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


CONCLUSIONS
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.
Peters
Harm
H
Division of Nephrology and Institute of Pathology, Charité, Campus Mitte, Humboldt-University, Berlin, Germany. Harm.Peters@charite.de
Daig
Ute
U
Martini
Sebastian
S
Rückert
Matthias
M
Schäper
Frank
F
Liefeldt
Lutz
L
Krämer
Stephanie
S
Neumayer
Hans-H
HH
D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D001794:Blood Pressure; D001835:Body Weight; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005353:Fibronectins / Q000235:genetics; D005355:Fibrosis; D015870:Gene Expression; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D007518:Isoantibodies / Q000494:pharmacology; D008297:Male; D008981:Molsidomine / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009573:Nitrites / Q000097:blood; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011507:Proteinuria / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D004791:Enzyme Inhibitors; D005353:Fibronectins; D007518:Isoantibodies; D009566:Nitrates; D020030:Nitric Oxide Donors; D009573:Nitrites; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C035678:anti-Thy antibody; D009569:Nitric Oxide; D001120:Arginine; D008981:Molsidomine; D019331:NG-Nitroarginine Methyl Ester