Novel Keap1-Nrf2 Protein-Protein Interaction Inhibitor UBE-1099 Ameliorates Progressive Phenotype in Alport Syndrome Mouse Model.

Autor:	Kaseda S; Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.; Program for Leading Graduate School 'HIGO (Health Life Science: Interdisciplinary and Glocal Oriented) Program,' Kumamoto University, Kumamoto, Japan., Sannomiya Y; Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan., Horizono J; Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan., Kuwazuru J; Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan., Suico MA; Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.; Global Center for Natural Resources Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan., Ogi S; Pharmaceuticals Research Laboratory, UBE Industries Ltd., Yamaguchi, Japan., Sasaki R; Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan., Sunamoto H; Pharmaceuticals Research Laboratory, UBE Industries Ltd., Yamaguchi, Japan., Fukiya H; Pharmaceuticals Research Laboratory, UBE Industries Ltd., Yamaguchi, Japan., Nishiyama H; Pharmaceuticals Research Laboratory, UBE Industries Ltd., Yamaguchi, Japan., Kamura M; Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.; Program for Leading Graduate School 'HIGO (Health Life Science: Interdisciplinary and Glocal Oriented) Program,' Kumamoto University, Kumamoto, Japan., Niinou S; Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan., Koyama Y; Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan., Nara F; Pharmaceuticals Research Laboratory, UBE Industries Ltd., Yamaguchi, Japan., Shuto T; Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.; Global Center for Natural Resources Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan., Onuma K; Pharmaceuticals Research Laboratory, UBE Industries Ltd., Yamaguchi, Japan., Kai H; Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.; Program for Leading Graduate School 'HIGO (Health Life Science: Interdisciplinary and Glocal Oriented) Program,' Kumamoto University, Kumamoto, Japan.; Global Center for Natural Resources Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Jazyk:	angličtina
Zdroj:	Kidney360 [Kidney360] 2021 Dec 01; Vol. 3 (4), pp. 687-699. Date of Electronic Publication: 2021 Dec 01 (Print Publication: 2022).
DOI:	10.34067/KID.0004572021
Abstrakt:	Background: Bardoxolone methyl activates nuclear factor erythroid 2-related factor 2 (Nrf2) via covalent binding and irreversible inhibition of Kelch-like ECH-associated protein 1 (Keap1), the negative regulator of Nrf2. Ongoing clinical trials of bardoxolone methyl show promising effects for patients with CKD. However, the direct inhibition of Keap1-Nrf2 protein-protein interaction (PPI) as an approach to activate Nrf2 is less explored. Methods: We developed a noncovalent Nrf2 activator UBE-1099, which highly selectively inhibits Keap1-Nrf2 PPI, and evaluated its efficacy on the progressive phenotype in an Alport syndrome mouse model ( Col4a5 -G5X). Results: Similar to bardoxolone methyl, UBE-1099 transiently increased proteinuria and reduced plasma creatinine in Alport mice. Importantly, UBE-1099 improved the glomerulosclerosis, renal inflammation, and fibrosis, and prolonged the life span of Alport mice. UBE-1099 ameliorated the dysfunction of Nrf2 signaling in the renal tissue of Alport mice. Moreover, transcriptome analysis in the glomerulus showed that UBE-1099 induced the expression of genes associated with the cell cycle and cytoskeleton, which may explain its unique mechanism of improvement such as glomerular morphologic change. Conclusions: UBE-1099 significantly ameliorates the progressive phenotype in Alport mice. Our results revealed the efficacy of Keap1-Nrf2 PPI inhibitor for glomerulosclerosis and present a potential therapeutic drug for CKD. Competing Interests: H. Kai received research funding from Grants-in-Aid for Scientific Research from the Ministry of Education, Sciences, Sports, and Culture (MEXT) of Japan. S. Kaseda received research funding from the Japan Society for the Promotion of Science. T. Shuto reports received research funding from Grants-in-Aid for Scientific Research from the Ministry of Education, Sciences, Sports, and Culture (MEXT) of Japan. All remaining authors have nothing to disclose. (Copyright © 2022 by the American Society of Nephrology.)
Databáze:	MEDLINE
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