Efficacy of Keap1-Nrf2 protein-protein interaction inhibitor for glomerulosclerosis in mouse model of chronic kidney disease

Abstract

Bardoxolone methyl is an electrophilic agent that induces Nrf2 activation by irreversibly and covalently binding to the cysteine residue of Keap1. Ongoing clinical trials of Bardoxolone methyl show promising effects for patients with chronic kidney disease (CKD). However, irreversible Keap1 inhibitors such as Bardoxolone methyl may covalently bind to other proteins in a non-specific manner and induce side effects due to off-target activities. In this study, we developed a reversible Keap1 inhibitor UBE-1099, which highly selectively and non-covalently inhibits Keap1-Nrf2 protein-protein interaction (PPI) and induces Nrf2 activation. We evaluated its efficacy on glomerulosclerosis in mouse model of CKD (Alport syndrome: Col4a5-G5X). Similar to Bardoxolone methyl, UBE-1099 transiently increased proteinuria and reduced plasma creatinine in CKD model mice. Importantly, UBE-1099 improved the glomerulosclerosis, renal inflammation and fibrosis, and prolonged the lifespan of CKD model mice. Moreover, transcriptome analysis in glomerulus showed that UBE-1099 induced the expression of genes associated with cell cycle and cytoskeleton, which may explain its unique mechanism of improvement such as glomerular morphological change. Thus, our results firstly revealed the efficacy of Keap1-Nrf2 PPI inhibitor for glomerulosclerosis and CKD.