Hydrodynamics-based delivery of the viral interleukin-10 gene suppresses experimental crescentic glomerulonephritis in Wistar-Kyoto rats.
Gene therapy is expected to revolutionize the treatment of kidney diseases. Viral interleukin (vIL)-10 has a variety of immunomodulatory properties. We examined the applicability of vIL-10 gene transfer to the treatment of rats with crescentic glomerulonephritis, a T helper 1 (Th 1) predominant disease. To produce the disease, Wistar-Kyoto rats were injected with a rabbit polyclonal anti-rat glomerular basement membrane antibody. After 3 h, a large volume of plasmid DNA expressing vIL-10 (pCAGGS-vIL-10) solution was rapidly injected into the tail vein. pCAGGS solution was similarly injected into control rats (pCAGGS rats). We confirmed the presence of vector-derived vIL-10 mainly in the liver and observed high serum vIL-10 levels in pCAGGS-vIL-10-injected rats. Compared with the pCAGGS rats, the pCAGGS-vIL-10 rats showed significant therapeutic effects: reduced frequency of crescent formation, decrease in the number of total cells, macrophages, and CD4+ T cells in the glomeruli, decrease in urine protein, and attenuation of kidney dysfunction. Using quantitative real-time polymerase chain reaction, we also observed that this model was Th1-predominant in the glomeruli and that the ratio of the transcripts of CD4, interferon-gamma, tumor necrosis factor-alpha, and monocyte chemotactic protein-1 to the transcripts of glucose-6-phosphate dehydrogenase in the glomeruli were all significantly lower in the pCAGGS-vIL-10 rats than in the pCAGGS rats. These results demonstrate that pCAGGS-vIL-10 gene transfer by hydrodynamics-based transfection suppresses crescentic glomerulonephritis.
Higuchi
N
N
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Maruyama
H
H
Kuroda
T
T
Kameda
S
S
Iino
N
N
Kawachi
H
H
Nishikawa
Y
Y
Hanawa
H
H
Tahara
H
H
Miyazaki
J
J
Gejyo
F
F
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018932:Chemokine CCL2 / Q000378:metabolism; D004247:DNA / Q000008:administration & dosage; D015316:Genetic Therapy / Q000379:methods*; D005921:Glomerulonephritis / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000032:analysis / Q000235:genetics*; D007668:Kidney / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D008297:Male; D023421:Models, Animal; D011817:Rabbits; D051381:Rats; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology; D014161:Transduction, Genetic / Q000379:methods*
D018932:Chemokine CCL2; D016753:Interleukin-10; D007371:Interferon-gamma; D004247:DNA; D005954:Glucosephosphate Dehydrogenase