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Kidney Week

Abstract: FR-PO390

Tolvaptan and Bardoxolone Methyl Synergistically Activate the Nrf2/HO-1 Pathway

Session Information

  • CKD: Mechanisms - II
    November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Fujiki, Tamami, Tokyo Medical and Dental University, Tokyo, Tokyo, Japan
  • Ando, Fumiaki, Tokyo Medical and Dental University, Tokyo, Tokyo, Japan
  • Mandai, Shintaro, Tokyo Medical and Dental University, Tokyo, Tokyo, Japan
  • Isobe, Kiyoshi, Tokyo Medical and Dental University, Tokyo, Tokyo, Japan
  • Mori, Takayasu, Tokyo Medical and Dental University, Tokyo, Tokyo, Japan
  • Susa, Koichiro, Tokyo Medical and Dental University, Tokyo, Tokyo, Japan
  • Nomura, Naohiro, Tokyo Medical and Dental University, Tokyo, Tokyo, Japan
  • Sohara, Eisei, Tokyo Medical and Dental University, Tokyo, Tokyo, Japan
  • Rai, Tatemitsu, Tokyo Medical and Dental University, Tokyo, Tokyo, Japan
  • Uchida, Shinichi, Tokyo Medical and Dental University, Tokyo, Tokyo, Japan
Background

Tolvaptan, a vasopressin type2 receptor antagonist, has been approved for the treatment of autosomal dominant polycystic kidney disease. Furthermore, tolvaptan has been shown to improve the renal function in rodent models of chronic kidney disease (CKD); however, the underlying molecular mechanisms remain unknown. CKD is characterized by increased levels of oxidative stress, and an antioxidant transcription factor-nuclear factor erythroid 2-related factor 2 (Nrf2)-has been gaining attention as a therapeutic target. Therefore, we investigated the effects of tolvaptan and a well-known Nrf2 activator, bardoxolone methyl (BARD) on Nrf2.

Methods

We investigated the effect of tolvaptan and bardoxolone methyl on Nrf2 using mouse cortical collecting duct (mpkCCD) cells and mice kidneys.

Results

Tolvaptan led to Nrf2 nuclear translocation and induced mRNA and protein expression of heme oxygenase 1 (HO-1) in mpkCCD cells and the outer medulla of mice kidneys. Phosphorylation of unfolded protein kinase RNA-like endoplasmic reticulum kinase (PERK) by tolvaptan played an important role in activation of Nrf2/HO-1 pathway. Moreover, tolvaptan and BARD synergistically activatied Nrf2/HO-1 antioxidant pathway in mpkCCD cells.

Conclusion

We found the novel pharmacological property of tolvaptan that activated the PERK/Nrf2/HO-1 signaling pathway. Nrf2-regulated antioxidant systems were synergistically activated by tolvaptan and BARD. Tolvaptan is a potential therapeutic candidate in renal disease.

Funding

  • Government Support - Non-U.S.