Journal
KIDNEY360
Volume 3, Issue 4, Pages 687-699Publisher
AMER SOC NEPHROLOGY
DOI: 10.34067/KID.0004572021
Keywords
CKD; Alport syndrome; bardoxolone methyl; GA-binding protein transcription factor; Keap1-Nrf2 protein-protein interaction inhibitor; Kelch-like ECH-associated protein 1; mice; nephritis; hereditary; NF-E2-related factor 2; phenotype; proteinuria
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Funding
- Japan Society for the Promotion of Science (JSPS) KAKENHI [JP26460098, JP17K08309, JP19H03379]
- Alport Syndrome Research Funding Program of the Alport Syndrome Foundation
- Pedersen family, Kidney Foundation of Canada
- Japan Agency for Medical Research and Development (AMED [JP21ek0310017]
- [JP19J23608]
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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.
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.
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