Preprint Article Version 1 This version is not peer-reviewed

Preclinical Study of DNA-Recognized Peptide Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Progressive Renal Diseases in Common Marmoset

Version 1 : Received: 3 August 2019 / Approved: 7 August 2019 / Online: 7 August 2019 (09:42:06 CEST)

How to cite: Otsuki, M..; Fukuda, N.; Inoue, T..; Mineshige, T..; Otsuki, T..; Horikoshi , S..; Endo, M..; Abe, M.. Preclinical Study of DNA-Recognized Peptide Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Progressive Renal Diseases in Common Marmoset. Preprints 2019, 2019080090 (doi: 10.20944/preprints201908.0090.v1). Otsuki, M..; Fukuda, N.; Inoue, T..; Mineshige, T..; Otsuki, T..; Horikoshi , S..; Endo, M..; Abe, M.. Preclinical Study of DNA-Recognized Peptide Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Progressive Renal Diseases in Common Marmoset. Preprints 2019, 2019080090 (doi: 10.20944/preprints201908.0090.v1).

Abstract

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 developed a PI polyamide targeting human TGF-b1 (hTGF-b1). To develop PI polyamide targeting hTGF-b1 (Polyamide) as a practical medicine for progressive renal diseases, we examined the effects of Polyamide in two common marmoset models of nephropathy.We performed lead optimization of PI polyamides targeting hTGF-b1 by the dose-dependent inhibition of the PMA-stimulated expression of TGF-b1 mRNA in marmoset fibroblasts. Marmosets were housed with a 0.05% NaCl and magnesium diet and treated with cyclosporine A (CsA; 37.5 mg/kg/day, 8 weeks) to establish chronic nephropathy. Marmosets with nephropathy were treated with Polyamide (1 mg/kg/week, 4 weeks). We also established a unilateral urethral obstruction(UUO) model and examined the effects of Polyamide (1 mg/kg/week, 4 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.Polyamidetreatment (1 mg/kg/week, 4 times) reduced hTGF-b1 staining and urinary protein excretion in CsA-treated marmosets. Polyamide reduced the glomerular injury score (GIS) and tubulointerstitial injury score (TIS) in UUO kidneys from marmosets. Polyamide significantly suppressed the hTGF-b1 and Snail mRNA expressionin UUO kidneys from marmosets.PI polyamide effectively improved CsA- and UUO-associated nephropathy, indicating its potential application in the prevention of renal fibrosis in progressive renal diseases.

Subject Areas

human; TGF-β1; pyrrole-imidazole polyamide; renal disease; marmoset

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