Previously, Our study has showed that
farrerol can activate Nrf2 and ameliorate
cisplatin-induced
acute kidney injury (AKI). Mitophagy reportedly can prevent
diabetic nephropathy,
cisplatin-induced AKI and other related nephropathy. In this study, we evaluated the correlation between mitophagy and the protective effect of the Nrf2 activator
farrerol on
cisplatin-induced CKD by using C57BL/6 wild-type and Nrf2 knockout mice. We confirmed that Nrf2 and PINK1/Parkin-mediated mitophagy was significantly increased on the 3rd day of
cisplatin stimulation but was reduced on the 38th day of
cisplatin stimulation. Similar to previous results,
farrerol activated Nrf2 on the 38th day of
cisplatin administration, subsequently stimulating the Nrf2-targeted
antioxidant enzymes HO-1 and NQO1. In addition,
farrerol triggered PINK1/Parkin-mediated mitophagy by recruiting the receptor
proteins LC3 and p62/SQSTM1, thereby eliminating damaged mitochondria. Furthermore, genetic deletion of Nrf2 reduced PINK1/Parkin-mediated mitophagy activation and led to increased renal tubular
necrosis and renal
fibrosis. We also found that
farrerol alleviated
inflammation and renal
fibrosis by inhibiting p-NF-κB/NLRP3 and TGF-β/Smad signaling. These data indicated that
farrerol effectively inhibited
cisplatin-induced
inflammation and renal
fibrosis by activating Nrf2 and PINK1/Parkin-mediated mitophagy, which provides a potential novel therapeutic target for CKD.