Pyrrole-imidazole polyamide targeting transforming growth factor β1 ameliorates encapsulating peritoneal sclerosis.
OBJECTIVE
Encapsulating peritoneal sclerosis (EPS) is a devastating fibrotic complication in patients treated with peritoneal dialysis (PD). Transforming growth factor β1 (TGF-β1) is a pivotal factor in the induction of EPS.


METHODS
To develop pyrrole-imidazole (PI) polyamide, a novel gene silencer, targeted to the TGF-β1 promoter (Polyamide) for EPS, we examined the effects of Polyamide on messenger RNA (mRNA) expression of TGF-β1, vascular endothelial growth factor (VEGF), and extracellular matrix (ECM) in mesothelial cells in vitro, and on the thickness of injured peritoneum evaluated by histology and high-resolution regional elasticity mapping in rats in vivo.


RESULTS
Polyamide significantly lowered mRNA expression of TGF-β1 and ECM in vitro. Polyamide labeled with fluorescein isothiocyanate was taken up into the injured peritoneum and was strongly localized in the nuclei of most cells. Polyamide 1 mg was injected intraperitoneally 1 or 3 times in rats receiving a daily intraperitoneal injection of chlorhexidine gluconate and ethanol (CHX) for 14 days. Polyamide significantly suppressed peritoneal thickening and the abundance of TGF-β1 and fibronectin mRNA, but did not affect expression of VEGF mRNA in the injured peritoneum. Elasticity distribution mapping showed that average elasticity was significantly lower in Polyamide-treated rats than in rats treated solely with CHX.


CONCLUSIONS
Polyamide suppressed the stiffness, ECM formation, and thickening of the injured peritoneum that occurs during EPS pathogenesis. These data suggest that PI polyamide targeted to the TGF-β1 promoter will be a specific and feasible therapeutic strategy for patients with EPS.
College of Engineering, Nihon University Graduate School, Koriyama, Fukushima, Japan.
Kazuo
K
Serie
Noboru
N
Fukuda
Shigeki
S
Nakai
Hiroyuki
H
Matsuda
Takashi
T
Maruyama
Yoshinobu
Y
Murayama
Sadao
S
Omata
D000818:Animals; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D005109:Extracellular Matrix; D020868:Gene Silencing; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009757:Nylons / Q000494:pharmacology*; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D056627:Peritoneal Fibrosis / Q000235:genetics / Q000378:metabolism*; D010537:Peritoneum / Q000187:drug effects / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A