MO578: UBE-1099, A Novel Non-Covalent Keap1-NRF2 Inhibitor, Protects Against Renal Ischemia-Reperfusion Injury

Abstract BACKGROUND AND AIMS Bardoxolone methyl is a covalent Kelch-like ECH-associated protein 1 (Keap1) inhibitor that induces nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Bardoxolone methyl improved glomerular filtration rate (GFR) in clinical trials for chronic kidney disease (CKD), although the mechanism remains unclear. Bardoxolone imidazole, an analog of Bardoxolone methyl suppressed tubular damage in a mouse acute kidney injury (AKI)-to-CKD model of unilateral ischemic reperfusion without contralateral nephrectomy (U-IR). Here, we evaluated the renal protective effect and the mechanism of a novel non-covalent Keap1 inhibitor, UBE-1099 in the U-IR mice. METHOD A fluorescence polarization-based (FP) assay and NQO1 activity-induction assay were performed to evaluate an inhibitory activity of Keap1 inhibitors. An U-IR mice were orally administered either the inhibitor (30 mg/kg, 10 mL/kg, once a day) or vehicle for 14 days and efficacy was evaluated. The whole transcriptome analysis with RNA-seq was conducted with whole kidney of the U-IR mice after 14 days treatment. A pathway analysis of the significantly differentially expressed genes detected was performed using Ingenuity Pathway Analysis (IPA) software. RESULTS UBE-1099 directly inhibited the interaction of Nrf2-Keap1 and induced NQO1 activity. The oral administration of UBE-1099 to the U-IR mice upregulated NQO1 expression in the kidney. UBE-1099 inhibited the decline in GFR and renal weight and significantly improved tubular damage and atrophic lesions in the U-IR model as effective as CDDO-Im without body weight loss. In addition, UBE-1099 significantly decreased the number of macrophages in the kidney. CONCLUSION A novel non-covalent Keap1 inhibitor, UBE-1099 improved the atrophic pathology, reduced tubular damage and inflammation resulting from Nrf2 activation in the U-IR mice. The compound has been suggested to be a promising drug for the renal diseases. Currently, the mechanism of action in improving renal function is being analyzed through RNA-seq analysis. Figure: