title: Transcriptional inhibition of progressive renal disease by gene silencing pyrrole-imidazole polyamide targeting of the transforming growth factor-β1 promoter.
abstract: 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.
authors.affiliation: Department of Life Science, Advanced Research Institute of the Sciences and Humanities, Nihon University, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Matsuda
authors.forename: Noboru
authors.initials: N
authors.lastname: Fukuda
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ueno
authors.forename: Mayumi
authors.initials: M
authors.lastname: Katakawa
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wang
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Sei-Ichi
authors.initials: S
authors.lastname: Matsui
authors.forename: Takahiko
authors.initials: T
authors.lastname: Aoyama
authors.forename: Kosuke
authors.initials: K
authors.lastname: Saito
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Bando
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagase
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugiyama
mesh_terms: 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*
chemical_list: D000596:Amino Acids; D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; C096654:N-methylpyrrole; C018100:1-methylimidazole