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

Abstract

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.

• Authors: 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
• Journal: Kidney360 (Kidney360) Vol. 3 Issue 4 Pg. 687-699 (04 28 2022) ISSN: 2641-7650 [Electronic] United States
• PMID: 35721612 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 by the American Society of Nephrology.

Chemical References

• Keap1 protein, mouse
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Oleanolic Acid
• bardoxolone

Topics

• Animals
• Disease Models, Animal
• Kelch-Like ECH-Associated Protein 1 (antagonists & inhibitors, genetics, metabolism)
• Mice
• NF-E2-Related Factor 2 (agonists, antagonists & inhibitors, metabolism)
• Nephritis, Hereditary (drug therapy, metabolism)
• Oleanolic Acid (analogs & derivatives, pharmacology)
• Phenotype
• Renal Insufficiency, Chronic