Inhibition of inducible nitric oxide synthase intensifies injury and functional deterioration in autoimmune interstitial nephritis.

Abstract

T lymphocytes are exquisitely sensitive to the antiproliferative effects of nitric oxide. We examined the effects of oral administration of two nitric oxide synthase inhibitors, Nw-nitro-L-arginine methyl ester (L-NAME) and L-N6-(1-iminoethyl)lysine (L-NIL), on the course of T cell-dependent autoimmune interstitial nephritis in Brown Norway rats. Kidneys from rats immunized to produce interstitial nephritis display a net generation of nitric oxide end products. By immunohistochemical staining, the cytokine-inducible nitric oxide synthase (iNOS) is expressed in cortical tubular epithelial cells. Treatment with either inhibitor results in markedly more severe disease following immunization. Animals receiving L-NAME were hypertensive, while those treated with L-NIL, a highly selective inhibitor of iNOS, were not. Evaluation of the expression of IFN-gamma, IL-2, and IL-4 in diseased kidneys by quantitative reverse transcriptase-PCR demonstrated that L-NAME-treated animals displayed significantly augmented levels of IFN-gamma and IL-2 with preserved ratios of IFN-gamma/IL-4 and IL-2/IL-4, while L-NIL-treated animals had augmented levels of IL-2 and IFN-gamma with augmented IFN-gamma/IL-4 and IL-2/IL-4 ratios. Animals treated with L-NAME or L-NIL both had augmented Ag-specific IgG responses. The L-NAME group demonstrated increases in both the IgG2a and IgG1 subtypes, with a constant IgG2a/IgG1 ratio, while the L-NIL group demonstrated an increase in the ratio of the IgG2a/IgG1 response. These Ab and cytokine data suggest that the L-NIL-treated animals had a skewing of their immune response toward a Th1-like response. We conclude that in autoimmune interstitial nephritis, generation of nitric oxide through the iNOS pathway has host-protective effects, and suggest that this may be broadly applicable to T cell-mediated pathologies.

• Authors: F B Gabbai, C Boggiano, T Peter, S Khang, C Archer, D P Gold, C J Kelly
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 159 Issue 12 Pg. 6266-75 (Dec 15 1997) ISSN: 0022-1767 [Print] United States
• PMID: 9550431 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Heymann Nephritis Antigenic Complex
• Immunoglobulin G
• Membrane Glycoproteins
• N(6)-(1-iminoethyl)lysine
• Nitrites
• RNA, Messenger
• Interferon-gamma
• Freund's Adjuvant
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nos2 protein, rat
• Lysine
• NG-Nitroarginine Methyl Ester

Topics

• Administration, Oral
• Animals
• Autoimmune Diseases (enzymology, pathology, physiopathology)
• Basement Membrane (immunology)
• Enzyme Induction (immunology)
• Freund's Adjuvant (immunology)
• Heymann Nephritis Antigenic Complex
• Immunoglobulin G (biosynthesis)
• Interferon-gamma (biosynthesis, genetics)
• Kidney Cortex (enzymology)
• Kidney Tubules (enzymology, immunology)
• Lysine (administration & dosage, analogs & derivatives)
• Male
• Membrane Glycoproteins (immunology)
• NG-Nitroarginine Methyl Ester (administration & dosage)
• Nephritis, Interstitial (enzymology, immunology, pathology, physiopathology)
• Nitric Oxide Synthase (biosynthesis)
• Nitric Oxide Synthase Type II
• Nitrites (metabolism)
• RNA, Messenger (biosynthesis, genetics)
• Rats
• Rats, Inbred BN