title: Alanine-glyoxylate aminotransferase-2 metabolizes endogenous methylarginines, regulates NO, and controls blood pressure.
abstract: OBJECTIVE
  Asymmetric dimethylarginine is an endogenous inhibitor of NO synthesis that may mediate cardiovascular disease. Alanine-glyoxylate aminotransferase-2 (AGXT2) has been proposed to degrade asymmetric dimethylarginine. We investigated the significance of AGXT2 in methylarginine metabolism in vivo and examined the effect of this enzyme on blood pressure.
  
  
  RESULTS
  In isolated mouse kidney mitochondria, we show asymmetric dimethylarginine deamination under physiological conditions. We demonstrate increased asymmetric dimethylarginine, reduced NO, and hypertension in an AGXT2 knockout mouse. We provide evidence for a role of AGXT2 in methylarginine metabolism in humans by demonstrating an inverse relationship between renal (allograft) gene expression and circulating substrate levels and an association between expression and urinary concentrations of the product. Finally, we examined data from a meta-analysis of blood pressure genome-wide association studies. No genome-wide significance was observed, but taking a hypothesis-driven approach, there was a suggestive association between the T allele at rs37369 (which causes a valine-isoleucine substitution and altered levels of AGXT2 substrate) and a modest increase in diastolic blood pressure (P=0.0052).
  
  
  CONCLUSIONS
  Although the effect of variation at rs37369 needs further study, these findings suggest that AGXT2 is an important regulator of methylarginines and represents a novel mechanism through which the kidney regulates blood pressure.
authors.affiliation: Nitric Oxide Signalling Group, Medical Research Council Clinical Sciences Center, Imperial College London, London, United Kingdom. b.caplin@ucl.ac.uks
authors.forename: Ben
authors.initials: B
authors.lastname: Caplin
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Anna
authors.initials: A
authors.lastname: Slaviero
authors.forename: James
authors.initials: J
authors.lastname: Tomlinson
authors.forename: Laura
authors.initials: L
authors.lastname: Dowsett
authors.forename: Mathew
authors.initials: M
authors.lastname: Delahaye
authors.forename: Alan
authors.initials: A
authors.lastname: Salama
authors.forename: David C
authors.initials: DC
authors.lastname: Wheeler
authors.forename: James
authors.initials: J
authors.lastname: Leiper
mesh_terms: D000328:Adult; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006973:Hypertension / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D000637:Transaminases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: C487735:dimethylarginine; D009569:Nitric Oxide; D001120:Arginine; D000637:Transaminases; C019635:Alanine-glyoxylate transaminase