Modulation of renal disease in MRL/lpr mice by pharmacologic inhibition of inducible nitric oxide synthase.
BACKGROUND
MRL-MPJFaslpr (MRL/lpr) mice spontaneously develop lupus-like disease characterized by immune complex glomerulonephritis and overproduction of nitric oxide (NO). Blocking NO production pharmacologically by a non-specific nitric oxide synthase (NOS) inhibitor ameliorated renal disease in MRL/lpr mice while genetically deficient inducible NOS (iNOS) mice developed proliferative glomerulonephritis similar to wild-type controls.


METHODS
To clarify the role of iNOS in the pathogenesis of nephritis in MRL/lpr mice, we treated mice with two different NOS inhibitors. Either NG-monomethyl-l-arginine (L-NMMA), a nonspecific NOS inhibitor, or l-N6-(1-iminoethyl)lysine (L-NIL), an iNOS specific inhibitor, was administered in the drinking water from 10 through 22 weeks of age with disease progression monitored over time. Control mice received water alone.


RESULTS
Both L-NMMA and L-NIL blocked NO production effectively in MRL/lpr mice. As expected, neither L-NNMA nor L-NIL had an effect on antibody production, immune complex deposition or complement activation. Although both NOS inhibitors decreased protein excretion, L-NMMA was more effective than L-NIL. Pathologic renal disease was significantly decreased at 19 weeks in both treatment groups. At 22 weeks the L-NIL treated mice, but not the L-NMMA mice, had significantly reduced renal disease scores compared to controls.


CONCLUSIONS
These results indicate that specific inhibition of iNOS blocks the development of pathologic renal disease in MRL/lpr mice.
Reilly
Christopher M
CM
Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina, 96 Jonathan Lucas Street, Box 250623, Charleston, SC 29425, USA. reillycm@musc.edu
Farrelly
Libby W
LW
Viti
Dana
D
Redmond
Shakisha T
ST
Hutchison
Florence
F
Ruiz
Phil
P
Manning
Pam
P
Connor
Jane
J
Gilkeson
Gary S
GS
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000473:pathology / Q000503:physiopathology*; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051379:Mice; D019463:Mice, Inbred MRL lpr / Q000502:physiology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D011507:Proteinuria / Q000652:urine; D019323:omega-N-Methylarginine / Q000494:pharmacology*
D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D008239:Lysine