Open AccessNovel Keap1-Nrf2 Protein-Protein Interaction Inhibitor UBE-1099 Ameliorates Progressive Phenotype in Alport Syndrome Mouse Model
Author(s) -
Shota Kaseda,
Yuya Sannomiya,
Jun Horizono,
Jun Kuwazuru,
Mary Ann Suico,
Sayaka Ogi,
Ryoko Sasaki,
Hidetoshi Sunamoto,
Hirohiko Fukiya,
Hayato Nishiyama,
Misato Kamura,
Saki Niinou,
Yuimi Koyama,
Futoshi Nara,
Tsuyoshi Shuto,
Kazuhiro Onuma,
Hirofumi Kai
Publication year - 2022
Publication title -
kidney360
Language(s) - English
Resource type - Journals
ISSN - 2641-7650
DOI - 10.34067/kid.0004572021
Subject(s) - glomerulosclerosis , alport syndrome , keap1 , focal segmental glomerulosclerosis , endocrinology , glomerulonephritis , medicine , biology , kidney , proteinuria , biochemistry , gene , transcription factor
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.