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.