Preclinical Study of DNA-Recognized Peptide Compound Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Progressive Renal Diseases in the Common Marmoset
Pyrrole-imidazole (PI) polyamides are novel gene silencers that strongly bind the promoter region of target genes in a sequence-specific manner to inhibit gene transcription. We created a PI polyamide targeting human TGF-β1 (hTGF-β1). To develop this PI polyamide targeting hTGF-&am...
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MDPI AG
2019-09-01
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| Online Access: | https://www.mdpi.com/1420-3049/24/17/3178 |
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| author | Masari Otsuki Noboru Fukuda Takashi Inoue Takayuki Mineshige Tomoyasu Otsuki Shu Horikoshi Morito Endo Masanori Abe |
| author_facet | Masari Otsuki Noboru Fukuda Takashi Inoue Takayuki Mineshige Tomoyasu Otsuki Shu Horikoshi Morito Endo Masanori Abe |
| author_sort | Masari Otsuki |
| collection | DOAJ |
| description | Pyrrole-imidazole (PI) polyamides are novel gene silencers that strongly bind the promoter region of target genes in a sequence-specific manner to inhibit gene transcription. We created a PI polyamide targeting human TGF-β1 (hTGF-β1). To develop this PI polyamide targeting hTGF-β1 (Polyamide) as a practical medicine for treating progressive renal diseases, we examined the effects of Polyamide in two common marmoset models of nephropathy. We performed lead optimization of PI polyamides that targeted hTGF-β1 by inhibiting in a dose-dependent manner the expression of TGF-β1 mRNA stimulated by PMA in marmoset fibroblasts. Marmosets were housed and fed with a 0.05% NaCl and magnesium diet and treated with cyclosporine A (CsA; 37.5 mg/kg/day, eight weeks) to establish chronic nephropathy. We treated the marmosets with nephropathy with Polyamide (1 mg/kg/week, four weeks). We also established a unilateral urethral obstruction (UUO) model to examine the effects of Polyamide (1 mg/kg/week, four times) in marmosets. Histologically, the renal medulla from CsA-treated marmosets showed cast formation and interstitial fibrosis in the renal medulla. Immunohistochemistry showed strong staining of Polyamide in the renal medulla from CsA-treated marmosets. Polyamide treatment (1 mg/kg/week, four times) reduced hTGF-β1 staining and urinary protein excretion in CsA-treated marmosets. In UUO kidneys from marmosets, Polyamide reduced the glomerular injury score and tubulointerstitial injury score. Polyamide significantly suppressed hTGF-β1 and snail mRNA expression in UUO kidneys from the marmosets. Polyamide effectively improved CsA- and UUO-associated nephropathy, indicating its potential application in the prevention of renal fibrosis in progressive renal diseases. |
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| last_indexed | 2024-04-13T07:18:51Z |
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| spelling | doaj.art-52bb5f1ac1b6447b803ea87f54d620cb2022-12-22T02:56:40ZengMDPI AGMolecules1420-30492019-09-012417317810.3390/molecules24173178molecules24173178Preclinical Study of DNA-Recognized Peptide Compound Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Progressive Renal Diseases in the Common MarmosetMasari Otsuki0Noboru Fukuda1Takashi Inoue2Takayuki Mineshige3Tomoyasu Otsuki4Shu Horikoshi5Morito Endo6Masanori Abe7Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo 173-8610, JapanDivision of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo 173-8610, JapanMarmoset Research Department, Central Institute for Experimental Animals, Kanagawa 210-0821, JapanMarmoset Research Department, Central Institute for Experimental Animals, Kanagawa 210-0821, JapanDivision of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo 173-8610, JapanDivision of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo 173-8610, JapanFaculty of Human Health Science, Hachinohe Gakuin University, Hachinohe, Aomori 031-8588, JapanDivision of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo 173-8610, JapanPyrrole-imidazole (PI) polyamides are novel gene silencers that strongly bind the promoter region of target genes in a sequence-specific manner to inhibit gene transcription. We created a PI polyamide targeting human TGF-β1 (hTGF-β1). To develop this PI polyamide targeting hTGF-β1 (Polyamide) as a practical medicine for treating progressive renal diseases, we examined the effects of Polyamide in two common marmoset models of nephropathy. We performed lead optimization of PI polyamides that targeted hTGF-β1 by inhibiting in a dose-dependent manner the expression of TGF-β1 mRNA stimulated by PMA in marmoset fibroblasts. Marmosets were housed and fed with a 0.05% NaCl and magnesium diet and treated with cyclosporine A (CsA; 37.5 mg/kg/day, eight weeks) to establish chronic nephropathy. We treated the marmosets with nephropathy with Polyamide (1 mg/kg/week, four weeks). We also established a unilateral urethral obstruction (UUO) model to examine the effects of Polyamide (1 mg/kg/week, four times) in marmosets. Histologically, the renal medulla from CsA-treated marmosets showed cast formation and interstitial fibrosis in the renal medulla. Immunohistochemistry showed strong staining of Polyamide in the renal medulla from CsA-treated marmosets. Polyamide treatment (1 mg/kg/week, four times) reduced hTGF-β1 staining and urinary protein excretion in CsA-treated marmosets. In UUO kidneys from marmosets, Polyamide reduced the glomerular injury score and tubulointerstitial injury score. Polyamide significantly suppressed hTGF-β1 and snail mRNA expression in UUO kidneys from the marmosets. Polyamide effectively improved CsA- and UUO-associated nephropathy, indicating its potential application in the prevention of renal fibrosis in progressive renal diseases.https://www.mdpi.com/1420-3049/24/17/3178humanTGF-β1pyrrole-imidazole polyamiderenal diseasemarmoset |
| spellingShingle | Masari Otsuki Noboru Fukuda Takashi Inoue Takayuki Mineshige Tomoyasu Otsuki Shu Horikoshi Morito Endo Masanori Abe Preclinical Study of DNA-Recognized Peptide Compound Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Progressive Renal Diseases in the Common Marmoset Molecules human TGF-β1 pyrrole-imidazole polyamide renal disease marmoset |
| title | Preclinical Study of DNA-Recognized Peptide Compound Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Progressive Renal Diseases in the Common Marmoset |
| title_full | Preclinical Study of DNA-Recognized Peptide Compound Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Progressive Renal Diseases in the Common Marmoset |
| title_fullStr | Preclinical Study of DNA-Recognized Peptide Compound Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Progressive Renal Diseases in the Common Marmoset |
| title_full_unstemmed | Preclinical Study of DNA-Recognized Peptide Compound Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Progressive Renal Diseases in the Common Marmoset |
| title_short | Preclinical Study of DNA-Recognized Peptide Compound Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Progressive Renal Diseases in the Common Marmoset |
| title_sort | preclinical study of dna recognized peptide compound pyrrole imidazole polyamide targeting human tgf β1 promoter for progressive renal diseases in the common marmoset |
| topic | human TGF-β1 pyrrole-imidazole polyamide renal disease marmoset |
| url | https://www.mdpi.com/1420-3049/24/17/3178 |
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