Inducible nitric oxide synthase inhibitor SD-3651 reduces proteinuria in MRL/lpr mice deficient in the NOS2 gene

Chinedu Njoku, Sally E. Self, Philip Ruiz, Ann F. Hofbauer, Gary S. Gilkeson, Jim C. Oates

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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-FASlpr (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 hadhigher 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 bylight 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.

Original languageEnglish (US)
Pages (from-to)911-919
Number of pages9
JournalJournal of Investigative Medicine
Volume56
Issue number7
DOIs
StatePublished - Oct 2008

Keywords

  • Animal models
  • Enzyme inhibitors
  • Lupus nephritis
  • Nitric oxide
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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