Oxidative stress is a key component of renal ischemia/reperfusion (I/R) injury. Fucoxanthin (Fx), a marine carotenoid with enhanced antioxidant capacity, acts as a ROS inhibitor in diseases such as ischemic stroke and acute lung injury. We hypothesized that fucoxanthin could attenuate renal I/R-induced oxidative damage. C57BL/6 mice ( n = 30 ) were randomly assigned to sham, IR, IR + DMSO , and IR + Fx (25, 50, and 100 mg/kg) groups. The renal I/R injury was induced by clamping the left kidney nephron tip in mice. Fucoxanthin was injected intraperitoneally 24 hours before surgery. Compared with the IR group, pretreatment with fucoxanthin significantly improved renal dysfunction and tissue structural damage and inhibited ROS levels and apoptosis. Consistent results were observed in HK-2 cells. Besides, we found that renal I/R resulted in decreased expression of Sirt1, Nrf2, and HO-1, while fucoxanthin upregulated the expression of Sirt1, Nrf2, and HO-1. The protective effects of fucoxanthin were significantly reversed by EX527 (a selective inhibitor of Sirt1) or si-Sirt1. In conclusion, our study investigated the protective effect of fucoxanthin against renal I/R injury, and the underlying mechanism may be related to the activation of the Sirt1/Nrf2/HO-1 signaling pathway by fucoxanthin to attenuate oxidative stress-induced apoptosis.

Endoplasmic reticulum (ER) stress, pyroptosis, and apoptosis are critical molecular events in the occurrence and progress of renal ischemia reperfusion (I/R) injury. Naringenin (4 ′ ,5,7-trihydroxyflavanone) is one of the most widely consumed flavonoids with powerful antioxidant and anti-inflammatory activities. However, whether naringenin is able to relieve renal I/R injury and corresponding mechanisms have not been fully clarified. This study was aimed at exploring its role and relevant mechanisms in renal I/R injury. The C57Bl/6 mice were randomly assigned to receive administration with naringenin (50 mg/kg/d) or sterile saline (1.0 mL/d) for 3 d by gavage and suffered from renal I/R surgery. One specific ER stress inhibitor, 4-phenylbutyric acid (4-PBA, 100 mg/kg/d), was intraperitoneally administered to validate the regulation of ER stress on pyroptosis and apoptosis. Cultured HK-2 cells went through the process of hypoxia/reoxygenation (H/R) to perform cellular experiments with the incubation of naringenin (200 μM), 4-PBA (5 mM), or brusatol (400 nM). The animal results verified that naringenin obviously relieved renal I/R injury, while it refined renal function and attenuated tissue structural damage. Furthermore, naringenin treatment inhibited I/R-induced ER stress as well as pyroptosis and apoptosis as indicated by decreased levels of specific biomarkers such as GRP78, CHOP, caspase-12, NLRP3, ASC, caspase-11, caspase-4, caspase-1, IL-1β, GSDMD-N, BAX, and cleaved caspase-3 in animals and HK-2 cells. Besides, the upregulated expression of Nrf2 and HO-1 proteins after naringenin treatment suggested that naringenin activated the Nrf2/HO-1 signaling pathway, which was again authenticated by the usage of brusatol (Bru), one unique inhibitor of the Nrf2 pathway. Importantly, the application of 4-PBA showed that renal I/R-generated pyroptosis and apoptosis were able to be regulated by ER stress in vivo and in vitro. In conclusion, naringenin suppressed ER stress by activating Nrf2/HO-1 signaling pathway and further alleviated pyroptosis and apoptosis to protect renal against I/R injury.

Energy stress is an unfavorable condition that tumor cells are often exposed to. Ferroptosis is considered an emerging target for tumor therapy. However, the role of ferroptosis in energy stress in renal cancer is currently unknown. In this study, we found that glucose deprivation significantly enhanced GPX4-dependent ferroptosis through AMPK activation. Further, AMPK activation suppressed GPX4 expression at the transcriptional level through the upregulation of P53 expression. Additionally, the inactivation of JAK2/STAT3 transcriptionally promoted P53 expression, thereby promoting AMPK-mediated GPX4-dependent ferroptosis. In conclusion, energy stress promotes AMPK-mediated GPX4-dependent erastin-induced ferroptosis in renal cancer through the JAK2/STAT3/P53 signaling axis.

Mitochondrial dysfunction is a critical factor contributing to oxidative stress and apoptosis in ischemia-reperfusion (I/R) diseases. Mitoquinone (MitoQ) is a mitochondria-targeted antioxidant whose potent anti-I/R injury capacity has been demonstrated in organs such as the heart and the intestine. In the present study, we explored the role of MitoQ in maintaining mitochondrial homeostasis and attenuating oxidative damage in renal I/R injury. We discovered that the decreased renal function and pathological damage caused by renal I/R injury were significantly ameliorated by MitoQ. MitoQ markedly reversed mitochondrial damage after I/R injury and inhibited renal reactive oxygen species production. In vitro, hypoxia/reoxygenation resulted in increased mitochondrial fission and decreased mitochondrial fusion in human renal tubular epithelial cells (HK-2), which were partially prevented by MitoQ. MitoQ treatment inhibited oxidative stress and reduced apoptosis in HK-2 cells by restoring mitochondrial membrane potential, promoting ATP production, and facilitating mitochondrial fusion. Deeply, renal I/R injury led to a decreased expression of sirtuin-3 (Sirt3), which was recovered by MitoQ. Moreover, the inhibition of Sirt3 partially eliminated the protective effect of MitoQ on mitochondria and increased oxidative damage. Overall, our data demonstrate a mitochondrial protective effect of MitoQ, which raises the possibility of MitoQ as a novel therapy for renal I/R.