Modulation of renal disease in MRL/lpr mice by pharmacologic inhibition of inducible nitric oxide synthase

Christopher M. Reilly, Libby W. Farrelly, Dana Viti, Shakisha T. Redmond, Florence Hutchison, Phil Ruiz, Pam Manning, Jane Connor, Gary S. Gilkeson

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Abstract

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-NM-MA), 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. Conclusion. These results indicate that specific inhibition of iNOS blocks the development of pathologic renal disease in MRL/lpr mice.

Original languageEnglish (US)
Pages (from-to)839-846
Number of pages8
JournalKidney international
Volume61
Issue number3
DOIs
StatePublished - Jan 1 2002

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Keywords

  • Autoantibody
  • Inflammation
  • Lupus
  • Nitric oxide
  • Rodent

ASJC Scopus subject areas

  • Nephrology

Cite this

Reilly, C. M., Farrelly, L. W., Viti, D., Redmond, S. T., Hutchison, F., Ruiz, P., Manning, P., Connor, J., & Gilkeson, G. S. (2002). Modulation of renal disease in MRL/lpr mice by pharmacologic inhibition of inducible nitric oxide synthase. Kidney international, 61(3), 839-846. https://doi.org/10.1046/j.1523-1755.2002.00230.x