In vivo administration of a nuclear transcription factor-kappaB decoy suppresses experimental crescentic glomerulonephritis.
Glomerular expression of cytokines, interleukin-1 (IL-1), and tumor necrosis factor-alpha (TNF-alpha), together with leukocytic infiltration, are prominent features in crescentic glomerulonephritis. Because these cytokines are targets for nuclear transcription factor-kappaB (NF-kappaB), the use of NF-kappaB decoy oligodeoxynucleotide (ODN) treatment was evaluated in an experimental disease model. Crescentic glomerulonephritis was induced in primed Wistar rats by injection of sheep antiglomerular basement membrane serum. Thirty minutes after injection, rats were anesthetized and the left kidney was perfused with NF-kappaB decoy ODN or scrambled ODN control mixed with a virus-liposome complex, and then killed 7 d later. Animals given the scrambled control ODN developed severe glomerulonephritis by day 7 with heavy proteinuria, glomerular crescents and interstitial lesions, marked leukocytic infiltration, and upregulated renal expression of cytokines (IL-1 and TNF-alpha) and adhesion molecules (intercellular adhesion molecule-1). In contrast, NF-kappaB decoy ODN treatment substantially inhibited the disease with a 50% reduction in proteinuria, a threefold reduction in histologic damage, a 50% reduction in leukocytic infiltration, and a 50 to 80% reduction in the renal expression of cytokines and leukocyte adhesion molecules. In conclusion, this study has demonstrated that NF-kappaB plays a key role in cytokine-mediated renal injury and that NF-kappaB decoy ODN treatment has clear therapeutic potential in rapidly progressive glomerulonephritis.
Tomita
Naruya
N
Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan.
Morishita
Ryuichi
R
Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan.|Gene Therapy Science, Osaka University Medical School, Suita, Japan.
Lan
Hui Y
HY
Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.
Yamamoto
Kei
K
Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan.
Hashizume
Masahide
M
Dainippon Pharmaceutical Co., Ltd., Suita, Japan.
Notake
Mitsue
M
Dainippon Pharmaceutical Co., Ltd., Suita, Japan.
Toyosawa
Kaoru
K
Dainippon Pharmaceutical Co., Ltd., Suita, Japan.
Fujitani
Buichi
B
Dainippon Pharmaceutical Co., Ltd., Suita, Japan.
Mu
Wei
W
Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.
Nikolic-Paterson
David J
DJ
Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.
Atkins
Robert C
RC
Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.
Kaneda
Yasufumi
Y
Gene Therapy Science, Osaka University Medical School, Suita, Japan.
Higaki
Jitsuo
J
Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan.
Ogihara
Toshio
T
Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan.
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004337:Drug Carriers; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000502:physiology; D008081:Liposomes; D008297:Male; D016328:NF-kappa B / Q000235:genetics*; D009841:Oligonucleotides / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D018108:Respirovirus / Q000235:genetics; D014162:Transfection
D016207:Cytokines; D004337:Drug Carriers; D008081:Liposomes; D016328:NF-kappa B; D009841:Oligonucleotides