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).