Abstract
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.
Highlights
Tolvaptan is a highly selective and orally effective vasopressin type 2 receptor (V2R) antagonist that inhibits vasopressin-mediated water reabsorption in the kidney and promotes free-water diuresis in patients with heart failure and with syndrome of inappropriate secretion of antidiuretic hormone (SIADH)[1,2]
We further confirmed that a protein kinase RNA-like endoplasmic reticulum kinase (PERK) inhibitor, GSK2606414, significantly attenuated the effect of tolvaptan on heme oxygenase-1 (HO-1) protein expression (Fig. 2d). These results indicated that PERK was an important mediator of tolvaptan-induced Nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 activation
We examined whether tolvaptan and bardoxolone methyl (BARD) additively or synergistically activate the Nrf2/HO-1 antioxidant pathway and found that BARD of concentration >25 nM activated the Nrf2/HO-1 antioxidant pathway in mpkCCD cells (Fig. 5a,b)
Summary
Tolvaptan is a highly selective and orally effective vasopressin type 2 receptor (V2R) antagonist that inhibits vasopressin-mediated water reabsorption in the kidney and promotes free-water diuresis in patients with heart failure and with syndrome of inappropriate secretion of antidiuretic hormone (SIADH)[1,2]. Tolvaptan is effective in suppressing renal cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD)[3]. These beneficial effects of tolvaptan are primarily caused by the inhibition of intracellular cyclic adenosine monophosphate (cAMP) productions[4,5]. Tolvaptan has been shown to reduce proteinuria and improve renal function in rodent models of CKD. Nrf[2] nuclear translocation is impaired, resulting in unresponsiveness of antioxidant enzymes to oxidative stress[13,14]. An Nrf[2] activator, bardoxolone methyl (BARD), has been demonstrated to ameliorate kidney functions in patients with CKD in several clinical trials (TSUBAKI; NCT02316821)[16,17]. We assumed that tolvaptan and BARD or synergistically activate the Nrf2/HO-1 antioxidant pathway
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