Pyrrole-imidazole polyamide targeting transforming growth factor β1 ameliorates encapsulating peritoneal sclerosis.

Abstract

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.

• Authors: Kazuo Serie, Noboru Fukuda, Shigeki Nakai, Hiroyuki Matsuda, Takashi Maruyama, Yoshinobu Murayama, Sadao Omata
• Journal: Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis (Perit Dial Int) 2012 Jul-Aug Vol. 32 Issue 4 Pg. 462-72 ISSN: 1718-4304 [Electronic] United States
• PMID: 22215658 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Imidazoles
• Nylons
• Pyrroles
• RNA, Messenger
• Tgfb1 protein, rat
• Transforming Growth Factor beta1
• Vascular Endothelial Growth Factor A

Topics

• Animals
• Cells, Cultured
• Electrophoretic Mobility Shift Assay
• Extracellular Matrix
• Gene Silencing
• Imidazoles (pharmacology, therapeutic use)
• Male
• Nylons (pharmacology)
• Peritoneal Dialysis (adverse effects)
• Peritoneal Fibrosis (genetics, metabolism)
• Peritoneum (drug effects, metabolism)
• Pyrroles (pharmacology, therapeutic use)
• RNA, Messenger (biosynthesis)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Transforming Growth Factor beta1 (genetics, metabolism)
• Vascular Endothelial Growth Factor A (genetics, metabolism)