Transcriptional inhibition of progressive renal disease by gene silencing pyrrole-imidazole polyamide targeting of the transforming growth factor-β1 promoter.
Pyrrole-imidazole (PI) polyamides are small synthetic molecules that recognize and attach to the minor groove of DNA, thereby inhibiting gene transcription by blocking transcription factor binding. These derivatives can act as gene silencers inhibiting target gene expression under stimulatory conditions such as disease. To evaluate PI polyamides as treatments for the progression of renal diseases, we examined morphological effects, pharmacological properties, and the specificity of PI polyamides targeted to the transforming growth factor (TGF)-β1 promoter during salt-induced hypertensive nephrosclerosis in Dahl salt-sensitive rats. The targeted PI polyamide markedly reduced glomerulosclerosis and interstitial fibrosis without side effects. PI polyamide significantly decreased expression of TGF-β1 and extracellular matrix in the renal cortex. Microarray analysis found that only 3% of the transcripts were affected by PI polyamide, but this included decreased expression of extracellular matrix, TGF-β1-related cytokines, angiogenic, and cell stabilizing factors, proteinases, and renal injury-related factors. Thus, targeted PI polyamides are potential gene silencers for diseases not treatable by current remedies.
Matsuda
Hiroyuki
H
Department of Life Science, Advanced Research Institute of the Sciences and Humanities, Nihon University, Tokyo, Japan.
Fukuda
Noboru
N
Ueno
Takahiro
T
Katakawa
Mayumi
M
Wang
Xiaofei
X
Watanabe
Takayoshi
T
Matsui
Sei-Ichi
S
Aoyama
Takahiko
T
Saito
Kosuke
K
Bando
Toshikazu
T
Matsumoto
Yoshiaki
Y
Nagase
Hiroaki
H
Matsumoto
Koichi
K
Sugiyama
Hiroshi
H
D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D005355:Fibrosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D005786:Gene Expression Regulation; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009757:Nylons / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D014158:Transcription, Genetic / Q000187:drug effects*; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
D000596:Amino Acids; D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; C096654:N-methylpyrrole; C018100:1-methylimidazole