/db mice, mesangial cells cultured under high glucose or H(2)O(2) and a test tube.
  
  
  METHODS
  ALA (2 mg/kg/day) was administered intraperitoneally for 12 weeks to 8-week-old db/m and db/db (D(ALA)E) mice or for 4 weeks to 16-week-old db/db mice (D(ALA)L). Oxidative stress markers (nitrotyrosine accumulation, expression and translocation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, cellular DCF-DA fluorescence) together with urinary albumin excretion and histological changes including mesangial expansion were measured. The concentration of H(2)O(2) in the presence and absence of ALA was measured by iodometric analysis in a test tube.
  
  
  RESULTS
  ALA significantly reduced not only urinary albumin excretion and renal pathological changes but also accumulation of pentosidine and nitrotyrosine and expression of NADPH oxidase subunits in db/db mice regardless of treatment protocol. In mesangial cells, ALA effectively prevented not only high glucose- but also H(2)O(2)-induced membrane translocation of NADPH oxidase subunit (p47 phox, p67 phox and rac1) and protein kinase C isoform (α, βI and βII) and Nox4 messenger RNA expression concomitant with cellular reactive oxygen species. Furthermore, ALA directly decreased H(2)O(2) in a test tube.
  
  
  CONCLUSIONS
  ALA has both direct and indirect antioxidant effects that may play important roles in ALA's renoprotective effect in diabetic kidneys.
authors.affiliation: Department of Bioinspired Science, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors.forename: Jehyun
authors.initials: J
authors.lastname: Park
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Kwon
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Huh
authors.forename: Won Jun
authors.initials: WJ
authors.lastname: Choi
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
authors.forename: Ryoji
authors.initials: R
authors.lastname: Nagai
authors.forename: Wan Young
authors.initials: WY
authors.lastname: Kim
authors.forename: Jin
authors.initials: J
authors.lastname: Kim
authors.forename: Geun Taek
authors.initials: GT
authors.lastname: Lee
authors.forename: Hi Bahl
authors.initials: HB
authors.lastname: Lee
authors.forename: Hunjoo
authors.initials: H
authors.lastname: Ha
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000419:Albuminuria / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013844:Thiazoles / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013844:Thiazoles; D006861:Hydrogen Peroxide; C406794:alagebrium; D019255:NADPH Oxidases; D011493:Protein Kinase C