Transcriptional regulation of NF-kappaB by ring type decoy oligodeoxynucleotide in an animal model of nephropathy.
Inflammation of the tubulointerstitial compartment, leading to fibrosis, is a major factor in the progressive loss of renal function in a wide variety of kidney diseases. In order to develop a therapeutic approach for nephropathy, we examined the simultaneous inhibition of transcription factor nuclear factor-kappaB (NF-kappaB), which is responsible for a wide range of cellular processes, especially inflammation, in a mouse model of unilateral ureteral obstruction. In this study, we employed a ring-type NF-kappaB (R-NF-kappaB) decoy oligodeoxynucleotide (ODN), containing consensus promoter sequences of NF-kappaB. This R-NF-kappaB decoy ODN is more highly resistant to degradation by nucleases than is the current phosphothiolated double stranded NF-kappaB decoy ODN. The inhibitory effect of R-NF-kappaB decoy ODN on nephropathy was confirmed by molecular and histological examinations. In addition, treatment with R-NF-kappaB decoy ODN reduced the activities of inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-1beta. Interestingly, the treatment with R-NF-kappaB decoy ODN also suppressed the gene expression of transforming growth factor-beta1 and fibronectin, resulting in the inhibition of fibrotic changes. These results suggest that the inhibition of NF-kappaB using R-NF-kappaB decoy ODN has potential therapeutic application in the prevention of renal fibrosis.
Kim
Kyung-Hyun
KH
Department of Pathology, Catholic University of Daegu, College of Medicine, Daegu, Republic of Korea.
Lee
Eun-Seok
ES
Cha
Sun-Hwa
SH
Park
Ji-Hyun
JH
Park
Jae-Shin
JS
Chang
Young-Chae
YC
Park
Kwan-Kyu
KK
D000818:Animals; D001483:Base Sequence; D001806:Blood Urea Nitrogen; D004195:Disease Models, Animal; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis / Q000150:complications / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005921:Glomerulonephritis / Q000150:complications / Q000235:genetics; D007150:Immunohistochemistry; D007249:Inflammation / Q000150:complications; D053583:Interleukin-1beta / Q000097:blood; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics*; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000494:pharmacology*; D051381:Rats; D044967:Serum; D014158:Transcription, Genetic / Q000187:drug effects*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D005353:Fibronectins; D053583:Interleukin-1beta; D016328:NF-kappa B; C468119:NF-kappaB decoy; D009838:Oligodeoxyribonucleotides; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha