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Kidney Week

Abstract: PO2508

UBE-1099, a Novel Non-Covalent Keap1-Nrf2 Inhibitor, Protects Against Renal Ischemia-Reperfusion Injury via Nrf2 Activation

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Ogi, Sayaka, Pharmaceuticals Research Laboratory,UBE industries,LTD., Ube, Yamaguchi, Japan
  • Sunamoto, Hidetoshi, Pharmaceuticals Research Laboratory,UBE industries,LTD., Ube, Yamaguchi, Japan
  • Fukiya, Hirohiko, Pharmaceuticals Research Laboratory,UBE industries,LTD., Ube, Yamaguchi, Japan
  • Nara, Futoshi, Pharmaceuticals Research Laboratory,UBE industries,LTD., Ube, Yamaguchi, Japan
  • Onuma, Kazuhiro, Pharmaceuticals Research Laboratory,UBE industries,LTD., Ube, Yamaguchi, Japan
Background

Patients with chronic kidney disease (CKD) showed a decline in renal function, as represented by glomerular filtration rate (GFR), as the disease progresses. A covalent Kelch-like ECH-associated protein 1 (Keap1) - Nuclear factor erythroid 2-related factor (Nrf2) inhibitor, bardoxolone methyl, has been reported to increase the estimated GFR in patients with advanced CKD. However, it is unclear how the Nrf2 activator improved GFR. Previous studies have shown that bardoxolone imidazole suppresses tubular damage in a mouse model of unilateral ischemic reperfusion without contralateral nephrectomy (U-IR). In this study, we evaluated in detail the effect of a novel non-covalent Keap1-Nrf2 inhibitor UBE-1099 on U-IR model.

Methods

A fluorescence polarization-based (FP) assay and NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme activity-inducting assay on murine Hepa1c1c7 hepatoma cell were used to investigate a non-covalent Keap1-Nrf2 inhibitor. U-IR model was established using 10 week old male C57BL/6 mice. These mice were orally administered either the inhibitor (30 mg/kg, 10 mL/kg, once a day) or vehicle for 14 days. Renal damage was then evaluated by histopathological analysis and measurement of GFR using a percutaneous GFR measurement system (MediBeacon, St. Louis, Missouri). Protein and mRNA expression in the whole kidney were assessed by Western blot analysis and real-time PCR, respectively.

Results

UBE-1099 directly inhibited Keap1-Nrf2 interaction as assessed by the FP assay, and induced NQO1 enzyme activity at Hepa1c1c7. UBE-1099 showed Nqo1 mRNA induction activity as well as bardoxolone imidazole in the kidney of a normal mice by single oral administration. Oral administration of UBE-1099 to U-IR model mice increased NQO1 protein and mRNA expression in the kidney and improved the atrophic pathology, including renal tubular damage. More surprisingly, UBE-1099 also showed an increasing trend in GFR in that model.

Conclusion

A novel non-covalent Keap1-Nrf2 inhibitor UBE-1099 improved the atrophic pathology and reduced tubular damage resulting from Nrf2 activation in U-IR model mice. UBE-1099 has been suggested to be a promising drug for renal diseases associated with oxidative stress.