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PMID: 7507509 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increased nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl-L-arginine.

The Journal of experimental medicine ·Vol. 179 ·No. 2 ·1994-02-01 ·Pages 651-60

Weinberg JB, Granger DL, Pisetsky DS, Seldin MF, Misukonis MA, Mason SN, Pippen AM, Ruiz P, Wood ER, Gilkeson GS

Abstract

MRL-lpr/lpr mice spontaneously develop various manifestations of autoimmunity including an inflammatory arthropathy and immune complex glomerulonephritis. This study examines the role of nitric oxide, a molecule with proinflammatory actions, in the pathogenesis of MRL-lpr/lpr autoimmune disease. MRL-lpr/lpr mice excreted more urinary nitrite/nitrate (an in vivo marker of nitric oxide production) than did mice of normal strains and MRL-(+/+) and B6-lpr/lpr congenic strains. In addition, MRL-lpr/lpr peritoneal macrophages had an enhanced capacity to produce nitric oxide in vitro as well as increased nitric oxide synthase activity, and certain tissues from MRL-lpr/lpr mice had increased expression of inducible nitric oxide synthase (NOS) mRNA and increased amounts of material immunoreactive for inducible NOS. Oral administration of NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, prevented the development of glomerulonephritis and reduced the intensity of inflammatory arthritis in MRL-lpr/lpr mice. By using interspecific backcross mice, the gene for inducible NOS (Nosi) was mapped to mouse chromosome 11. This chromosomal localization was different from those loci that we have previously demonstrated to be linked to enhanced susceptibility to renal disease in an MRL-lpr/lpr cross. However, the chromosomal location of the NOS gene was consistent with an insulin-dependent diabetes locus identified in an analysis of nonobese diabetic (NOD) mice. These results suggest that elevated nitric oxide production could be important in the pathogenesis of autoimmunity, and that treatments to block the production of nitric oxide or block its effects might be valuable therapeutically.

Related Genes
MRL
MeSH Terms
Administration, Oral Amino Acid Oxidoreductases/biosynthesis Animals Arginine/analogs & derivatives,antagonists & inhibitors,pharmacology Arthritis/etiology Autoimmune Diseases/etiology,genetics Chromosome Mapping Crosses, Genetic Female Glomerulonephritis/etiology Male Mice Mice, Inbred BALB C Mice, Inbred C3H Mice, Inbred C57BL Nitrates/urine Nitric Oxide/antagonists & inhibitors,biosynthesis,physiology Nitric Oxide Synthase Nitrites/urine omega-N-Methylarginine
Chemicals
Nitrates Nitrites omega-N-Methylarginine Nitric Oxide Arginine Nitric Oxide Synthase Amino Acid Oxidoreductases
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Weinberg J B
Department of Medicine, Veterans Administration Medical Center, Durham, North Carolina 27705.
Granger D L
Pisetsky D S
Seldin M F
Misukonis M A
Mason S N
Pippen A M
Ruiz P
Wood E R
Gilkeson G S
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.179.2.651
Published
1994-02-01
Pages
651-60
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2191384
Subset
IM
Grants
NIAID NIH HHS · AI-26188 · United States
NIAMS NIH HHS · AR-39162 · United States
NIAMS NIH HHS · AR-41053 · United States
External Links
PubMed source DOI: 10.1084/jem.179.2.651 PMC Full Text View journal details
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