Kidney Week

Abstract: SA-PO640

Kidney Protection by a Novel Keap1-Nrf2 Protein-Protein Interaction Inhibitor for a Mouse Model of Alport Syndrome

Session Information

• Genetic Kidney Diseases: Models, Mechanisms, and Therapies
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Horizono, Jun, Department of Molecular Medicine, Graduate School of Pharmaceutical Science, Kumamoto University, Kumamoto, Kumamoto, Japan

Jun Horizono, MSc

• Kaseda, Shota, Department of Molecular Medicine, Graduate School of Pharmaceutical Science, Kumamoto University, Kumamoto, Japan

Shota Kaseda

• Sannomiya, Yuya, Department of Molecular Medicine, Graduate School of Pharmaceutical Science, Kumamoto University, Kumamoto, Kumamoto, Japan

Yuya Sannomiya, MD

• Suico, Mary Ann, Department of Molecular Medicine, Graduate School of Pharmaceutical Science, Kumamoto University, Kumamoto, Kumamoto, Japan

Mary Ann Suico, PhD

• Fukiya, Hirohiko, Pharmaceuticals Research Laboratory, UBE Corporation, Yamaguchi, Japan

Hirohiko Fukiya, MS

• Sunamoto, Hidetoshi, Pharmaceuticals Research Laboratory, UBE Corporation, Yamaguchi, Japan

Hidetoshi Sunamoto, MS

• Watanabe, Hiroshi, Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Kumaoto, Japan

Hiroshi Watanabe, PhD

• Nakano, Takehiro, Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Kumaoto, Japan

Takehiro Nakano, PharmD

• Tokumaru, Kai, Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Kumaoto, Japan

Kai Tokumaru

• Davenport, John Bernard, Wellcome Centre for Cell-Matrix Research, University of Manchester, Manchester, United Kingdom

John Bernard Davenport, PhD

• Shuto, Tsuyoshi, Department of Molecular Medicine, Graduate School of Pharmaceutical Science, Kumamoto University, Kumamoto, Kumamoto, Japan

Tsuyoshi Shuto, PhD

• Lennon, Rachel, Wellcome Centre for Cell-Matrix Research, University of Manchester, Manchester, United Kingdom

Rachel Lennon, MBBS, PhD

• Onuma, Kazuhiro, Pharmaceuticals Research Laboratory, UBE Corporation, Yamaguchi, Japan

Kazuhiro Onuma, MS

• Kai, Hirofumi, Department of Molecular Medicine, Graduate School of Pharmaceutical Science, Kumamoto University, Kumamoto, Kumamoto, Japan

Hirofumi Kai, PharmD, PhD

Background

Keap1-Nrf2 pathway plays an important role in the defense mechanism against oxidative stress in the kidney. We have shown that UBE-1099, a Keap1-Nrf2 protein-protein interaction (PPI) inhibitor, exerts renoprotective effects in Alport syndrome (AS) mice (Kidney 360, 2022). Furthermore, we found a more promising Keap1-Nrf2 PPI inhibitor UD-051 having a high Nrf2 activation potency at lower concentrations. In the present study, we aim to elucidate the effects of UD-051 on AS pathophysiology.

Methods

We studied the effects of UD-051 using AS (Col4a5-G5X) and Nrf2 KO-AS mice. In addition, we evaluated the survival of AS mice treated with UD-051 in combination with losartan, an angiotensin II receptor blocker (ARB).

Results

UD-051 improved the glomerular and tubular damage, renal inflammation, and fibrosis in AS mice. UD-051 transiently increased proteinuria in AS mice. The renoprotective effect of UD-051 and the transient increase in proteinuria were abolished in Nrf2 KO-AS mice. Interestingly, UD-051 suppressed the albumin accumulation in the proximal tubules of AS mice, and decreased the expression of albumin reabsorption transporter megalin. These results suggest that UD-051 inhibits excessive albumin reabsorption in the tubules of AS mice and exerts a tubular protective effect. Moreover, UD-051 decreased oxidized albumin ratio (OAR), the clinical biomarker for the progression of kidney disease in the plasma of AS mice. Importantly, OAR highly inverse correlated with the expression level of Nqo1 which is the Nrf2 target gene in vehicle- and UD-051-treated AS mice kidney tissue, suggesting that OAR is a highly sensitive biomarker that reflects Nrf2 activity in kidney tissue. Notably, survival studies showed that UD-051 (3 mg/kg, p.o.) increased the median survival of AS mice by 22 %, losartan alone by 8.4%, and the combination of UD-051 (3 mg/kg, p.o.) and losartan extended the median survival by 65% more than the vehicle-treated AS mice.

Conclusion

The present study demonstrated a renoprotective effect of UD-051. The results also suggest that the combination treatment with UD-051 and ARBs may be useful for AS and other chronic kidney diseases.

Funding

• Commercial Support – UBE Corporation, Japan