title: L-arginine supplementation accelerates renal fibrosis and shortens life span in experimental lupus nephritis.
abstract: BACKGROUND
  Inducible, high-output nitric oxide (NO) production has been identified as a central mediator of cell injury in immune-mediated renal disease. In acute anti-thy-1 glomerulonephritis prefeeding with the NO precursor L-arginine increases mesangial cell injury and the subsequent fibrosis. The present study tested the hypothesis that L-arginine supplementation may also be detrimental in chronic, NO-mediated murine lupus nephritis.
  
  
  METHODS
  Groups (N = 18) of female MRL/lpr mice with lupus nephritis were fed the following diets: (1) normal protein (22% casein); (2) normal protein and 1.0% L-arginine in the drinking water; (3) low protein (6% casein); (4) low protein + 0.4%l-arginine; and (5) low protein + 1.0% L-arginine. After 40 days mouse survival, albuminuria, matrix accumulation, inflammatory cell infiltration, immunoglobulin G (IgG) deposition, expression of transforming growth factor-beta 1 (TGF-beta 1), fibronectin and plasminogen activator inhibitor-1 (PAI-1) mRNA and protein, anti-DNA antibody titer, inducible nitric oxide synthase (iNOS) mRNA expression, blood amino acid levels, blood urea nitrogen (BUN) concentrations and blood and urinary NOx (nitrite + nitrate) levels were assessed.
  
  
  RESULTS
  L-Arginine supplementation increased mortality significantly (P < 0.02). The death rate increased from 0% in the lowest to 50% in the highest L-arginine intake group (normal protein + 1.0% L-arginine). L-Arginine administration increased albuminuria, renal matrix accumulation, TGF-beta 1, fibronectin, PAI-1, blood L-arginine, L-citrulline, BUN and blood and urine NOx levels, while protein restriction reduced these parameters. Renal cell infiltration and iNOS mRNA expression were decreased in the low protein group only. Anti-ds DNA-IgG and renal IgG deposition were comparable in all groups
  
  
  CONCLUSIONS
  Increasing L-arginine intake increases the severity of renal fibrosis and the likelihood of death in MRL/lpr mice. The results appear to be at least in part mediated through enhanced cytotoxic NO generation via iNOS. The data suggest that L-arginine restriction should be considered in human immune-mediated renal diseases.
authors.affiliation: Division of Nephrology, Charité, Campus Mitte, Humboldt-University Berlin, Germany. harm.peters@charite.de
authors.forename: Harm
authors.initials: H
authors.lastname: Peters
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Border
authors.forename: Matthias
authors.initials: M
authors.lastname: Rückert
authors.forename: Stephanie
authors.initials: S
authors.lastname: Krämer
authors.forename: Hans-H
authors.initials: HH
authors.lastname: Neumayer
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Noble
mesh_terms: D000419:Albuminuria / Q000276:immunology / Q000401:mortality / Q000473:pathology; D000596:Amino Acids / Q000097:blood; D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D001323:Autoantibodies / Q000097:blood; D001806:Blood Urea Nitrogen; D004247:DNA / Q000276:immunology; D005109:Extracellular Matrix / Q000473:pathology; D005260:Female; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D007074:Immunoglobulin G / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008181:Lupus Nephritis / Q000276:immunology / Q000401:mortality* / Q000473:pathology*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009566:Nitrates / Q000097:blood / Q000652:urine; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood / Q000652:urine; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1
chemical_list: D000596:Amino Acids; D001323:Autoantibodies; D005353:Fibronectins; D007074:Immunoglobulin G; D009566:Nitrates; D009573:Nitrites; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004247:DNA; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse