Figure 6
From: Tolvaptan activates the Nrf2/HO-1 antioxidant pathway through PERK phosphorylation
The schematic summary of the regulation of the Nrf2/HO-1 antioxidant pathway by tolvaptan. Tolvaptan phosphorylated PERK independently of cAMP signaling, following which PERK directly phosphorylates Nrf2, leading to the dissociation of Nrf2 from Keap110,25. Once released from Keap1, Nrf2 is not degraded by proteasome and translocates from the cytosol to nucleus. Tolvaptan increases the transcription of an antioxidant enzyme HO-1 in mpkCCD cells and the outer medulla of mouse kidneys. A PERK inhibitor, GSK2606414, counteracted the effect of tolvaptan on HO-1 expression. Although the precise mechanisms remain unclear, tolvaptan may bind to membrane- and ER-localized V2R and modulate PERK phosphorylation. Tolvaptan activated Nrf2 via a different mechanism to that of BARD. As a consequence, the combination therapy of tolvaptan and BARD could synergistically activate the Nrf2/HO-1 antioxidant pathway.
