Forefronts In Nephrology: Nitric Oxide And Inflammation
Kidney International (2002) 61, 839–846; doi:10.1046/j.1523-1755.2002.00230.x
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 and Gary S Gilkeson
Department of Medicine, Medical University of South Carolina, and the Medical Research Service, Ralph H. Johnson VA Medical Center, Charleston, South Carolina; Department of Pathology, University of Miami School of Medicine, Miami, Florida; and Pharmacia Corporation, St. Louis, Missouri, USA
Correspondence: Christopher M. Reilly, Ph.D., Division of Rheumatology and Immunology, Medical University of South Carolina, 96 Jonathon Lucas St., Suite 912, P.O. Box 250623, Charleston, South Carolina 29425, USA. E-mail: reillycm@musc.edu
Abstract
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.
Conclusion
These results indicate that specific inhibition of iNOS blocks the development of pathologic renal disease in MRL/lpr mice.
Keywords:
lupus, rodent, autoantibody, inflammation, nitric oxide
