Chemical induction of HO-1 suppresses lupus nephritis by reducing local iNOS expression and synthesis of anti-dsDNA antibody.
There is accumulating evidence that haem oxygenase (HO)-1 plays a protective role in various disorders. The beneficial efficacy of HO-1 induction therapy has been shown in renal diseases such as glomerulonephritis, interstitial nephritis and drug induced nephrotoxicity. However, involvement of HO-1 in the development of autoimmune renal diseases remains uncertain. To assess the clinical efficacy of HO-1 induction therapy for lupus glomerulonephritis, MRL/lpr mice were intraperitoneally injected with 100 micromol/kg hemin, a potent HO-1 inducer, or PBS as controls, once a week from 6 weeks of age to 21-24 weeks-old. We found that treatment with hemin led to a significant reduction of proteinuria and remarkable amelioration of glomerular lesions accompanied by decreased immune depositions. In addition, the circulating IgG anti-double-stranded DNA antibody level was significantly decreased in hemin treated mice when compared with controls. A single intraperitoneal injection with hemin resulted in reduction of inducible nitric oxide synthase expression in the kidney and spleen, and serum interferon-gamma level. Our results suggest that HO-1 induction therapy ameliorates lupus nephritis by suppressing nitric oxide (NO) dependent inflammatory responses and attenuating production of pathogenic autoantibodies.
Takeda
Y
Y
Yokohama City University Graduate School of Medicine, Department of Internal Medicine and Clinical Immunology, Yokohama, Japan.
Takeno
M
M
Iwasaki
M
M
Kobayashi
H
H
Kirino
Y
Y
Ueda
A
A
Nagahama
K
K
Aoki
I
I
Ishigatsubo
Y
Y
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis*; D002478:Cells, Cultured; D016207:Cytokines / Q000032:analysis; D004247:DNA / Q000276:immunology*; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000276:immunology*; D051547:Heme Oxygenase-1; D006427:Hemin / Q000008:administration & dosage / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000276:immunology; D007678:Kidney Glomerulus / Q000276:immunology; D008181:Lupus Nephritis / Q000276:immunology*; D008565:Membrane Proteins; D051379:Mice; D019463:Mice, Inbred MRL lpr; D019001:Nitric Oxide Synthase / Q000032:analysis*; D052247:Nitric Oxide Synthase Type II; D013154:Spleen / Q000276:immunology
D000974:Antibodies, Antinuclear; D016207:Cytokines; D007074:Immunoglobulin G; D008565:Membrane Proteins; D006427:Hemin; D004247:DNA; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse