Kidney Week

Abstract: SA-PO847

Tolvaptan Activates Nrf2/HO-1 Pathway Through PERK Phosphorylation

Session Information

• Molecular Mechanisms of CKD - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 1903 CKD (Non-Dialysis): Mechanisms

Authors

• Fujiki, Tamami, Tokyo Medical and Dental University, Bunkyo-Ku, ToKyo, Japan

Tamami Fujiki,

• Ando, Fumiaki, Tokyo Medical and Dental University, Bunkyo-Ku, ToKyo, Japan

Fumiaki Ando,

• Isobe, Kiyoshi, Tokyo Medical and Dental University, Bunkyo-Ku, ToKyo, Japan

Kiyoshi Isobe,

• Mori, Takayasu, Tokyo Medical and Dental University, Bunkyo-Ku, ToKyo, Japan

Takayasu Mori,

• Susa, Koichiro, Tokyo Medical and Dental University, Bunkyo-Ku, ToKyo, Japan

Koichiro Susa,

• Nomura, Naohiro, Tokyo Medical and Dental University, Bunkyo-Ku, ToKyo, Japan

Naohiro Nomura,

• Sohara, Eisei, Tokyo Medical and Dental University, Bunkyo-Ku, ToKyo, Japan

Eisei Sohara,

• Rai, Tatemitsu, Tokyo Medical and Dental University, Bunkyo-Ku, ToKyo, Japan

Tatemitsu Rai,

• Uchida, Shinichi, Tokyo Medical and Dental University, Bunkyo-Ku, ToKyo, Japan

Shinichi Uchida,

Background

Tolvaptan slows the increase in total kidney volume (TKV) and the decline in kidney function in Autosomal Dominant Polycystic Kidney Disease (ADPKD). In addition, vasopressin type2 receptor (V2R) antagonists improve renal function in various rodent models of chronic kidney disease (CKD). However, the mechanism of tolvaptan improving renal function remains totally unclear. It has been reported that oxidative stress is associated with CKD progression, and the antioxidant transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), is attracting the attention as therapeutic target. In fact, Nrf2 activator, bardoxolone methyl, improves renal function in patients with CKD. In this study, we examined the effects of tolvaptan on Nrf2.

Methods

The effect of tolvaptan was examined by mouse cortical collecting duct (mpkCCD) cells, H9C2 cells, and mice kidneys that endogenously express V2R.

Results

Tolvaptan led to Nrf2 nuclear translocation and induced mRNA and protein expression of heme oxygenase 1 (HO-1) in mpkCCD cells and H9C2 cells. Phosphorylation of unfolded protein kinase RNA-like endoplasmic reticulum(ER) kinase (PERK) by tolvaptan played an important role in activation of Nrf2/HO-1 pathway. Moreover, tolvaptan successfully activated Nrf2/HO-1 pathway in the outer medulla of mice kidneys.

Conclusion

This is the first report describing that tolvaptan activates Nrf2/HO-1 pathway through PERK phosphorylation. Tolvaptan may be a potential therapeutic target of CKD.

Funding

• Government Support - Non-U.S.