A Pyrrole-Imidazole Polyamide Targeting Human USF1 Binding Suppresses High Glucose-Induced TGF-β1 and Osteopontin Expression in Human Renal Mesangial Cells.
- 1Division of Nephrology, Hypertension, and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, 30-1 Oyaguchi Kami-chou, Itabashi-ku, Tokyo 173-8610, Japan.
- 2Division of Nephrology and Endocrinology, Ukima Chuo Hospital, Tokyo 115-0052, Japan.
Abstract
Transforming growth factor-β1 (TGF-β1) is a key profibrotic mediator in diabetic kidney disease. Upstream stimulatory factor 1 (USF1) enhances TGF-β1 transcription through an E-box/glucose-response element in the TGF-β1 promoter under high-glucose conditions. We designed a sequence-specific pyrrole-imidazole (PI) polyamide targeting the human USF1-binding site in the TGF-β1 promoter and evaluated its activity in human renal mesangial cells (HRMCs). A target PI polyamide and a mismatch PI polyamide were synthesized. DNA binding and inhibition of the USF1-DNA interaction were assessed by gel mobility shift assays. HRMCs were exposed to high glucose with or without PI polyamides, and TGF-β1 and osteopontin expression were quantified by real-time PCR and Western blotting. The target PI polyamide bound the intended promoter sequence and reduced recombinant USF1 binding in vitro. In high-glucose-exposed HRMCs, the target PI polyamide suppressed TGF-β1 mRNA and protein expression, whereas the mismatch PI polyamide did not suppress TGF-β1 expression. The target PI polyamide also reduced osteopontin mRNA expression. These findings provide proof-of-concept that PI polyamide-mediated targeting of the human USF1-TGF-β1 axis can attenuate high-glucose-associated profibrotic responses in HRMCs.
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BibTeX
@article{akiya2026pyrroleimidazole,
title = {{A Pyrrole-Imidazole Polyamide Targeting Human USF1 Binding Suppresses High Glucose-Induced TGF-β1 and Osteopontin Expression in Human Renal Mesangial Cells.}},
author = {Yurie Akiya and Hiroki Kobayashi and Akiko Tsunemi and Noboru Fukuda and Masanori Abe},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15191818},
url = {https://europepmc.org/article/MED/42882515},
note = {CC BY},
}
RIS
TY - JOUR
TI - A Pyrrole-Imidazole Polyamide Targeting Human USF1 Binding Suppresses High Glucose-Induced TGF-β1 and Osteopontin Expression in Human Renal Mesangial Cells.
AU - Yurie Akiya
AU - Hiroki Kobayashi
AU - Akiko Tsunemi
AU - Noboru Fukuda
AU - Masanori Abe
PY - 2026
DA - 2026/10/06
JO - Cells
DO - 10.3390/cells15191818
UR - https://europepmc.org/article/MED/42882515
AB - Transforming growth factor-β1 (TGF-β1) is a key profibrotic mediator in diabetic kidney disease. Upstream stimulatory factor 1 (USF1) enhances TGF-β1 transcription through an E-box/glucose-response element in the TGF-β1 promoter under high-glucose conditions. We designed a sequence-specific pyrrole-imidazole (PI) polyamide targeting the human USF1-binding site in the TGF-β1 promoter and evaluated its activity in human renal mesangial cells (HRMCs). A target PI polyamide and a mismatch PI polyamide were synthesized. DNA binding and inhibition of the USF1-DNA interaction were assessed by gel mobility shift assays. HRMCs were exposed to high glucose with or without PI polyamides, and TGF-β1 and osteopontin expression were quantified by real-time PCR and Western blotting. The target PI polyamide bound the intended promoter sequence and reduced recombinant USF1 binding in vitro. In high-glucose-exposed HRMCs, the target PI polyamide suppressed TGF-β1 mRNA and protein expression, whereas the mismatch PI polyamide did not suppress TGF-β1 expression. The target PI polyamide also reduced osteopontin mRNA expression. These findings provide proof-of-concept that PI polyamide-mediated targeting of the human USF1-TGF-β1 axis can attenuate high-glucose-associated profibrotic responses in HRMCs.
SN - 2073-4409
ER -