Tolvaptan activates the Nrf2/HO-1 antioxidant pathway through PERK phosphorylation

Sci Rep. 2019 Jun 25;9(1):9245. doi: 10.1038/s41598-019-45539-8.


Tolvaptan, a vasopressin type 2 receptor antagonist initially developed to increase free-water diuresis, has been approved for the treatment of autosomal dominant polycystic kidney disease in multiple countries. Furthermore, tolvaptan has been shown to improve the renal functions 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. To determine the role of tolvaptan, we used a renal cortical collecting duct (mpkCCD) cell line and mouse kidneys. Tolvaptan activated Nrf2 and increased mRNA and protein expression of antioxidant enzyme heme oxygenase-1 (HO-1) in mpkCCD cells and the outer medulla of mouse kidneys. In contrast to BARD, tolvaptan regulated the antioxidant systems via a unique mechanism. Tolvaptan activated the Nrf2/HO-1 antioxidant pathway through phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK). As a result, tolvaptan and BARD could successfully generate synergistic activating effects on Nrf2/HO-1 antioxidant pathway, suggesting that this combination therapy can contribute to the treatment of CKD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism*
  • Endoplasmic Reticulum
  • Gene Expression Regulation
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Kidney Cortex / cytology
  • Kidney Cortex / drug effects
  • Kidney Cortex / metabolism*
  • Kidney Tubules, Collecting / cytology
  • Kidney Tubules, Collecting / drug effects
  • Kidney Tubules, Collecting / metabolism*
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress
  • Phosphorylation
  • Tolvaptan / pharmacology*
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism*


  • Antioxidants
  • Membrane Proteins
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Tolvaptan
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • EIF2AK3 protein, human
  • eIF-2 Kinase