NO mediates antifibrotic actions of L-arginine supplementation following induction of anti-thy1 glomerulonephritis.

Unlabelled: NO mediates antifibrotic actions of L-arginine supplementation following induction of anti-thy1 glomerulonephritis.

Background: L-Arginine plays a complex role in renal matrix expansion, involving endogenous metabolism into nitric oxide (NO), polyamines, L-proline and agmatine. Supplementing dietary L-arginine intake has been shown to limit transforming growth factor (TGF)-beta 1 overproduction and matrix accumulation in rats with induced anti-thy1 glomerulonephritis (GN). The present study tests the hypothesis that this beneficial effect on in vivo TGF-beta overexpression is mediated via the generation of NO.

Methods: One day after induction of anti-thy1 GN, male Wistar rats fed a normal protein diet were assigned to the following groups: (1) normal controls; (2) GN; (3) GN-Arg (plus 500 mg L-arginine/day); (4) GN-Arg-NAME [plus 500 mg L-arginine/day and 75 mg/L of the NO synthase inhibitor nitro-L-arginine-methyl ester (L-NAME) in the drinking water]; and (5) GN-Molsi (10 mg/day of the NO donor molsidomine). In protocol 1, treatment lasted until day 7, and in protocol 2, until day 12 after disease induction, respectively. Analysis included systolic blood pressure, a glomerular histologic matrix score, and the glomerular mRNA and protein expression of the key fibrogen TGF-beta1, the matrix protein fibronectin, and the protease inhibitor plasminogen activator inhibitor type 1 (PAI-1).

Results: Blood pressure was normal in untreated anti-thy1 animals and not significantly affected by any of the treatments. Compared to untreated nephritic rats, administration of both L-arginine and molsidomine reduced glomerular TGF-beta 1 overexpression significantly and to a similar degree in both protocols, while the beneficial effect of L-arginine was abolished by concomitant NO synthesis inhibition. Glomerular matrix accumulation, fibronectin and PAI-1 mRNA and protein expression closely followed the expression of TGF-beta 1.

Conclusion: The present study shows that L-arginine's antifibrotic action in normotensive anti-thy1 GN is mainly mediated by endogenous production of NO. The data suggest that NO limits in vivo TGF-beta overexpression in a pressure-independent manner and that NO donors may be of benefit in the treatment of human fibrotic renal disease.