Inhibition of inducible nitric oxide synthase intensifies injury and functional deterioration in autoimmune interstitial nephritis.
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.
Gabbai
F B
FB
Department of Medicine, University of California, San Diego 92161, USA.
Boggiano
C
C
Peter
T
T
Khang
S
S
Archer
C
C
Gold
D P
DP
Kelly
C J
CJ
D000284:Administration, Oral; D000818:Animals; D001327:Autoimmune Diseases / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D001485:Basement Membrane / Q000276:immunology; D004790:Enzyme Induction / Q000276:immunology; D005620:Freund's Adjuvant / Q000276:immunology; D026541:Heymann Nephritis Antigenic Complex; D007074:Immunoglobulin G / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007672:Kidney Cortex / Q000201:enzymology; D007684:Kidney Tubules / Q000201:enzymology / Q000276:immunology; D008239:Lysine / Q000008:administration & dosage / Q000031:analogs & derivatives; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009395:Nephritis, Interstitial / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011914:Rats, Inbred BN
D026541:Heymann Nephritis Antigenic Complex; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; C090663:N(6)-(1-iminoethyl)lysine; D009573:Nitrites; D012333:RNA, Messenger; D007371:Interferon-gamma; D005620:Freund's Adjuvant; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D008239:Lysine; D019331:NG-Nitroarginine Methyl Ester