Development of Pyrrole–Imidazole Polyamide Targeting Fc Receptor Common Gamma Chain for the Treatment of Immune-Complex Related Renal Disease

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概要

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• 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.

著者

• Ueno Takahiro

  Division Of Nephrology Hypertension And Endocrinology Department Of Medicine Nihon University School

• Fukuda Noboru

  Advanced Research Institute Of Science And Humanities Nihon University

• Fukuda Noboru

  Advanced Res. Inst. For The Sci. And Humanities Nihon Univ.

• Fujita Takayuki

  Division of Nephrology and Endocrinology, Department of Medicine, Nihon University School of Medicin

• Tsunemi Akiko

  Division Of Nephrology And Endocrinology Department Of Medicine Nihon University School Of Medicine

• Fukuda Noboru

  Division Of Nephrology And Endocrinology Department Of Medicine Nihon University School Of Medicine

• Matsumoto Koichi

  Division Of Nephrology And Endocrinology Department Of Medicine Nihon University School Of Medicine

• Ra Chisei

  Division Of Molecular Biology Allergy Research Center Juntendo University School Of Medicine

• Matsumoto Yoshiaki

  Department Of Clinical Pharmacokinetics College Of Pharmacy Nihon University

• Soma Masayoshi

  Division Of General Medicine Department Of Internal Medicine Nihon University School Of Medicine

• Fuke Yoshinobu

  Division Of Nephrology Hypertension And Endocrinology Department Of Internal Medicine Nihon Universi

• Kajiwara Mamiko

  Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine

• Matsuda Hiroyuki

  Division of General Medicine, Department of Medicine, Nihon University School of Medicine

• Shimokawa Toshibumi

  Division of Molecular Cell Immunology and Allergology, Department of Biomedical Sciences, Nihon University School of Medicine

• Kitai Maki

  Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine

• Kajiwara Mamiko

  Division Of Nephrology Hypertension And Endocrinology Department Of Medicine Nihon University School Of Medicine

• Soma Masayoshi

  Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, School of Medicine, Nihon University

• Ra Chisei

  Division of Molecular Cell Immunology and Allergology, Department of Biomedical Sciences, School of Medicine, Nihon University

• Fukuda Noboru

  Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, School of Medicine, Nihon University

• Fuke Yoshinobu

  Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, School of Medicine, Nihon University

• Tsunemi Akiko

  Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, School of Medicine, Nihon University

• Shimokawa Toshibumi

  Division of Molecular Cell Immunology and Allergology, Department of Biomedical Sciences, School of Medicine, Nihon University

• Kitai Maki

  Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, School of Medicine, Nihon University

• Matsumoto Koichi

  Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, School of Medicine, Nihon University

• Fujita Takayuki

  Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, School of Medicine, Nihon University

• Fukuda Noboru

  Division of Life Science, Advanced Research Institute of the Sciences and Humanities, Nihon University Graduate School

• Ueno Takahiro

  Division of Nephrology and Endocrinology, Department of Medicine, Nihon University School of Medicine

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