title: Inducible nitric oxide synthase inhibitor SD-3651 reduces proteinuria in MRL/lpr mice deficient in the NOS2 gene.
abstract: Several studies have demonstrated the effectiveness of arginine analog nitric oxide synthase (NOS) inhibitor therapy in preventing and treating murine lupus nephritis. However, MRL/MpJ-FAS (MRL/lpr) mice lacking a functional NOS2 (inducible NOS [iNOS]) gene (NOS2) develop proliferative glomerulonephritis in a fashion similar to their wild-type (wt) littermates. This finding suggests that the effect of arginine analog NOS inhibitors is through a non-iNOS-mediated mechanism. This study was designed to address this hypothesis.NOS2 mice were given either vehicle or a NOS inhibitor (SD-3651) to determine if pharmacological NOS inhibition prevented glomerulonephritis, using wt mice as positive controls. Urine was collected fortnightly to measure albumin. At the time of full disease expression in wt mice, all mice were killed, and renal tissue was examined for light, immunofluorescence, and electron microscopic evidence of disease. Serum was analyzed for anti-double-stranded DNA antibody production.NOS2 mice had higher serum anti-double-stranded DNA antibody antibody levels than those of wt mice. SD-3651 therapy reduced proteinuria, glomerular immunoglobulin G deposition, and electron microscopic evidence of podocytopathy and endothelial cell swelling without affecting proliferative lesions by light microscopy.These studies confirm that genetic iNOS deficiency alone is insufficient to prevent proliferative glomerulonephritis and suggest that iNOS activity may inhibit autoantibody production. These results also suggest that SD-3651 therapy acts via a non-iNOS-mediated mechanism to prevent endothelial cell and podocyte pathology. Studies that elucidate this mechanism could provide a useful drug target for the treatment of nephritis.
authors.affiliation: Department of Medicine, Division of Rheumatology, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29525, USA.
authors.forename: Chinedu
authors.initials: C
authors.lastname: Njoku
authors.forename: Sally E
authors.initials: SE
authors.lastname: Self
authors.forename: Philip
authors.initials: P
authors.lastname: Ruiz
authors.forename: Ann F
authors.initials: AF
authors.lastname: Hofbauer
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gilkeson
authors.forename: Jim C
authors.initials: JC
authors.lastname: Oates
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D008181:Lupus Nephritis / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000235:genetics; D011507:Proteinuria / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*
chemical_list: D000974:Antibodies, Antinuclear; D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D008239:Lysine
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