title: Role of alanine:glyoxylate aminotransferase 2 in metabolism of asymmetric dimethylarginine in the settings of asymmetric dimethylarginine overload and bilateral nephrectomy.
abstract: BACKGROUND
  Asymmetric and symmetric dimethylarginines (ADMA and SDMA) predict complications and mortality in cardiovascular and renal diseases. Alanine:glyoxylate aminotransferase 2 (AGXT2) can metabolize both ADMA and SDMA; however, this metabolic pathway is still poorly understood. The goal of our study was to test the hypothesis that AGXT2 is compensatory upregulated in the settings of ADMA overload and bilateral nephrectomy.
  
  
  METHODS
  ADMA was infused for 3 days using osmotic minipumps in mice. Half of the mice underwent bilateral nephrectomy 24 h before the end of the infusion.
  
  
  RESULTS
  Infusion of ADMA caused a 3- to 4-fold increase in plasma and urine ADMA levels and a 2- to 3-fold increase in plasma and urine levels of the ADMA-specific metabolite of AGXT2 α-keto-δ-(N,N-dimethylguanidino)valeric acid (DMGV). Bilateral nephrectomy led to an ∼4-fold increase of plasma SDMA levels, but did not change plasma ADMA levels. Interestingly, plasma levels of DMGV were elevated 32-fold in the mice, which underwent bilateral nephrectomy. Neither bilateral nephrectomy nor ADMA infusion caused upregulation of AGXT2 expression or activity.
  
  
  CONCLUSIONS
  Our data demonstrate that short-term elevation of systemic levels of ADMA leads to a dramatic increase of DMGV formation without upregulation of AGXT2 expression or activity, which suggests that AGXT2-mediated pathway of ADMA metabolism is not saturated under normal conditions and may play a major role in the maintenance of ADMA homeostasis in the setting of local or systemic elevation of ADMA levels.
authors.affiliation: University Center for Vascular Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Roman N
authors.initials: RN
authors.lastname: Rodionov
authors.affiliation: Institute of Clinical Pharmacology, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Martens-Lobenhoffer
authors.affiliation: University Center for Vascular Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Brilloff
authors.affiliation: Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Hohenstein
authors.affiliation: Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Jarzebska
authors.affiliation: University Center for Vascular Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Normund
authors.initials: N
authors.lastname: Jabs
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Kittel
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Renke
authors.initials: R
authors.lastname: Maas
authors.affiliation: University Center for Vascular Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Weiss
authors.affiliation: Institute of Clinical Pharmacology, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Bode-Böger
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000409:Alanine / Q000502:physiology*; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D015415:Biomarkers / Q000097:blood / Q000652:urine; D015153:Blotting, Western; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D005786:Gene Expression Regulation; D007262:Infusions, Intravenous; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D009392:Nephrectomy; D012313:RNA / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000637:Transaminases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D012313:RNA; C018524:N,N-dimethylarginine; D001120:Arginine; D000637:Transaminases; C019635:Alanine-glyoxylate transaminase; D000409:Alanine
keywords: ADMA; AGXT2; DMGV; acute renal failure; nephrectomy