{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:45:30Z","timestamp":1760240730581,"version":"build-2065373602"},"reference-count":32,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2019,9,1]],"date-time":"2019-09-01T00:00:00Z","timestamp":1567296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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-\u03b21 (hTGF-\u03b21). To develop this PI polyamide targeting hTGF-\u03b21 (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-\u03b21 by inhibiting in a dose-dependent manner the expression of TGF-\u03b21 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-\u03b21 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-\u03b21 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.<\/jats:p>","DOI":"10.3390\/molecules24173178","type":"journal-article","created":{"date-parts":[[2019,9,2]],"date-time":"2019-09-02T03:16:12Z","timestamp":1567394172000},"page":"3178","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Preclinical Study of DNA-Recognized Peptide Compound Pyrrole-Imidazole Polyamide Targeting Human TGF-\u03b21 Promoter for Progressive Renal Diseases in the Common Marmoset"],"prefix":"10.3390","volume":"24","author":[{"given":"Masari","family":"Otsuki","sequence":"first","affiliation":[{"name":"Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noboru","family":"Fukuda","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan"},{"name":"Research Center Nihon University, Tokyo 101-0061, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Inoue","sequence":"additional","affiliation":[{"name":"Marmoset Research Department, Central Institute for Experimental Animals, Kanagawa 210-0821, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9767-0507","authenticated-orcid":false,"given":"Takayuki","family":"Mineshige","sequence":"additional","affiliation":[{"name":"Marmoset Research Department, Central Institute for Experimental Animals, Kanagawa 210-0821, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoyasu","family":"Otsuki","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu","family":"Horikoshi","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morito","family":"Endo","sequence":"additional","affiliation":[{"name":"Faculty of Human Health Science, Hachinohe Gakuin University, Hachinohe, Aomori 031-8588, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masanori","family":"Abe","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/382559a0","article-title":"Recognition of DNA by designed ligands at subnanomolar concentrations","volume":"382","author":"Trauger","year":"1996","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/S1074-5521(97)90243-X","article-title":"On the pairing rules for recognition in the minor groove of DNA by pyrrole-imidazole polyamides","volume":"4","author":"White","year":"1997","journal-title":"Chem. 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