3.1 Nrf2 KO aggravates cisplatin-induced kidney injury and iron
accumulation
Nrf2 and its regulatory genes are reported to be involved in preventing
the progression of ferroptosis, but their regulatory effect on
ferroptosis in CI-AKI has not been clarified. As shown in Fig. 1A-D,
Nrf2 KO aggravated cisplatin-induced kidney injury, which was
characterized by elevated levels of Bun and SCr as well as more
morphological damage, including necrosis, brush edge loss, cast
formation, tubular degeneration, and vacuolization. Nrf2 targets play
key roles in mediating iron metabolism, which is important for the
initiation of ferroptosis. Therefore, we investigated the changes in the
iron levels in Nrf2 KO mice and found that cisplatin injection increased
the iron levels in Nrf2 KO mice compared with wild-type mice (Fig. 1E).
In addition, lower expression levels of the antioxidant response genes
Nrf2, HO-1 and NQO1 were observed in Nrf2 KO mice compared with
wild-type mice. Interestingly, loss of Nrf2 not only increased TFR
expression but also led to a compensatory increase in FTH-1 and FTL
(Fig. 1F-H).