The Ace Inhibitor, Quinapril, Ameliorates Peritoneal Fibrosis in an Encapsulating Peritoneal Sclerosis Model in Mice

♦ 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 highresolution 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.

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“…32,No. 4 PDI in the normal wound healing process, but it has also been implicated in excessive scar formation and fibrotic disorders (27).…”

Section: Discussionmentioning

confidence: 99%

“…32,No. 4 EFFECT OF TGFβ POLYAMIDE ON EPS production by mesothelial cells of transforming growth factor β (TGF-β) and vascular endothelial growth factor (VEGF).…”

mentioning

confidence: 99%

Pyrrole-Imidazole Polyamide Targeting Transforming Growth Factor β1 Ameliorates Encapsulating Peritoneal Sclerosis

et al. 2012

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“…Mice were given daily intraperitoneal administration of 0.3 ml or 10 ml saline/kg body weight containing 0.1% CG in 15% ethanol [97,98]. Peritoneal fibrosis and increased infiltration of mononuclear cells were observed over time.…”

Section: Zymosan-induced Fungal Peritonitis Modelmentioning

confidence: 99%

Peritonitis-induced peritoneal injury models for research in peritoneal dialysis review of infectious and non-infectious models

et al. 2017

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Peritonitis is an important complication of peritoneal dialysis. Several animal peritonitis models have been described, including bacterial and fungal models that are useful for studying inflammation in peritonitis. However, these models have limitations for investigating peritoneal fibrosis induced by acute inflammation and present difficulties in handling the infected animals. Animal models of peritonitis which induced peritoneal fibrosis are important for establishing new therapies to improve peritoneal damage induced by peritonitis. Here, we present an overview of representative animal models of peritoneal dialysis-associated infectious and non-infectious peritonitis, including our novel animal models (scraping and zymosan models) that mimic peritoneal injury associated with fibrosis and neoangiogenesis caused by bacterial or fungal peritonitis.

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“…Furthermore, these authors showed that ACE inhibitors directly inhibited MMP-2 activity in the peritoneal effluent from patients on PD [47]. In experimental animal models, use of ACE inhibitors protected the animals from peritoneal injury with fibrosis thickening and functional decline, such as increased solute transport [48][49][50]. Sampimon et al have reported the clinical possibility of a protective effect of ACE inhibitors on the development of EPS although it did not achieve statistical significance [51].…”

Section: Protection From Peritoneal Injury By Inhibition Of Mmp-2mentioning

confidence: 99%

Matrix Metalloproteinases Cause Peritoneal Injury in Peritoneal Dialysis

Hirahara¹,

Akimoto²,

Morishita³

et al. 2011

Progress in Peritoneal Dialysis

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The Ace Inhibitor, Quinapril, Ameliorates Peritoneal Fibrosis in an Encapsulating Peritoneal Sclerosis Model in Mice

Cited by 45 publications

References 20 publications

Pyrrole-Imidazole Polyamide Targeting Transforming Growth Factor β1 Ameliorates Encapsulating Peritoneal Sclerosis

Pyrrole-Imidazole Polyamide Targeting Transforming Growth Factor β1 Ameliorates Encapsulating Peritoneal Sclerosis

Peritonitis-induced peritoneal injury models for research in peritoneal dialysis review of infectious and non-infectious models

Matrix Metalloproteinases Cause Peritoneal Injury in Peritoneal Dialysis

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