title: Increased renal semicarbazide-sensitive amine oxidase activity and methylglyoxal levels in aristolochic acid-induced nephrotoxicity.
abstract: OBJECTIVE
  Aristolochic acid (AA) nephrotoxicity is related to accumulation of methylglyoxal (MGO) and N(ε)-(carboxymethyl)lysine (CML) in the mouse kidney. We studied the activity of renal semicarbazide-sensitive amine oxidase (SSAO), a key enzyme involved in MGO generation, in AA-treated mice, and investigated nephroprotective effects produced by metformin, a MGO scavenger.
  
  
  METHODS
  Mice were orally administered water or metformin for 15 days (12 or 24 mg kg(-1)day(-1)), and injected AA (5mgkg(-1)day(-1)) intraperitoneally for 8 days starting on day 8. Renal function was studied, and histopathological examination, determination of renal SSAO activity, and measurement of MGO levels were performed.
  
  
  RESULTS
  Compared to control mice, AA-injected mice showed significant renal damage and approximately 2.7-fold greater renal SSAO activity (p<0.05). Further, compared to control treatment, administration of 12 mg/kg metformin inhibited formation of renal lesions, and significantly decreased renal MGO levels (37.33 ± 9.78 vs. 5.89 ± 2.64 μg/mg of protein, respectively, p<0.01). In the AA-treated mice, metformin also inhibited the accumulation of CML in renal tubules, but did not affect SSAO activity.
  
  
  CONCLUSIONS
  This study is the first to show elevated renal SSAO activity in AA-treated mice, which could be involved in MGO accumulation. Moreover, MGO scavenging by metformin reduces AA nephrotoxicity. These findings suggest that reducing MGO accumulation produces nephroprotection, revealing new therapeutic strategies for the management. SSAO is a key enzyme involved in MGO generation, and consequently, inhibition of renal SSAO activity is worth investigating in AA nephrotoxicity and other renal pathologies further.
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wuxing St., Taipei 11031, Taiwan. Electronic address: d301096001@tmu.edu.tw.
authors.forename: Tzu-Chuan
authors.initials: TC
authors.lastname: Huang
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wuxing St., Taipei 11031, Taiwan. Electronic address: smchen@tmu.edu.tw.
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Chen
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wuxing St., Taipei 11031, Taiwan. Electronic address: d301097002@tmu.edu.tw.
authors.forename: Yi-Chieh
authors.initials: YC
authors.lastname: Li
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wuxing St., Taipei 11031, Taiwan. Electronic address: jenai@tmu.edu.tw.
authors.forename: Jen-Ai
authors.initials: JA
authors.lastname: Lee
mesh_terms: D006631:Amine Oxidase (Copper-Containing) / Q000378:metabolism*; D000818:Animals; D034341:Aristolochic Acids / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011765:Pyruvaldehyde / Q000378:metabolism*
chemical_list: D034341:Aristolochic Acids; C048496:N(6)-carboxymethyllysine; D011765:Pyruvaldehyde; D008687:Metformin; C000228:aristolochic acid I; D006631:Amine Oxidase (Copper-Containing); D008239:Lysine
keywords: Aristolochic acid; Metformin; Methylglyoxal; N(ε)-(carboxymethyl)lysine; Nephrotoxicity; Semicarbazide-sensitive amine oxidase