title: Development of pyrrole-imidazole polyamide targeting fc receptor common gamma chain for the treatment of immune-complex related renal disease.
abstract: Fcγ receptors I and III are thought to be involved in the development of lupus nephritis. Expression of Fc receptor common gamma chain (FcRγ) is necessary for the stable expression of Fcγ receptors I and III. The aim of this study was to develop a novel agent for the treatment of immune complex related renal disease using a gene regulator, pyrrole(Py)-imidazole(Im) (PI) polyamide, targeting the mouse FcRγ gene promoter. Two PI polyamides targeting FcRγ promoters were designed and synthesized. The effect of the PI polyamides on FcRγ mRNA expression was evaluated in J774.A cells by real-time polymerase chain reaction (PCR), and CD16/32 protein expression was determined by immunocytochemical analysis and flow cytometry. The effects of these polyamides on FcRγ gene expression and CD16/32 protein expression were evaluated in mouse peripheral blood mononuclear cells (PBMCs). One milligram per kilogram body weight of PI polyamide was injected via the tail vein every 2 d for 1 week and PBMCs were collected and analyzed. PI polyamide showed a specific binding to the target DNA in a gel mobility shift assay. Treatment of J774.A cells with 1.0 µM PI polyamide 1 significantly reduced FcRγ mRNA expression and CD16/32 surface protein expression in J774.A cells. Similarly, PI polyamide significantly decreased expression of FcRγ mRNA and CD16/32 in the PBMCs of C57B6 mice. PI polyamide designed to bind the FcRγ promoter decreased FcRγ gene and CD16/32 protein expression. PI polyamide targeting the FcRγ gene may be a novel gene regulator for the prevention of lupus nephritis or other immune complex-related disease.
authors.affiliation: Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, School of Medicine, Nihon University, 7–7–1 Narashinodai, Funabashi, Chiba 274–8555, Japan.
authors.forename: Mamiko
authors.initials: M
authors.lastname: Kajiwara
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ueno
authors.forename: Noboru
authors.initials: N
authors.lastname: Fukuda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Matsuda
authors.forename: Toshibumi
authors.initials: T
authors.lastname: Shimokawa
authors.forename: Maki
authors.initials: M
authors.lastname: Kitai
authors.forename: Akiko
authors.initials: A
authors.lastname: Tsunemi
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Fuke
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujita
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Chisei
authors.initials: C
authors.lastname: Ra
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Soma
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D007093:Imidazoles / Q000737:chemistry*; D007105:Immune Complex Diseases / Q000188:drug therapy; D007674:Kidney Diseases / Q000188:drug therapy; D007963:Leukocytes, Mononuclear; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009757:Nylons / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011758:Pyrroles / Q000737:chemistry*; D012333:RNA, Messenger / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics*
chemical_list: D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D012333:RNA, Messenger; D017452:Receptors, IgG; C029899:imidazole