Farrerol Ameliorated Cisplatin-Induced Chronic Kidney Disease Through Mitophagy Induction via Nrf2/PINK1 Pathway

Abstract

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.

Protective Effects of Liquiritigenin against Cisplatin-Induced Nephrotoxicity via NRF2/SIRT3-Mediated Improvement of Mitochondrial Function

“…A recent study found that NRF2-knockout mice are more sensitive to CP and more likely to suffer severe kidney damage than other mice [26]. Furthermore, based on the close association of oxidative stress and mitochondrial dysfunction, this study hypothesized that the protective effect of liquiritigenin depends on the classic antioxidant signaling-NRF2 pathway.…”

Metformin Promotes Differentiation and Attenuates H2O2-Induced Oxidative Damage of Osteoblasts via the PI3K/AKT/Nrf2/HO-1 Pathway

“…Nrf2 participates in the expression and maturation of various anti-oxidative proteins to maintain the homeostasis of oxidation and reduction ( Ying et al, 2018 ). HO-1 is an essential anti-oxidative factor modulated by Nrf2 ( Ma et al, 2021 ). HO-1 decomposes heme to produce carbon monoxide (CO) that promotes the expression of glutamate-cysteine ligase for GSH transformation ( Consoli et al, 2021 ).…”

Sulforaphane Acts Through NFE2L2 to Prevent Hypoxia-Induced Apoptosis in Porcine Granulosa Cells via Activating Antioxidant Defenses and Mitophagy

“…NFE2L2 is a momentous involvement in supporting the integrity of mitochondria from structural and functional aspect . It was reported that NFE2L2-prompted transcriptional-level regulation of PINK1 rebounds mitophagy and aberrant mitochondrial activity in kidney diseases. , Therefore, SFN may activate mitophagy through the NFE2L2 pathway to obliterate mitochondria and reduce the release of mitochondrial apoptotic factors, thereby inhibiting apoptosis. On the other hand, SFN may mitigate mitochondria oxidative damage through the NFE2L2 pathway, reducing mitochondrial ROS levels, thereby reducing hypoxia-induced oxidative damage to GCs.…”