Tolvaptan activates the Nrf2/HO-1 antioxidant pathway through PERK phosphorylation
2019
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 diseasein multiple countries. Furthermore,
tolvaptanhas 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
tolvaptanand 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.
Tolvaptanactivated 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,
tolvaptanregulated the antioxidant systems via a unique mechanism.
Tolvaptanactivated the Nrf2/HO-1 antioxidant pathway through phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK). As a result,
tolvaptanand 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.
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