Pyrrole-Imidazole Polyamide Targeting Transforming Growth Factor β1 Ameliorates Encapsulating Peritoneal Sclerosis
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. To develop pyrrole-imidazole (PI) polyamide, a novel gene silencer, targeted to the T...
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| Veröffentlicht in: | Peritoneal dialysis international 2012-07, Vol.32 (4), p.462-472 |
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| creator | Serie, Kazuo Fukuda, Noboru Nakai, Shigeki Matsuda, Hiroyuki Maruyama, Takashi Murayama, Yoshinobu Omata, Sadao |
| description | 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.
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.
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.
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. |
| doi_str_mv | 10.3747/pdi.2011.00092 |
| format | Article |
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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.
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.
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.</description><identifier>ISSN: 0896-8608</identifier><identifier>EISSN: 1718-4304</identifier><identifier>DOI: 10.3747/pdi.2011.00092</identifier><identifier>PMID: 22215658</identifier><language>eng</language><publisher>United States: Multimed Inc</publisher><subject>Animals ; Cells, Cultured ; Electrophoretic Mobility Shift Assay ; Extracellular Matrix ; Gene Silencing ; Imidazoles - pharmacology ; Imidazoles - therapeutic use ; Male ; Nylons - pharmacology ; Original ; Peritoneal Dialysis - adverse effects ; Peritoneal Fibrosis - genetics ; Peritoneal Fibrosis - metabolism ; Peritoneum - drug effects ; Peritoneum - metabolism ; Pyrroles - pharmacology ; Pyrroles - therapeutic use ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; RNA, Messenger - biosynthesis ; Transforming Growth Factor beta1 - genetics ; Transforming Growth Factor beta1 - metabolism ; Vascular Endothelial Growth Factor A - genetics ; Vascular Endothelial Growth Factor A - metabolism</subject><ispartof>Peritoneal dialysis international, 2012-07, Vol.32 (4), p.462-472</ispartof><rights>Copyright © 2012 International Society for Peritoneal Dialysis 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4012-a27b5975b22a44fe387b520ba2b232730e5aaac79edb69e50b202571039934fc3</citedby><cites>FETCH-LOGICAL-c4012-a27b5975b22a44fe387b520ba2b232730e5aaac79edb69e50b202571039934fc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3524855/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3524855/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22215658$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Serie, Kazuo</creatorcontrib><creatorcontrib>Fukuda, Noboru</creatorcontrib><creatorcontrib>Nakai, Shigeki</creatorcontrib><creatorcontrib>Matsuda, Hiroyuki</creatorcontrib><creatorcontrib>Maruyama, Takashi</creatorcontrib><creatorcontrib>Murayama, Yoshinobu</creatorcontrib><creatorcontrib>Omata, Sadao</creatorcontrib><title>Pyrrole-Imidazole Polyamide Targeting Transforming Growth Factor β1 Ameliorates Encapsulating Peritoneal Sclerosis</title><title>Peritoneal dialysis international</title><addtitle>Perit Dial Int</addtitle><description>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.
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.
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.
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.</description><subject>Animals</subject><subject>Cells, Cultured</subject><subject>Electrophoretic Mobility Shift Assay</subject><subject>Extracellular Matrix</subject><subject>Gene Silencing</subject><subject>Imidazoles - pharmacology</subject><subject>Imidazoles - therapeutic use</subject><subject>Male</subject><subject>Nylons - pharmacology</subject><subject>Original</subject><subject>Peritoneal Dialysis - adverse effects</subject><subject>Peritoneal Fibrosis - genetics</subject><subject>Peritoneal Fibrosis - metabolism</subject><subject>Peritoneum - drug effects</subject><subject>Peritoneum - metabolism</subject><subject>Pyrroles - pharmacology</subject><subject>Pyrroles - therapeutic use</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Rats, Wistar</subject><subject>RNA, Messenger - biosynthesis</subject><subject>Transforming Growth Factor beta1 - genetics</subject><subject>Transforming Growth Factor beta1 - metabolism</subject><subject>Vascular Endothelial Growth Factor A - genetics</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><issn>0896-8608</issn><issn>1718-4304</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkE-P0zAQxS0EYrsLV44oF44p47EdJxek1Wr_SStRiXK2JqnTGjlxZWeJysfig_CZcLewgtPMk997Y_0Ye8dhKbTUH_cbt0TgfAkADb5gC655XUoB8iVbQN1UZV1BfcbOU_oGIFCAfs3OEJGrStULllaHGIO35f3gNvQjb8Uq-ANlZYs1xa2d3Lgt1pHG1Ic4HMVtDPO0K26om0Isfv3kxeVgvQuRJpuK67GjfXr09BRc2eimMFryxZfO2xiSS2_Yq558sm__zAv29eZ6fXVXPny-vb-6fCg7CRxLQt2qRqsWkaTsraizRmgJWxSoBVhFRJ1u7KatGqugRUClOYimEbLvxAX7dOrdP7aD3XR2nCJ5s49uoHgwgZz5_2V0O7MN341QKGulcsHyVNDlf6do--csB3PEbzJ-c8RvnvDnwPt_Lz7b__LOhg8nw85td7OL1qSBvM92NPM8CzTSyArFb0iJkeI</recordid><startdate>201207</startdate><enddate>201207</enddate><creator>Serie, Kazuo</creator><creator>Fukuda, Noboru</creator><creator>Nakai, Shigeki</creator><creator>Matsuda, Hiroyuki</creator><creator>Maruyama, Takashi</creator><creator>Murayama, Yoshinobu</creator><creator>Omata, Sadao</creator><general>Multimed Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>201207</creationdate><title>Pyrrole-Imidazole Polyamide Targeting Transforming Growth Factor β1 Ameliorates Encapsulating Peritoneal Sclerosis</title><author>Serie, Kazuo ; Fukuda, Noboru ; Nakai, Shigeki ; Matsuda, Hiroyuki ; Maruyama, Takashi ; Murayama, Yoshinobu ; Omata, Sadao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4012-a27b5975b22a44fe387b520ba2b232730e5aaac79edb69e50b202571039934fc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Cells, Cultured</topic><topic>Electrophoretic Mobility Shift Assay</topic><topic>Extracellular Matrix</topic><topic>Gene Silencing</topic><topic>Imidazoles - pharmacology</topic><topic>Imidazoles - therapeutic use</topic><topic>Male</topic><topic>Nylons - pharmacology</topic><topic>Original</topic><topic>Peritoneal Dialysis - adverse effects</topic><topic>Peritoneal Fibrosis - genetics</topic><topic>Peritoneal Fibrosis - metabolism</topic><topic>Peritoneum - drug effects</topic><topic>Peritoneum - metabolism</topic><topic>Pyrroles - pharmacology</topic><topic>Pyrroles - therapeutic use</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Rats, Wistar</topic><topic>RNA, Messenger - biosynthesis</topic><topic>Transforming Growth Factor beta1 - genetics</topic><topic>Transforming Growth Factor beta1 - metabolism</topic><topic>Vascular Endothelial Growth Factor A - genetics</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Serie, Kazuo</creatorcontrib><creatorcontrib>Fukuda, Noboru</creatorcontrib><creatorcontrib>Nakai, Shigeki</creatorcontrib><creatorcontrib>Matsuda, Hiroyuki</creatorcontrib><creatorcontrib>Maruyama, Takashi</creatorcontrib><creatorcontrib>Murayama, Yoshinobu</creatorcontrib><creatorcontrib>Omata, Sadao</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Peritoneal dialysis international</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Serie, Kazuo</au><au>Fukuda, Noboru</au><au>Nakai, Shigeki</au><au>Matsuda, Hiroyuki</au><au>Maruyama, Takashi</au><au>Murayama, Yoshinobu</au><au>Omata, Sadao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pyrrole-Imidazole Polyamide Targeting Transforming Growth Factor β1 Ameliorates Encapsulating Peritoneal Sclerosis</atitle><jtitle>Peritoneal dialysis international</jtitle><addtitle>Perit Dial Int</addtitle><date>2012-07</date><risdate>2012</risdate><volume>32</volume><issue>4</issue><spage>462</spage><epage>472</epage><pages>462-472</pages><issn>0896-8608</issn><eissn>1718-4304</eissn><abstract>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.
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.
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.
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.</abstract><cop>United States</cop><pub>Multimed Inc</pub><pmid>22215658</pmid><doi>10.3747/pdi.2011.00092</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Peritoneal dialysis international, 2012-07, Vol.32 (4), p.462-472 |
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| source | SAGE Complete A-Z List; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Animals Cells, Cultured Electrophoretic Mobility Shift Assay Extracellular Matrix Gene Silencing Imidazoles - pharmacology Imidazoles - therapeutic use Male Nylons - pharmacology Original Peritoneal Dialysis - adverse effects Peritoneal Fibrosis - genetics Peritoneal Fibrosis - metabolism Peritoneum - drug effects Peritoneum - metabolism Pyrroles - pharmacology Pyrroles - therapeutic use Rats Rats, Sprague-Dawley Rats, Wistar RNA, Messenger - biosynthesis Transforming Growth Factor beta1 - genetics Transforming Growth Factor beta1 - metabolism Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor A - metabolism |
| title | Pyrrole-Imidazole Polyamide Targeting Transforming Growth Factor β1 Ameliorates Encapsulating Peritoneal Sclerosis |
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